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JCANCE_NP psychological_JJ Issues_NNS in_IN Genetic_NP Testing_NP for_IN Breast_NP Cancer_NP Susceptibility_NP 2_CD it_PP3 is_BEZ estimated_VBN that_CS approximately_RB 180000_CD American_JNP women_NNS developed_VBN breast_NN cancer_NN in_IN 1993_CD , and_CC 46000_CD of_IN these_DTS women_NNS died_VBD of_IN this_DT disease_NN Recent_NP work_NN in_IN molecular_JJ genetics_NNS has_HVZ led_VBN to_IN the_ATI identification_NN of_IN genes_NNS that_WPR confer_VB susceptibility_NN to_TO breast_NN cancer_NN , including_IN a_AT major_JJ breast-ovarian_NN cancer_NN susceptibility_NN gene_NN on_IN chromosome_NN 17_CD as_QL many_AP as_CS one_CD1 in_IN 300_CD women_NNS may_MD carry_VB germline_VB mutations_NNS on_IN one_CD1 or_CC more_QL breast_NN cancer_NN susceptibility_NN genes_NNS 3_CD these_DTS advances_NNS bring_VB promise_NN of_IN clinical_JJ genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN in_IN a_JJ few_AP settings_NNS , this_DT information_NN already_RB is_BEZ being_BEG applied_VBN to_TO identify_VB gene_NN carriers_NNS and_CC noncarriers_NNS within_IN families_NNS with_IN hereditary_JJ breast_NN cancer_NN as_CS yet_RB , however_RB , there_EX are_BER no_ATI guidelines_NNS for_IN communicating_JJ genetic_JJ information_NN about_IN breast_NN cancer_NN susceptibility_NN or_CC for_IN providing_VBG recommendations_NNS and_CC follow- up_NN care_NN for_IN identified_JJ gene_NN carriers_NNS this_DT is_BEZ a_AT serious_JJ concern_NN , as_IN previous_JJ research_NN suggests_VBZ that_CS cancer_NN risk_NN notification_NN can_MD have_HV serious_JJ negative_JJ psychological_JJ consequences_NNS moreover_RB , in_IN the_ATI absence_NN of_IN proper_JJ counseling_NN and_CC follow-up_NN , psychological_JJ distress_NN has_HVZ the_ATI potential_JJ to_TO impair_VB adherence_NN to_IN current_JJ recommendations_NNS for_IN surveillance_NN and_CC possible_JJ prevention_NN 4_CD in_IN this_DT article_NN , we_PP1AS discuss_VB psychological_JJ and_CC behavioral_JJ issues_NNS relevant_JJ to_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN recent_JJ findings_NNS in_IN the_ATI field_NN of_IN breast_NN cancer_NN genetics_NNS are_BER reviewed_VBN briefly_RB , and_CC a_AT conceptual_JJ model_NN for_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN is_BEZ presented.=20_CD 5_CD three_CD key_NN psychological_JJ and_CC behavioral_JJ issues_NNS are_BER addressed_VBN : (_( 1_CD1 )_) ensuring_VBG informed_JJ consent_NN for_IN testing_NN , (_( 2_CD )_) minimizing_VBG adverse_JJ psychological_JJ consequences_NNS , and_CC (_( 3_CD )_) promoting_VBG breast_NN cancer_NN prevention_NN and_CC screening_NN practices.=20_CD 6_CD these_DTS issues_NNS and_CC accompanying_JJ recommendations_NNS are_BER based_VBN on_IN our_PP$ comprehensive_JJ review_NN of_IN the_ATI literature_NN on_IN the_ATI psychological_JJ impact_NN of_IN genetic_JJ testing_NN for_IN traditional_JJ mendelian_NN diseases_NNS , as_QL well_RB as_CS our_PP$ previous_JJ research_NN on_IN the_ATI psychological_JJ and_CC behavioral_JJ impact_NN of_IN cancer_NN risk_NN notification_NN and_CC promoting_VBG adherence_NN to_TO cancer_NN control_NN regimens_NNS Recommendations_NNS for_IN research_NN to_TO evaluate_VB pilot_NN programs_NNS for_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN are_BER presented_VBN 7_CD GENETIC_NPT TESTING_NPT FOR_NPT BREAST_NP CANCER_NP 8_CD family_NN and_CC Genetic_NP Studies_NP 9_CD a_AT positive_JJ family_NN history_NN is_BEZ the_ATI most_QL important_JJ determinant_NN of_IN a_AT woman's_NN$ risk_NN of_IN developing_VBG breast_NN cancer_NN having_HVG one_CD1 first-degree_JJB relative_JJ (_( FDR_NP )_) with_IN breast_NN cancer_NN imparts_VBZ about_IN a_AT twofold_JJ to_IN threefold_JJ increased_JJ risk_NN risk_NN also_RB increases_VBZ as_IN the_ATI age_NN at_IN onset_NN of_IN breast_NN cancer_NN in_IN the_ATI FDR_NP decreases_VBZ the_ATI earlier_RBR the_ATI age_NN at_IN onset_NN and_CC the_ATI greater_JJR the_ATI number_NN of_IN FDRs_NP , the_ATI higher_JJR the_ATI probability_NN that_CS a_AT positive_JJ family_NN history_NN is_BEZ the_ATI result_NN of_IN an_AT inherited_VBN genetic_JJ predisposition_NN , rather_RB than_IN somatic_JJ genetic_JJ changes_NNS occurring_VBG in_IN a_AT woman's_NN$ breast_NN cells_NNS during_IN her_PP$ lifetime_NN 10_CD hereditary_JJ breast_NN cancer_NN (_( HBC_NP )_) syndromes_NNS exhibit_VB a_AT pattern_NN of_IN disease_NN occurrence_NN consistent_JJ with_IN autosomal_JJ dominant_JJ inheritance_NN of_IN a_AT single_JJ disease_NN gene_NN it_PP3 is_BEZ estimated_VBN that_CS HBC_NP accounts_NNS for_IN about_IN 5%_NN to_IN 10%_CD of_IN all_ABN breast_NN cancer_NN and_CC as_IN many_AP as_IN 25%_NN of_IN early-onset_NN cases_NNS the_ATI clinical_JJ indicators_NNS of_IN HBC_NP include_VB multiple_JJ cases_NNS with_IN early_JJ age_NN at_IN onset_NN (_( often_RB before_IN age_NN 45_CD years_NNS )_) , vertical_JJ transmission_NN through_IN the_ATI maternal_JJ and_or_CC paternal_JJ lineages_NNS in_IN the_ATI pedigree_NN , specific_JJ tumor_NN associations_NNS (_( most_QL often_RB ovarian_JJ and_or_CC colon_NN malignant_JJ neoplasms_NNS )_) , and_CC an_AT excess_NN of_IN bilaterality_NN extended_JJ family_NN pedigrees_NNS have_HV served_VBN as_IN the_ATI primary_JJ tool_NN for_IN identifying_VBG HBC_NP families_NNS and_CC counseling_VBG unaffected_JJ women_NNS who_WPR may_MD have_HV inherited_VBN a_AT breast_NN cancer_NN susceptibility_NN gene_NN 11_CD recent_JJ molecular_JJ studies_NNS have_HV established_VBN a_AT foundation_NN for_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN

initial_JJ linkage_NN studies_NNS identified_VBN a_AT 50-cM_NP region_NN on_IN the_ATI long_JJ arm_NN of_IN chromosome_NN 17_CD that_CS includes_VBZ a_AT major_JJ breast_NN cancer_NN susceptibility_NN gene_NN more_QL recently_RB , this_DT gene_NN , labeled_VBN BRCA1_CD , has_HVZ been_BEN localized_VBN to_IN an_AT 8-cM_NN region_NN on_IN chromosome_NN 17q12_CD however_RB , since_IN BRCA1_CD has_HVZ yet_RB to_TO be_BE cloned_VBN , determination_NN of_IN breast_NN cancer_NN susceptibility_NN on_IN the_ATI basis_NN of_IN this_DT locus_NN requires_VBZ analysis_NN of_IN blood_NN and_or_CC tissue_NN samples_NNS from_IN multiple_JJ family_NN members_NNS 12_CD this_DT linkage_NN analysis_NN approach_NN takes_VBZ advantage_NN of_IN the_ATI fact_NN that_CS alleles_NNS close_RB together_RB on_IN the_ATI same_AP chromosome_NN tend_VB to_TO be_BE transmitted_VBN together_RB the_ATI probability_NN that_CS breast_NN cancer_NN occurrence_NN in_IN a_AT given_VBN family_NN is_BEZ linked_VBN to_IN this_DT locus_NN has_HVZ been_BEN shown_VBN to_TO be_BE higher_JJR for_IN families_NNS that_CS manifest_JJ early-onset_NN breast_NN cancer_NN (_( mean_VB age_NN at_IN diagnosis_NN , {_( 45_CD years_NNS )_) and_CC those_DTS with_IN multiple_JJ cases_NNS of_IN breast_NN and_CC ovarian_NN cancer_NN Data_NP from_IN both_ABX population-based_JJ and_CC family_NN studies_NNS suggest_VB that_CS the_ATI BRCA1_CD gene_NN is_BEZ highly_RB penetrant_JJ , producing_VBG a_AT risk_NN of_IN breast_NN or_CC ovarian_NN cancer_NN that_CS approaches_NNS 80%_NP to_IN 90%_NP by_IN the_ATI age_NN of_IN 70_CD years_NNS the_ATI probability_NN of_IN misclassification_NN when_WRB linkage_NN analysis_NN is_BEZ used_VBN in_IN families_NNS with_IN hereditary_JJ breast-ovarian_NN cancer_NN (_( HBOC_NP )_) has_HVZ been_BEN estimated_VBN to_TO be_BE less_AP than_IN 2%_JJ 13_CD genetic_JJ Testing_NP and_CC Counseling_NP Model_NP 14_CD the_ATI concept_NN and_CC practice_NN of_IN genetic_JJ testing_NN is_BEZ being_BEG expanded_VBN to_TO include_VB genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN while_CS the_ATI approach_NN to_TO testing_NN and_CC counseling_VBG is_BEZ based_VBN on_IN the_ATI traditional_JJ medical_JJ genetics_NNS model_NN , several_AP key_NN differences_NNS exist_VB the_ATI most_AP important_JJ of_IN

these_DTS relates_VBZ to_IN the_ATI underlying_JJ cause_NN and_CC expression_NN of_IN the_ATI diseases_NNS for_IN which_WDTR testing_NN is_BEZ provided_VBN

traditionally_RB , genetic_JJ testing_NN has_HVZ been_BEN applied_VBN to_IN well- defined_JJ , monogenic_JJ syndromes_NNS that_CS are_BER inherited_VBN in_IN a_AT strict_JJ mendelian_NN fashion_NN , such_IN as_IN Huntington's_NP$ disease_NN (_( HD_NP )_) , cystic_JJ fibrosis_NN , and_CC Duchenne's_NP$ muscular_JJ dystrophy.=20_CD 15_CD for_IN these_DTS diseases_NNS , inheritance_NN of_IN the_ATI disease_NN gene_NN leads_VBZ to_TO expression_NN of_IN the_ATI disease_NN phenotype_NN by_IN contrast_NN , studies_VBZ of_IN inherited_VBN breast_NN cancer_NN susceptibility_NN provide_VB evidence_NN of_IN incomplete_JJ penetrance_NN , suggesting_VBG that_CS the_ATI inheritance_NN of_IN an_AT altered_JJ breast_NN cancer_NN gene_NN is_BEZ not_XNOT sufficient_JJ to_TO produce_VB the_ATI disease_NN additional_JJ genetic_JJ events_NNS , acting_VBG in_IN conjunction_NN with_IN environmental_JJ cofactors_NNS , may_MD be_BE necessary_JJ in_IN fact_NN , much_AP of_IN breast_NN cancer_NN is_BEZ not_XNOT caused_VBN by_IN inherited_JJ susceptibility_NN at_IN all_ABN , but_CC results_NNS from_IN somatic_JJ events_NNS that_WPR produce_VB genetic_JJ changes_NNS in_IN a_AT woman's_NN$ breast_NN cells_NNS during_IN her_PP$ lifetime_NN moreover_RB , the_ATI majority_NN of_IN women_NNS who_WPR develop_VB breast_NN cancer_NN have_HV no_ATI known_VBN major_JJ risk_NN factors_NNS 16_CD the_ATI complexity_NN of_IN breast_NN cancer_NN development_NN creates_VBZ new_JJ challenges_VBZ for_IN the_ATI practice_NN of_IN genetic_JJ testing_NN for_IN example_NN , identification_NN of_IN HBC_NP families_NNS that_DT may_MD be_BE appropriate_JJ for_IN genetic_JJ testing_NN is_BEZ difficult_JJ one_CD1 reason_NN is_BEZ that_CS the_ATI occurrence_NN of_IN multiple_JJ breast_NN cancer_NN cases_NNS in_IN a_AT family_NN may_MD be_BE attributable_JJ to_IN common_JJ environmental_JJ exposures_NNS , rather_RB than_CS to_IN inherited_JJ susceptibility_NN even_RB when_WRB breast_NN cancer_NN in_IN a_AT given_VBN family_NN is_BEZ the_ATI result_NN of_IN a_AT major_JJ gene_NN effect_NN , it_PP3 may_MD be_BE difficult_JJ to_TO identify_VB the_ATI gene_JJ responsible_JJ for_IN example_NN , as_QL many_AP as_CS 50%_NP of_IN HBC_NP families_NNS tested_VBN for_IN BRCA1_CD have_HV been_BEN found_VBN to_TO be_BE _** unlinked_JJ _** at_IN this_DT locus_NN one_CD1 clinical_JJ implication_NN is_BEZ that_CS a_AT substantial_JJ proportion_NN of_IN families_NNS who_WPR provide_VB genetic_JJ material_NN will_MD not_XNOT receive_VB any_DTI genetic_JJ information_NN Moreover_NP , even_RB when_WRB a_AT carrier_NN of_IN a_AT specific_JJ breast_NN cancer_NN gene_NN can_MD be_BE identified_VBN with_IN a_AT high_JJ level_NN of_IN certainty_NN , her_PP$ risk_NN of_IN developing_VBG the_ATI disease_NN remains_VBZ less_AP than_IN 100%_CD (_( ie_NN , incomplete_JJ penetrance_NN )_) 17_CD the_ATI incomplete_JJ penetrance_NN of_IN the_ATI major_JJ breast_NN cancer-related_JJ genes_NNS affords_VBZ a_AT major_JJ opportunity-the_JJ potential_JJ for_IN prevention_NN or_CC early_JJ detection_NN in_RP as_IN yet_RB unaffected_JJ gene_NN carriers_NNS whether_CS breast_NN cancer_NN morbidity_NN and_CC mortality_NN can_MD be_BE reduced_VBN through_IN the_ATI adoption_NN of_IN prevention_NN and_CC surveillance_NN practices_NNS remains_VBZ an_AT open_JJ question_NN if_CS current_JJ prevention_NN trials_NNS provide_VB conclusive_JJ evidence_NN of_IN efficacy_NN , a_AT more_QL prescriptive_JJ approach_NN to_IN counseling_VBG high- risk_NN women_NNS would_MD be_BE suggested_VBN this_DT approach_NN emphasizes_VBZ personal_JJ risk_NN , as_QL well_RB as_CS options_NNS and_CC advice_NN for_IN possible_JJ breast_NN cancer_NN prevention_NN and_CC early_JJ detection_NN This_NN is_BEZ in_IN sharp_JJ contrast_NN to_IN genetic_JJ counseling_NN for_IN HD_NP , which_WDTR emphasizes_VBZ existential_JJ issues_NNS surrounding_JJ inevitable_JJ premature_JJ death_NN and_CC employs_VBZ a_AT nondirective_JJ counseling_NN approach_NN to_TO protect_VB a_AT woman's_NN$ privacy_NN in_IN making_VBG reproductive_JJ decisions_NNS as_CS will_MD be_BE illustrated_VBN below_IN , these_DTS differences_NNS in_IN the_ATI two_CD genetic_JJ counseling_NN approaches_NNS have_HV important_JJ implications_NNS for_IN the_ATI clinical_JJ and_CC psychological_JJ treatment_NN of_IN women_NNS who_WPR present_JJ for_IN genetic_JJ testing_NN and_CC counseling_VBG for_IN breast_NN cancer_NN susceptibility_NN 18_CD PSYCHOLOGICAL_NPT AND_NPT BEHAVIORAL_NP ISSUES_NP 19_CD ensuring_VBG Informed_NP Consent_NP for_IN Genetic_NP Testing_NP 20_CD to_TO make_VB an_AT informed_JJ decision_NN about_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN , potential_JJ screenees_NNS must_MD understand_VB the_ATI potential_JJ benefits_NNS as_QL well_RB as_IN the_ATI limitations_NNS and_CC potential_JJ risks_NNS three_CD key_NN limitations_NNS of_IN genetic_JJ testing_NN must_MD be_BE addressed_VBN in_IN this_DT regard_NN first_OD , potential_JJ participants_NNS must_MD be_BE informed_VBN that_CS genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN may_MD not_XNOT be_BE informative_JJ second_OD , potential_JJ screenees_NNS must_MD also_RB be_BE made_VBN aware_JJ that_CS genetic_JJ information_NN , when_WRB available_JJ , is_BEZ probabilistic_JJ in_IN nature_NN more_QL specifically_RB , not_XNOT all_ABN gene_NN carriers_NNS develop_VB cancer_NN (_( incomplete_JJ penetrance_NN )_) , while_CS not_XNOT all_ABN noncarriers_NNS remain_VB protected_VBN from_IN cancer_NN (_( causative_JJ heterogeneity_NN )_) Third_NP , potential_JJ screenees_NNS must_MD be_BE informed_VBN of_IN the_ATI limitations_NNS of_IN current_JJ options_NNS for_IN cancer_NN prevention_NN and_CC early_JJ detection_NN as_CS yet_RB , there_EX are_BER no_ATI proven_JJ methods_NNS of_IN preventing_VBG the_ATI disease_NN while_CS gene_NN mutation_NN carriers_NNS may_MD benefit_VB from_IN increased_JJ surveillance_NN with_IN mammography_NN , clinical_JJ breast_NN examination_NN , and_CC breast_NN self-examination_NN , the_ATI efficacy_NN of_IN early_JJ detection_NN methods_NNS for_IN ovarian_NN cancer_NN is_BEZ suboptimal_JJ 21_CD several_AP potential_JJ risks_NNS of_IN genetic_JJ testing_NN have_HV been_BEN identified_VBN in_IN previous_JJ research_NN and_CC must_MD be_BE included_VBN as_IN part_NN of_IN the_ATI informed_JJ consent_NN process_NN for_IN example_NN , the_ATI potential_JJ negative_JJ psychological_JJ consequences_NNS of_IN testing_NN , for_IN both_ABX the_ATI screenee_NN and_CC family_NN members_NNS , must_MD be_BE addressed_VBN In_NP addition_NN , persons_NNS identified_VBN as_IN gene_NN carriers_NNS may_MD be_BE vulnerable_JJ to_TO loss_NN of_IN insurance_NN or_CC employment_NN as_IN a_AT result_NN of_IN their_PP$ altered_JJ risk_NN status_NN social_JJ stigmatization_NN also_RB has_HVZ been_BEN reported_VBN by_IN some_DTI carriers_NNS of_IN disease_NN genes_NNS , and_CC therefore_RB should_MD be_BE mentioned_VBN as_IN a_AT possible_JJ consequence_NN of_IN testing_NN 22_CD a_AT major_JJ challenge_NN to_IN genetic_JJ counseling_NN will_MD be_BE to_TO ensure_VB that_CS screenees_NNS not_XNOT only_RB receive_VB information_NN about_IN the_ATI risks_NNS and_CC benefits_NNS of_IN testing_NN but_CC also_RB comprehend_JJ this_DT information_NN research_NN on_IN informed_VBN consent_NN for_IN breast_NN cancer_NN treatment_NN has_HVZ shown_VBN that_CS a_AT substantial_JJ proportion_NN of_IN patients_NNS fail_VB to_TO comprehend_VB key_NN details_NNS of_IN the_ATI benefits_NNS and_CC risks_NNS of_IN cancer_NN treatment_NN , despite_IN disclosure_NN by_IN their_PP$ medical_JJ oncologists_NNS even_RB when_WRB patients_NNS receive_VB complete_JJ information_NN , their_PP$ ability_NN to_TO process_VB specific_JJ details_NNS may_MD be_BE impaired_VBN by_IN their_PP$ high_JJ levels_NNS of_IN anxiety_NN thus_RB , it_PP3 is_BEZ prudent_JJ to_TO provide_VB genetic_JJ information_NN at_IN a_AT subsequent_JJ visit_NN , rather_RB than_IN immediately_RB after_IN receipt_NN of_IN consent_NN 23_CD it_PP3 is_BEZ possible_JJ that_CS a_AT discussion_NN of_IN the_ATI limitations_NNS and_CC potential_JJ risks_NNS of_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN will_MD dissuade_VB some_DTI individuals_NNS from_IN participation_NN for_IN example_NN , the_ATI desire_NN to_TO reduce_VB uncertainty_NN and_CC to_TO protect_VB one's_CD1$ future_NN health_NN have_HV been_BEN cited_VBN as_CS primary_JJ reasons_NNS for_IN undergoing_VBG genetic_JJ testing_NN for_IN traditional_JJ mendelian_NN disorders_NNS as_CS such_ABL , potential_JJ screenees_NNS are_BER likely_JJ to_TO be_BE discouraged_VBN when_WRB they_PP3AS learn_VB of_IN the_ATI limitations_NNS of_IN genetic_JJ testing_NN and_CC the_ATI lack_NN of_IN conclusive_JJ evidence_NN concerning_IN available_JJ options_NNS for_IN prevention_NN and_CC early_JJ detection_NN if_CS genetic_JJ testing_NN commences_VBZ without_IN previous_JJ awareness_NN of_IN these_DTS limitations_NNS , participants_NNS are_BER likely_JJ to_TO be_BE disappointed_JJ with_IN the_ATI results_NNS and_CC may_MD be_BE more_QL vulnerable_JJ to_IN the_ATI adverse_JJ psychological_JJ consequences_NNS of_IN testing_NN 24_CD despite_IN these_DTS caveats_NNS , preliminary_JJ data_NNS indicate_VB that_CS the_ATI majority_NN of_IN persons_NNS who_WPR express_VB initial_JJ interest_NN in_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN will_MD consent_VB to_IN complete_JJ the_ATI testing_NN process_NN Lynch_NP and_CC colleagues_NNS offered_VBD genetic_JJ information_NN to_IN the_ATI members_NNS of_IN a_AT large_JJ hereditary_JJ breast-ovarian_NN cancer_NN family_NN who_WPR had_HVD previously_RB provided_VBN genetic_JJ material_NN as_IN part_NN of_IN a_AT linkage_NN study_NN after_IN receipt_NN of_IN information_NN about_IN the_ATI benefits_NNS and_CC risks_NNS of_IN testing_NN , 70%_NP percent_NNU of_IN the_ATI women_NNS and_CC 15%_CD of_IN the_ATI men_NNS in_IN this_DT family_NN requested_VBD their_PP$ results_NNS However_NP , rates_NNS of_IN use_NN may_MD be_BE lower_JJR among_IN high- risk_NN persons_NNS in_IN the_ATI general_JJ population_NN who_WPR have_HV not_XNOT already_RB provided_VBN genetic_JJ material_NN as_IN genetic_JJ testing_NN for_IN cancer_NN is_BEZ integrated_VBN into_IN routine_JJ medical_JJ practice_NN , it_PP3 will_MD be_BE critical_JJ to_TO develop_VB and_CC evaluate_VB protocols_NNS for_IN educating_VBG individuals_NNS about_IN the_ATI benefits_NNS and_CC risks_NNS of_IN testing_NN and_CC , moreover_RB , to_TO ensure_VB that_CS testing_NN is_BEZ never_RB provided_VBN without_IN previous_JJ informed_JJ consent_NN 25_CD minimizing_VBG Adverse_NPT Psychological_NP Consequences_NP of_IN Genetic_NP Testing_NP 26_CD a_AT recent_JJ prospective_JJ study_NN of_IN the_ATI impact_NN of_IN predictive_JJ testing_NN for_IN HD_NP provides_VBZ some_DTI important_JJ insights_NNS into_IN the_ATI potential_JJ psychological_JJ sequelae_NN of_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN participants_NNS in_IN a_AT pilot_NN HD_NP program_NN were_BED administered_VBN a_AT battery_NN of_IN psychological_JJ measures_NNS for_IN depression_NN , general_JJ well-being_NN , and_CC psychiatric_JJ symptoms_NNS before_CS testing_NN and_CC at_IN multiple_JJ follow-up_NN points_NNS at_IN first_OD follow-up_NN (_( 7_CD to_IN 10_CD days_NNS after_IN genetic_JJ testing_NN )_) , there_EX were_BED significant_JJ differences_NNS on_IN all_ABN measures_NNS between_IN persons_NNS identified_VBN as_IN gene_NN carriers_NNS and_CC those_DTS identified_VBN as_IN noncarriers.=20_CD 27_CD these_DTS differences_NNS resulted_VBD from_IN both_ABX increased_JJ distress_NN from_IN baseline_NN in_IN carriers_NNS and_CC decreased_VBD distress_NN in_IN noncarriers_NNS however_RB , at_IN the_ATI 6-month_NN follow-up_NN , the_ATI carriers_NNS and_CC noncarriers_NNS were_BED distinguished_JJ only_RB by_IN their_PP$ scores_NNS on_IN the_ATI measure_NN of_IN general_JJ well-being_NN by_IN 12_CD months_NNS , all_ABN measures_NNS of_IN distress_NN declined_VBD significantly_RB for_IN both_ABX carriers_NNS and_CC noncarriers_NNS , and_CC these_DTS two_CD groups_NNS no_RB longer_RBR differed_VBD on_IN any_DTI of_IN the_ATI psychological_JJ dimensions_NNS examined_VBN an_AT interesting_JJ feature_NN of_IN this_DT study_NN was_BEDZ the_ATI inclusion_NN of_IN 40_CD participants_NNS who_WPR did_DOD not_XNOT receive_VB genetic_JJ information_NN , either_DTX because_CS they_PP3AS withdrew_VBD their_PP$ consent_NN or_CC because_CS testing_NN was_BEDZ not_XNOT informative_JJ psychologically_RB , these_DTS persons_NNS did_DOD not_XNOT fare_VB as_CS well_RB during_IN the_ATI study_NN period_NN although_CS these_DTS subjects_NNS did_DOD not_XNOT differ_VB from_IN screening_NN participants_NNS in_IN terms_NNS of_IN their_PP$ baseline_JJ psychological_JJ status_NN , at_IN 12-month_CD-CD follow-up_NN they_PP3AS manifested_VBD significantly_RB higher_JJR scores_NNS on_IN depression_NN and_CC lower_JJR scores_NNS on_IN general_JJ well-being_NN than_IN both_ABX carriers_NNS and_CC noncarriers_NNS while_CS these_DTS findings_NNS are_BER relevant_JJ to_IN genetic_JJ testing_NN for_IN BRCA1_CD , the_ATI generalizability_NN awaits_NNS empiric_JJ study_NN although_CS both_ABX HD_NP and_CC breast_NN cancer_NN are_BER late-onset_NN diseases_NNS , only_RB breast_NN cancer_NN offers_VBZ any_DTI hope_VB for_IN prevention_NN , early_JJ detection_NN , or_CC treatment_NN 28_CD preliminary_JJ data_NNS are_BER now_RN available_JJ on_IN the_ATI psychological_JJ responses_NNS of_IN members_NNS of_IN an_AT extended_VBN hereditary_JJ breast- ovarian_NN cancer_NN family_NN after_IN predictive_JJ testing_NN for_IN the_ATI BRCA1_CD gene_NN structured_JJ telephone_NN interviews_NNS , conducted_VBN 3_CD to_IN 6_CD weeks_NNS after_IN disclosure_NN of_IN genetic_JJ information_NN , indicated_VBN that_CS a_AT substantial_JJ proportion_NN of_IN women_NNS identified_VBN as_IN gene_NN carriers_NNS were_BED experiencing_VBG some_DTI level_NN of_IN psychological_JJ distress_NN ; specific_JJ responses_NNS included_VBN persistent_JJ worries_NNS , depression_NN , confusion_NN , and_CC sleep_NN disturbance_NN interestingly_RB , 50%_NP of_IN noncarriers_NNS reported_VBN that_CS they_PP3AS continued_VBD to_TO worry_VB about_IN their_PP$ risk_NN status_NN determination_NN of_IN the_ATI severity_NN and_CC clinical_JJ implications_NNS of_IN these_DTS reactions_NNS to_IN genetic_JJ information_NN awaits_NNS future_NN studies_NNS that_WPR employ_VB standardized_VBN psychological_JJ measures_NNS 29_CD the_ATI suggestion_NN of_IN negative_JJ short-term_JJB effects_NNS of_IN genetic_JJ testing_NN is_BEZ consistent_JJ with_IN previous_JJ studies_NNS of_IN the_ATI impact_NN of_IN breast_NN cancer_NN risk_NN factor_NN information_NN for_IN example_NN , significant_JJ adverse_JJ psychological_JJ reactions_NNS have_HV been_BEN documented_VBN among_IN women_NNS after_IN notification_NN of_IN abnormal_JJ mammogram_NN results_NNS other_AP studies_NNS have_HV indicated_VBN that_CS a_AT substantial_JJ proportion_NN of_IN women_NNS with_IN a_AT positive_JJ family_NN history_NN of_IN breast_NN cancer_NN manifest_JJ persistent_JJ psychological_JJ distress_NN .=20_CD 30_CD in_IN one_CD1 of_IN these_DTS studies_NNS , 27%_NN of_IN high-risk_NN women_NNS who_WPR self-referred_JJ to_TO a_AT breast_NN cancer_NN screening_NN program_NN exhibited_VBN serious_JJ symptoms_NNS that_CS warranted_VBD psychological_JJ counseling_NN a_AT recent_JJ population-based_JJ study_NN of_IN FDRs_NP of_IN index_NN patients_NNS with_IN breast_NN cancer_NN showed_VBD that_QL as_QL many_AP as_CS one_CD1 half_ABN of_IN these_DTS women_NNS experienced_JJ traumatic_JJ stress_NN symptoms_NNS related_VBN to_TO their_PP$ breast_NN cancer_NN risk_NN , including_IN intrusive_JJ thoughts_NNS and_CC feelings_NNS , sleep_NN disturbance_NN , and_CC impairment_NN in_IN daily_JJ activities_NNS thus_RB , one_CD1 would_MD expect_VB the_ATI psychological_JJ consequences_NNS of_IN risk_NN notification_NN based_VBN on_IN DNA_NP testing_NN to_TO be_BE at_RB least_RB as_QL significant_JJ as_CS these_DTS effects_NNS 31_CD taken_VBN together_RB , these_DTS studies_NNS provide_VB empiric_JJ justification_NN for_IN the_ATI importance_NN of_IN psychological_JJ preparation_NN for_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN in_IN the_ATI context_NN of_IN predictive_JJ testing_NN programs_NNS for_IN HD_NP , pretest_JJT counseling_VBG typically_RB is_BEZ delivered_VBN in_IN two_CD to_IN three_CD sessions_NNS with_IN a_AT genetic_JJ counselor_NN and_CC psychologist_NN one_CD1 important_JJ objective_NN of_IN pretest_JJT counseling_VBG is_BEZ to_TO identify_VB individuals_NNS with_IN psychiatric_JJ disorders_NNS or_CC those_DTS who_WPR are_BER psychologically_RB vulnerable_JJ to_IN the_ATI negative_JJ consequences_NNS of_IN testing_NN such_ABL persons_NNS may_MD be_BE identified_VBN by_IN means_NNS of_IN standard_NN psychological_JJ instruments_NNS or_CC structured_JJ interviews_NNS that_WPR assess_VB depression_NN , suicide_NN potential_JJ , and_CC life_NN stressors_NNS 32_CD in_IN addition_NN , preparatory_JJ counseling_NN is_BEZ critical_JJ to_TO plan_VB for_IN the_ATI impact_NN of_IN test_NN results_NNS and_CC the_ATI tailoring_NN of_IN follow-up_NN programs_NNS for_IN HD_NP have_HV found_VBN it_PP3 useful_JJ to_TO explore_VB strategies_NNS that_CS potential_JJ screenees_NNS can_MD use_VB to_TO cope_VB with_IN positive_JJ or_CC negative_JJ results_NNS maladaptive_JJ coping_NN responses_NNS (_( eg_NN , denial_NN or_CC substance_NN use_NN )_) can_MD be_BE identified_VBN and_CC more_QL adaptive_JJ strategies_NNS can_MD be_BE rehearsed_VBD (_( eg_NN , seeking_VBG social_JJ support_NN or_CC obtaining_VBG more_QL frequent_JJ surveillance_NN )_) studies_NNS in_IN the_ATI traditional_JJ genetic_JJ testing_NN domain_NN suggest_VB that_CS such_ABL preparation_NN is_BEZ essential_JJ to_TO minimize_VB the_ATI likelihood_NN of_IN untoward_JJ psychological_JJ consequences_NNS 33_CD it_PP3 also_RB is_BEZ critical_JJ that_CS genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN not_XNOT be_BE initiated_VBN before_CS establishing_VBG resources_NNS and_CC plans_NNS for_IN follow-up_NN counseling_NN in_IN one_CD1 report_NN of_IN participants_NNS in_IN a_AT predictive_JJ testing_NN program_NN for_IN HD_NP , 40%_NP required_VBD additional_JJ psychological_JJ counseling_NN to_TO adjust_VB to_IN the_ATI results_NNS other_AP reports_NNS indicate_VB that_CS follow-up_NN also_RB is_BEZ critical_JJ for_IN persons_NNS identified_VBN as_IN noncarriers_NNS for_IN example_NN , 10%_CD of_IN noncarriers_NNS of_IN the_ATI HD_NP gene_NN reported_VBD difficulties_NNS adjusting_VBG to_IN this_DT information_NN and_CC required_VBD additional_JJ psychological_JJ counseling_NN for_IN these_DTS individuals_NNS , who_WPR have_HV lived_VBN their_PP$ lives_NNS under_IN the_ATI cloud_NN of_IN heightened_VBN risk_NN , the_ATI prospect_NN of_IN a_AT long_JJ life_NN without_IN disease_NN may_MD be_BE unexpected_JJ and_CC unplanned_JJ for_IN in_IN addition_NN , the_ATI prospective_JJ HD_NP study_NN described_VBD above_IN suggests_VBZ that_CS psychological_JJ follow-up_NN also_RB should_MD be_BE provided_VBN for_IN potential_JJ screenees_NNS who_WPR do_DO not_XNOT receive_VB genetic_JJ information_NN finally_RB , it_PP3 must_MD be_BE recognized_VBN that_CS genetic_JJ information_NN has_HVZ implications_NNS , not_XNOT only_RB for_IN the_ATI individuals_NNS who_WPR undergo_VB testing_NN but_CC also_RB for_IN their_PP$ partners_NNS , children_NNS , siblings_NNS , and_CC parents_NNS as_IN such_ABL , follow-up_NN support_NN should_MD be_BE extended_VBN to_IN family_NN members_NNS as_IN well_RB 34_CD promoting_VBG Prevention_NN and_CC Surveillance_NP 35_CD early_JJ Detection_NN Strategies_NP the_ATI benefits_NNS of_IN mammography_NN for_IN women_NNS aged_JJ 50_CD years_NNS and_CC older_JJR have_HV received_VBN consistent_JJ support_NN in_IN trials_NNS across_IN Europe_NP and_CC Canada_NP the_ATI results_NNS of_IN these_DTS trials_NNS have_HV led_VBN most_QL professional_JJ medical_JJ organizations_NNS to_TO recommend_VB mammography_NN annually_RB for_IN women_NNS aged_JJ 50_CD years_NNS and_CC older_JJR and_CC every_AT 1_CD1 to_IN 2_CD years_NNS for_IN women_NNS aged_JJ 40_CD to_IN 49_CD years_NNS however_RB , the_ATI results_NNS of_IN a_AT recent_JJ Canadian_JNP trial_NN , which_WDTR failed_VBN to_TO demonstrate_VB any_DTI reduction_NN in_IN mortality_NN among_IN screened_VBN women_NNS aged_JJ 40_CD to_IN 49_CD years_NNS , has_HVZ generated_VBN significant_JJ controversy_NN regarding_IN the_ATI most_QL appropriate_JJ screening_NN interval_NN for_IN women_NNS in_IN this_DT age_NN group_NN 36_CD one_CD1 of_IN the_ATI greatest_JJT potential_JJ benefits_NNS of_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN may_MD be_BE the_ATI identification_NN of_IN younger_JJR women_NNS who_WPR may_MD benefit_VB from_IN mammography_NN surveillance_NN initiated_VBN at_IN an_AT earlier_RBR age_NN and_or_CC on_IN a_AT more_QL frequent_JJ basis_NN while_CS there_EX presently_RB is_BEZ no_ATI consensus_NN on_IN mammography_NN screening_NN intervals_NNS for_IN women_NNS in_IN HBC_NP families_NNS , some_DTI providers_NNS recommend_VB that_CS these_DTS women_NNS begin_VB mammography_NN screening_NN at_IN 25_CD years_NNS of_IN age_NN , or_CC 5_CD years_NNS before_IN the_ATI earliest_JJT age_NN at_IN diagnosis_NN of_IN an_AT affected_VBN FDR_NP thereafter_RB , biannual_JJ clinical_JJ breast_NN examinations_NNS and_CC annual_JJ mammograms_NNS are_BER advised_VBN .=20_CD 37_CD however_RB , mammography_NN in_IN younger_JJR women_NNS may_MD be_BE less_QL sensitive_JJ because_CS of_IN increased_JJ breast_NN tissue_NN density_NN in_IN addition_NN , the_ATI possible_JJ effects_NNS of_IN long-term_JJB exposure_NN to_IN ionizing_VBG radiation_NN must_MD be_BE considered_VBN proponents_NNS of_IN mammography_NN for_IN younger_JJR high-risk_NN women_NNS emphasize_VB data_NNS that_WPR show_VB that_CS in_IN younger_JJR women_NNS , mammograms_NNS can_MD detect_VB microcalcifications_NNS that_CS are_BER indicative_NN of_IN malignant_JJ conditions_NNS also_RB , state-of-the-art_NN mammography_NN uses_VBZ low_JJ radiation_NN doses_NNS , and_CC there_EX is_BEZ no_ATI evidence_NN of_IN significant_JJ risk_NN of_IN mammography_NN screening_NN in_IN women_NNS over_IN age_NN 35_CD years_NNS 38_CD moreover_RB , anecdotal_JJ reports_NNS indicate_VB that_CS mammography_NN is_BEZ effective_JJ in_IN detecting_JJ very_QL early_JJ lesions_NNS in_IN gene_NN carriers_NNS younger_JJR than_IN 30_CD years_NNS For_NP ataxia_NN telangectasia_NN heterozygotes_NNS , who_WPR may_MD be_BE more_QL susceptible_JJ to_TO the_ATI effects_NNS of_IN ionizing_VBG radiation_NN , ultrasound_NN may_MD be_BE an_AT option_NN for_IN women_NNS who_WPR present_JJ with_IN a_AT breast_NN lump_NN these_DTS controversial_JJ issues_NNS potentially_RB can_MD be_BE resolved_VBN by_IN mammography_NN screening_NN trials_NNS of_IN gene_NN carriers_NNS 39_CD while_CS there_EX have_HV not_XNOT yet_RB been_BEN any_DTI studies_NNS of_IN the_ATI mammography_NN screening_NN practices_NNS of_IN female_JJ members_NNS of_IN HBC_NP families_NNS , there_EX have_HV been_BEN several_AP reports_NNS of_IN underuse_NN of_IN mammography_NN among_IN women_NNS with_IN a_AT positive_JJ family_NN history_NN of_IN breast_NN cancer_NN for_IN example_NN , Vogel_NP and_CC colleagues_NNS showed_VBD that_CS only_RB 31.5%_CD of_IN these_DTS women_NNS had_HVD ever_RB received_VBN a_AT mammogram_NN Lack_NP of_IN a_AT physician_NN referral_JJ was_BEDZ cited_VBN as_IN a_AT major_JJ screening_NN barrier_NN Similarly_NP , a_AT study_NN of_IN FDRs_NP of_IN patients_NNS with_IN breast_NN cancer_NN aged_JJ 50_CD years_NNS and_CC older_JJR showed_VBD that_CS while_CS 49%_NN had_HVD mammograms_NNS , only_RB 14%_CD adhered_VBN to_TO annual_JJ screening_NN among_IN those_DTS who_WPR had_HVD never_RB been_BEN screened_VBN , 92%_NN reported_VBN that_CS their_PP$ physicians_NNS had_HVD never_RB recommended_JJ mammography_NN 40_CD notification_NN of_IN genetic_JJ breast_NN cancer_NN susceptibility_NN potentially_RB can_MD motivate_VB women_NNS to_TO adhere_VB to_IN recommended_JJ guidelines_NNS for_IN breast_NN cancer_NN screening_NN however_RB , as_CS noted_VBN above_IN , risk_NN notification_NN may_MD also_RB generate_VB psychological_JJ distress_NN in_IN some_DTI women_NNS this_DT is_BEZ a_AT particular_JJ concern_NN because_CS of_IN the_ATI possible_JJ impact_NN of_IN distress_NN on_IN subsequent_JJ adherence_NN to_TO breast_NN cancer_NN screening_NN for_IN example_NN , anxiety_NN and_CC cancer_NN worries_NNS have_HV been_BEN associated_VBN with_IN lower_JJR rates_NNS of_IN mammography_NN as_QL well_RB as_CS reductions_NNS in_IN breast_NN self-examination_NN and_CC clinical_JJ breast_NN examination_NN in_IN one_CD1 study_NN of_IN women_NNS with_IN a_AT positive_JJ family_NN history_NN of_IN breast_NN cancer_NN , those_DTS with_IN serious_JJ breast_NN cancer_NN worries_NNS were_BED about_RB 2.5_CD times_NNS less_QL likely_JJ to_TO adhere_VB to_TO mammography_VB screening_NN guidelines_NNS than_IN were_BED women_NNS without_IN such_ABL worries_NNS 41_CD the_ATI genetic_JJ testing_NN encounter_NN may_MD be_BE an_AT optimal_JJ time_NN for_IN promoting_VBG adherence_NN in_IN high-risk_NN women_NNS studies_NNS have_HV shown_VBN that_CS an_AT unequivocal_JJ medical_JJ recommendation_NN is_BEZ the_ATI most_QL powerful_JJ predictor_NN of_IN mammography_NN adherence_NN the_ATI impact_NN of_IN a_AT simple_JJ medical_JJ recommendation_NN is_BEZ likely_JJ to_TO be_BE enhanced_VBN by_IN emphasizing_VBG the_ATI possible_JJ benefits_NNS of_IN breast_NN cancer_NN screening_NN , including_IN the_ATI potential_JJ for_IN detection_NN of_IN early_JJ stage_NN 1_CD1 tumors_NNS , increased_JJ treatment_NN options_NNS , and_CC increased_JJ probability_NN of_IN long-term_JJB survival_NN health_NN care_NN professionals_NNS should_MD also_RB address_VB known_VBN barriers_NNS to_TO breast_NN cancer_NN screening_NN , including_IN concerns_VBZ about_IN radiation_NN , embarrassment_NN , and_CC anxiety_NN about_IN positive_JJ results_NNS the_ATI effects_NNS of_IN these_DTS communications_NNS may_MD be_BE enhanced_VBN by_IN provision_NN of_IN written_VBN educational_JJ materials_NNS and_CC follow-up_NN telephone_NN counseling_VBG to_TO address_VB barriers_NNS to_TO adherence_NN psychological_JJ barriers_NNS to_TO adherence_NN , such_IN as_IN denial_NN and_CC fear_NN of_IN finding_VBG cancer_NN , may_MD be_BE seen_VBN among_IN women_NNS who_WPR manifest_JJ difficulties_NNS adjusting_VBG to_IN genetic_JJ information_NN these_DTS effects_NNS are_BER likely_JJ to_TO be_BE addressed_VBN by_IN arranging_VBG follow-up_NN psychological_JJ counseling_NN services_NNS for_IN these_DTS women_NNS it_PP3 also_RB is_BEZ critical_JJ for_IN noncarriers_NNS of_IN susceptibility_NN genes_NNS , who_WPR remain_VB susceptible_JJ to_IN the_ATI development_NN of_IN environmental_JJ or_CC _** sporadic_JJ _** malignant_JJ neoplasms_NNS , to_TO adhere_VB to_IN guidelines_NNS for_IN women_NNS in_IN the_ATI general_JJ population_NN additionally_RB , all_ABN women_NNS should_MD be_BE instructed_VBN in_IN breast_NN self-examination_NN to_TO increase_VB confidence_NN and_CC proficiency_NN in_IN lump_NN detection_NN and_CC reduce_VB anxiety_NN about_IN self-examination_NN performance_NN of_IN breast_NN self-examination_NN may_MD be_BE especially_RB important_JJ for_IN younger_JJR women_NNS , for_IN whom_WPOR mammography_NN is_BEZ less_QL efficacious_JJ 42_CD since_CS carriers_NNS of_IN the_ATI BRCA1_CD gene_NN also_RB may_MD be_BE predisposed_VBN to_TO develop_VB ovarian_NN cancer_NN , guidelines_VBZ for_IN screening_NN of_IN the_ATI female_JJ reproductive_JJ tract_NN also_RB should_MD be_BE provided_VBN however_RB , there_EX presently_RB is_BEZ no_ATI consensus_NN with_IN regard_NN to_TO ovarian_VB cancer_NN screening_NN guidelines_NNS , because_CS of_IN concerns_VBZ about_IN the_ATI efficacy_NN of_IN available_JJ methods_NNS in_IN some_DTI settings_NNS , women_NNS at_IN excess_JJ genetic_JJ risk_NN for_IN ovarian_NN cancer_NN are_BER being_BEG advised_VBN to_TO undergo_VB biannual_JJ screening_NN with_IN pelvic_JJ examination_NN , CA-125_CD-CD , and_CC transvaginal_JJ sonography_NN as_CS yet_RB , little_JJ is_BEZ known_VBN about_IN patterns_NNS of_IN use_NN or_CC barriers_NNS to_IN participation_NN among_IN high-risk_NN women_NNS 43_CD prevention_NN Strategies_NP women_NNS at_IN high_JJ risk_NN for_IN breast_NN cancer_NN are_BER increasingly_RB seeking_VBG counseling_VBG about_IN prophylactic_JJ mastectomy_NN (_( PM_NP )_) , and_CC PM_NP has_HVZ been_BEN advocated_VBN for_IN selected_JJ members_NNS of_IN HBC_NP families_NNS potential_JJ postoperative_JJ complications_NNS of_IN PM_NP include_VB skin_NN flap_NN necrosis_NN , hematoma_NN , and_CC infection_NN in_IN a_AT small_JJ proportion_NN of_IN patients_NNS the_ATI efficacy_NN of_IN PM_NP has_HVZ yet_RB to_TO be_BE established_VBN in_IN controlled_JJ trials_NNS it_PP3 has_HVZ been_BEN estimated_VBN that_CS about_IN 0.5%_NP of_IN patients_NNS who_WPR received_VBD subcutaneous_JJ mastectomy_NN will_MD develop_VB breast_NN cancer_NN however_RB , this_DT figure_NN probably_RB underestimates_VBZ the_ATI results_NNS that_DT would_MD be_BE obtained_VBN with_IN a_AT longer_RBR follow-up_NN period_NN and_CC a_AT high-risk_NN group_NN of_IN women_NNS 44_CD the_ATI psychological_JJ aspects_NNS of_IN PM_NP have_HV received_VBN little_JJ attention_NN in_IN the_ATI literature_NN prophylactic_JJ mastectomy_NN may_MD provide_VB important_JJ psychological_JJ benefits_NNS , especially_RB for_IN women_NNS in_IN high-risk_NN families_NNS for_IN example_NN , long-term_JJB uncertainty_NN and_CC worry_VB might_MD be_BE reduced_VBN , as_IN would_MD dependence_NN on_IN screening_NN and_CC self- examination_NN prophylactic_JJ mastectomy_NN also_RB may_MD reduce_VB the_ATI likelihood_NN of_IN experiencing_VBG the_ATI distress_NN associated_VBN with_IN false-positive_JJ mammography_NN results_NNS 45_CD the_ATI potential_JJ psychological_JJ costs_NNS of_IN PM_NP also_RB must_MD be_BE addressed_VBN Although_NP several_AP studies_NNS have_HV examined_VBN the_ATI psychological_JJ consequences_NNS of_IN mastectomy_NN in_IN patients_NNS with_IN cancer_NN , the_ATI impact_NN of_IN these_DTS procedures_NNS among_IN asymptomatic_JJ women_NNS is_BEZ unknown_JJ recent_JJ controversies_NNS about_IN silicone_NN breast_NN implants_NNS are_BER likely_JJ to_TO raise_VB anxiety_NN among_IN women_NNS who_WPR opt_VB for_IN breast_NN reconstruction_NN .=20_CD 46_CD however_RB , because_CS of_IN the_ATI lack_NN of_IN empiric_JJ data_NNS , it_PP3 is_BEZ difficult_JJ to_TO prepare_VB women_NNS effectively_RB for_IN the_ATI problems_NNS in_IN adjustment_NN they_PP3AS are_BER likely_JJ to_TO experience_VB moreover_RB , the_ATI distress_NN experienced_VBN by_IN carriers_NNS who_WPR desire_NN but_CC cannot_NN afford_VB the_ATI high_JJ cost_NN of_IN mastectomy_NN and_CC reconstruction_NN may_MD be_BE especially_RB great_JJ finally_RB , the_ATI long-term_JJB efficacy_NN of_IN PM_NP is_BEZ unknown_JJ , but_CC the_ATI degree_NN to_TO which_WDTR this_DT fact_NN will_MD be_BE appreciated_VBN by_IN potential_JJ genetic_JJ testing_NN participants_NNS is_BEZ unclear_JJ 47_CD prophylactic_JJ oopherectomy_NN also_RB is_BEZ being_BEG advised_VBN for_IN women_NNS genetically_RB predisposed_VBN to_TO ovarian_VB cancer_NN however_RB , major_JJ questions_NNS about_IN the_ATI protective_JJ effects_NNS of_IN oopherectomy_NN were_BED raised_VBN after_IN reports_NNS of_IN three_CD cases_NNS of_IN intra-abdominal_JJ carcinomatosis_NN among_IN 28_CD women_NNS who_WPR had_HVD surgery_NN 48_CD an_AT additional_JJ challenge_NN to_IN clinicians_NNS will_MD be_BE to_IN counsel_NN women_NNS about_IN dietary_JJ modification_NN and_CC chemoprevention_NN practices_NNS while_CS the_ATI role_NN of_IN dietary_JJ fat_NN in_IN breast_NN cancer_NN remains_VBZ controversial_JJ , there_EX is_BEZ little_JJ harm_NN in_IN encouraging_JJ women_NNS to_TO reduce_VB fat_NN intake_NN to_IN 25_CD g_d_NN , in_IN accordance_NN with_IN the_ATI recommendations_NNS of_IN the_ATI American_JNP Cancer_NP Society_NP additionally_RB , high-risk_NN women_NNS may_MD opt_VB to_TO enroll_VB in_IN the_ATI Tamoxifen_NP Chemoprevention_NN Trial_NP this_DT long-term_JJB , randomized_JJ trial_NN will_MD compare_VB the_ATI effects_NNS of_IN tamoxifen_NN with_IN those_DTS of_IN placebo_NN in_IN 16000_CD women_NNS at_IN increased_JJ risk_NN for_IN breast_NN cancer_NN however_RB , the_ATI lack_NN of_IN proved_VBN benefits_NNS of_IN these_DTS interventions_NNS must_MD be_BE emphasized_VBN to_IN women_NNS to_TO avoid_VB generating_NN a_AT false_JJ sense_NN of_IN reassurance_NN 49_CD suggestions_NNS for_IN Research_NP to_IN Evaluate_NPT Genetic_NP Testing_NP for_IN Breast_NP Cancer_NP Susceptibility_NP 50_CD a_AT large_JJ number_NN of_IN professional_JJ publications_NNS have_HV appeared_VBN recently_RB concerning_IN the_ATI ethical_JJ , legal_JJ , and_CC social_JJ aspects_NNS of_IN genetic_JJ research_NN and_CC testing_NN nevertheless_RB , much_AP of_IN the_ATI debate_NN concerning_IN the_ATI potential_JJ impact_NN of_IN testing_NN has_HVZ occurred_VBN in_IN the_ATI absence_NN of_IN relevant_JJ empiric_JJ evidence_NN as_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN is_BEZ initiated_VBN on_IN a_AT larger_JJR scale_NN , it_PP3 will_MD be_BE critical_JJ to_TO conduct_VB carefully_RB designed_JJ studies_NNS to_TO evaluate_VB the_ATI impact_NN of_IN these_DTS programs_NNS on_IN psychological_JJ status_NN and_CC cancer_NN prevention_NN and_CC control_NN practices_NNS the_ATI selection_NN of_IN research_NN designs_NNS and_CC measures_NNS for_IN these_DTS studies_NNS should_MD be_BE guided_VBN by_IN behavioral_JJ science_NN theory_NN and_CC informed_VBN by_IN work_NN conducted_VBN in_IN other_AP domains_NNS of_IN risk_NN factor_NN screening_NN and_CC cancer_NN prevention_NN and_CC control_NN 51_CD prospective_JJ studies_NNS are_BER essential_JJ to_TO determine_VB the_ATI psychological_JJ and_CC behavioral_JJ impact_NN of_IN genetic_JJ risk_NN information_NN assessments_NNS should_MD be_BE conducted_VBN at_IN multiple_JJ time_NN points_NNS , including_IN before_CS testing_NN , immediately_RB after_IN notification_NN , at_IN short-term_JJB follow-up_NN (_( eg_NN , 3_CD months_NNS )_) , and_CC at_IN long-term_JJB follow-up_NN (_( eg_NN , 1_CD1 year_NN )_) critical_JJ outcome_NN variables_NNS include_VB psychological_JJ status_NN , marital_JJ and_CC family_NN functioning_NN , quality_NN of_IN life_NN , health_NN behaviors_NNS , reproductive_JJ intentions_NNS , and_CC health_NN care_NN use_NN Assessment_NP of_IN psychological_JJ status_NN should_MD include_VB , but_CC not_XNOT be_BE limited_JJ to_TO , well-validated_JJ , global_JJ measures_NNS of_IN functioning_NN , including_IN those_DTS that_CS assess_VB anxiety_NN , depression_NN , and_CC somatic_JJ complaints.=20_CD 52_CD however_RB , while_CS these_DTS measures_NNS can_MD be_BE useful_JJ for_IN screening_NN and_CC follow-up_NN purposes_NNS , they_PP3AS also_RB can_MD be_BE insensitive_JJ to_IN the_ATI kinds_NNS of_IN changes_NNS that_CS are_BER likely_JJ to_TO occur_VB among_IN well-adjusted_JJ individuals_NNS psychological_JJ reactions_NNS , such_IN as_IN intrusive_JJ breast_NN cancer_NN worries_NNS , survivor_NN guilt_NN , carrier_NN guilt_NN (_( eg_NN , a_AT father_NN who_WPR passes_VBZ an_AT abnormal_JJ gene_NN to_IN his_PP$ daughter_NN )_) , and_CC the_ATI psychosexual_JJ responses_NNS surrounding_JJ PM_NP , may_MD not_XNOT be_BE captured_VBN by_IN these_DTS global_JJ measures_NNS of_IN distress_NN therefore_RB , preliminary_JJ studies_NNS should_MD also_RB include_VB open- ended_JJ questions_NNS and_CC interview_NN formats_NNS that_WPR allow_VB these_DTS complex_JJ themes_NNS to_TO emerge_VB for_IN the_ATI purpose_NN of_IN comparison_NN , assessments_NNS should_MD be_BE conducted_VBN not_XNOT only_RB with_IN carriers_NNS but_CC also_RB with_IN noncarriers_NNS and_CC individuals_NNS who_WPR decline_NN to_TO be_BE tested_VBN much_AP of_IN the_ATI early_JJ work_NN on_IN genetic_JJ testing_NN and_CC counseling_VBG has_HVZ focused_VBN on_IN participants_NNS in_IN early_JJ pilot_NN programs_NNS , a_AT group_NN that_WPR may_MD be_BE highly_RB self-selected_JJ and_CC whose_WP$R responses_NNS may_MD not_XNOT be_BE representative_NN of_IN the_ATI entire_JJB at-risk_NN population_NN 53_CD a_AT major_JJ goal_NN of_IN this_DT research_NN should_MD be_BE to_TO understand_VB why_WRB two_CD individuals_NNS can_MD react_VB so_QL differently_RB to_IN similar_JJ information_NN regarding_IN breast_NN cancer_NN risk_NN thus_RB , variables_NNS that_CS moderate_JJ the_ATI impact_NN of_IN genetic_JJ information_NN should_MD be_BE identified_VBN for_IN example_NN , sociodemographic_JJ characteristics_NNS such_IN as_IN educational_JJ level_NN are_BER likely_JJ to_TO influence_VB how_WRB genetic_JJ information_NN is_BEZ processed_VBN and_CC acted_VBD on_RP in_IN addition_NN , data_NNS on_IN personality_NN and_CC coping_NN styles_NNS , collected_VBD before_CS testing_NN , are_BER prerequisites_NNS to_IN meaningful_JJ subgroup_NN comparisons_NNS of_IN impact_NN .=20_CD 54_CD this_DT research_NN also_RB should_MD examine_VB the_ATI role_NN of_IN values_NNS and_CC beliefs_NNS , as_CS well_RB as_IN the_ATI processes_NNS by_IN which_WDTR personal_JJ disease-related_JJ experiences_NNS affect_VB perceptions_NNS of_IN genetic_JJ information_NN in_IN addition_NN , studies_NNS should_MD explore_VB ethnic_JJ and_CC cultural_JJ differences_NNS in_IN perceptions_NNS of_IN and_CC reactions_NNS to_IN genetic_JJ testing_NN concerns_VBZ surrounding_JJ possible_JJ discrimination_NN may_MD contribute_VB to_IN an_AT especially_RB adverse_JJ impact_NN of_IN genetic_JJ testing_NN on_IN members_NNS of_IN ethnic_JJ minority_NN groups_NNS these_DTS concerns_VBZ underscore_VB the_ATI importance_NN of_IN including_IN persons_NNS with_IN diverse_JJ socioeconomic_JJ backgrounds_NNS in_IN studies_NNS of_IN the_ATI impact_NN of_IN genetic_JJ testing_NN 55_CD the_ATI second_OD stage_NN of_IN psychological_JJ research_NN on_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN should_MD include_VB controlled_VBN clinical_JJ trials_NNS of_IN different_JJ counseling_NN protocols_NNS because_CS of_IN unique_JJ aspects_NNS of_IN breast_NN cancer_NN causes_NNS and_CC prevention_NN , counseling_VBG protocols_NNS developed_VBN for_IN traditional_JJ mendelian_NN diseases_NNS may_MD have_HV limited_JJ applicability_NN to_IN genetic_JJ testing_NN for_IN breast_NN cancer_NN thus_RB , it_PP3 will_MD be_BE important_JJ to_TO develop_VB and_CC test_NN new_JJ counseling_NN approaches_NNS that_WPR vary_VB in_IN terms_NNS of_IN the_ATI content_NN , process_NN , and_CC timing_NN of_IN delivery_NN of_IN genetic_JJ information_NN also_RB , standard_NN adjunctive_JJ psychoeducational_JJ interventions_NNS should_MD be_BE examined_VBN for_IN their_PP$ efficacy_NN in_IN ameliorating_VBG psychological_JJ distress_NN and_CC enhancing_VBG adherence_NN behaviors_NNS among_IN genetic_JJ testing_NN participants_NNS the_ATI rapid_JJ expansion_NN of_IN genetic_JJ testing_NN will_MD demand_VB that_CS these_DTS programs_NNS be_BE justified_VBN empirically_RB in_IN terms_NNS of_IN cost_NN and_CC effectiveness_NN 56_CD CONCLUSION_NP 57_CD clinical_JJ genetic_JJ tests_NNS soon_RB will_MD become_VB available_JJ to_TO identify_VB persons_NNS at_IN risk_NN for_IN a_AT common_JJ form_NN of_IN cancer_NN although_CS HBC_NP may_MD account_VB for_IN only_RB 5%_JJ to_IN 10%_CD of_IN all_ABN breast_NN cancer_NN cases_NNS , as_QL many_AP as_CS one_CD1 in_IN 300_CD persons_NNS are_BER carriers_NNS of_IN these_DTS gene_NN mutations_NNS these_DTS discoveries_NNS raise_VB hope_VB concerning_IN the_ATI potential_JJ public_JJ health_NN impact_NN of_IN genetic_JJ testing_NN However_NP , before_CS testing_NN programs_NNS are_BER implemented_VBN , effective_JJ and_CC ethical_JJ means_NNS of_IN communicating_JJ genetic_JJ risk_NN information_NN must_MD be_BE identified_VBN Genetic_NP testing_NN protocols_NNS must_MD be_BE informed_VBN by_IN empiric_JJ research_NN that_CS examines_VBZ the_ATI psychosocial_JJ impact_NN of_IN pilot_NN testing_NN programs_NNS on_IN participants_NNS and_CC their_PP$ families_NNS consensus_NN guidelines_NNS for_IN surveillance_NN and_CC prevention_NN of_IN breast_NN cancer_NN among_IN carriers_NNS must_MD also_RB be_BE established_VBN , including_IN validated_JJ methods_NNS for_IN enhancing_VBG patient_NN adherence_NN these_DTS issues_NNS will_MD be_BE best_JJT addressed_VBN if_CS genetic_JJ testing_NN for_IN breast_NN cancer_NN susceptibility_NN initially_RB is_BEZ conducted_VBN within_IN the_ATI context_NN of_IN research_NN that_CS carefully_RB assesses_VBZ the_ATI immediate_JJ and_CC long-term_JJB impact_NN of_IN risk_NN notification_NN 58_CD acoustic_JJ Neuroma=20_CD 59_CD the_ATI 1991_CD Consensus_JJ Development_NP Conference_NP on_IN Vestibular_NP Schwannoma_NP was_BEDZ convened_VBN to_TO consider_VB how_WRB patients_NNS can_MD acquire_VB an_AT accurate_JJ diagnosis_NN and_CC to_TO review_VB the_ATI best_JJT options_NNS for_IN management_NN of_IN this_DT disease_NN , including_IN primary_JJ therapy_NN , follow-up_NN , and_CC rehabilitation_NN 60_CD we_PP1AS use_VB the_ATI term_NN vestibular_NN schwannomas_NNS throughout_IN this_DT report_NN because_CS these_DTS tumors_NNS are_BER composed_VBN of_IN Schwann_NP cells_NNS and_CC typically_RB involve_VB the_ATI vestibular_NN rather_RB than_IN the_ATI acoustic_JJ division_NN of_IN the_ATI eighth_OD cranial_JJ nerve_NN although_CS benign_JJ , because_CS of_IN their_PP$ location_NN vestibular_NN schwannomas_NNS can_MD produce_VB serious_JJ morbidity_NN or_CC even_RB death_NN , by_IN compression_NN of_IN vital_JJ structures_NNS , including_IN the_ATI cranial_JJ nerves_NNS and_CC the_ATI brain_NN stem_NN advances_NNS in_IN microsurgery_NN have_HV dramatically_RB reduced_VBN operative_JJ mortality_NN and_CC have_HV made_VBN tumor_NN removal_NN without_IN additional_JJ neurologic_JJ deficit_NN a_AT realistic_JJ but_CC challenging_JJ goal_NN 61_CD an_AT estimated_VBN 2000_CD to_IN 3000_CD new_JJ cases_NNS of_IN unilateral_JJ vestibular_NN schwannoma_NN are_BER diagnosed_VBN in_IN the_ATI United_NP States_NP each_DT year_NN , an_AT incidence_NN of_IN about_IN one_CD1 per_NNU 100000_CD per_NNU year_NN the_ATI most_AP common_JJ presenting_VBG symptoms_NNS are_BER change_NN in_IN hearing_VBG in_IN one_CD1 ear_NN , tinnitus_JJ (_( noise_NN in_IN the_ATI ear_NN )_) , and_CC poor_JJ balance_NN the_ATI advent_NN of_IN magnetic_JJ resonance_NN imaging_VBG (_( MRI_NP )_) with_IN gadolinium_NN enhancement_NN has_HVZ permitted_VBN the_ATI identification_NN of_IN many_AP very_QL small_JJ , previously_RB undetectable_JJ tumors_NNS some_DTI studies_NNS suggest_VB that_CS the_ATI prevalence_JJ of_IN vestibular_NN schwannomas_NNS at_IN autopsy_NN may_MD be_BE as_QL high_JJ as_CS 0.9%_NP , but_CC this_DT is_BEZ quite_RB likely_JJ an_AT overestimate_VB in_IN any_DTI event_NN , the_ATI vast_JJ majority_NN of_IN these_DTS tumors_NNS are_BER very_QL small_JJ and_CC are_BER not_XNOT recognized_VBN clinically_RB at_RB least_RB 95%_NN of_IN diagnosed_JJ vestibular_NN schwannomas_NNS are_BER unilateral_JJ these_DTS tumors_NNS are_BER encapsulated_VBN and_CC rounded_JJ and_CC usually_RB appear_VB as_IN a_AT single_JJ mass_NN about_IN 5%_JJ of_IN patients_NNS exhibit_VB bilateral_JJ schwannomas_NNS associated_VBN with_IN an_AT inherited_VBN syndrome_NN known_VBN as_IN neurofibromatosis_NN type_NN 2_CD (_( NF2_NP )_) (_( Table_NP 1_CD1 )_) Population-based_NP data_NNS from_IN the_ATI United_NP Kingdom_NPL suggest_VB that_CS one_CD1 in_IN 35000_CD individuals_NNS carries_VBZ the_ATI gene_NN for_IN NF2_NP 62_CD WHAT_NPT ARE_NPT ACOUSTIC_NPT NEUROMAS_NPT AND_NPT HOW_NPT SHOULD_NPT THEY_NPT BE_NP CLASSIFIED_NP ? 63_CD cytologically_RB , no_ATI differences_NNS have_HV been_BEN found_VBN between_IN the_ATI vestibular_NN schwannomas_NNS of_IN NF2_NP and_CC those_DTS found_VBN in_IN sporadic_JJ cases_NNS histologically_RB , however_RB , the_ATI tumors_NNS in_IN NF2_NP often_RB appear_VB as_IN grapelike_NN clusters_NNS that_DT can_MD infiltrate_VB the_ATI fibers_NNS of_IN individual_JJ nerves_NNS and_CC may_MD adumbrate_VB a_AT polyclonal_JJ origin_NN both_ABX unilateral_JJ and_CC bilateral_JJ tumors_NNS vary_VB in_IN their_PP$ precise_JJ location_NN along_IN the_ATI vestibular_NN nerve_NN , tending_VBG to_TO arise_VB at_IN the_ATI border_NN between_IN the_ATI central_JJ and_CC peripheral_JJ segments_NNS of_IN the_ATI nerve_NN why_WRB tumors_NNS arise_VB at_IN this_DT transition_NN zone_NN is_BEZ not_XNOT known_VBN , but_CC variation_NN in_IN the_ATI site_NN at_IN which_WDTR a_AT tumor_NN is_BEZ located_VBN can_MD have_HV a_AT major_JJ influence_NN on_IN the_ATI symptoms_NNS it_PP3 produces_VBZ 64_CD for_IN clinical_JJ management_NN , the_ATI most_QL useful_JJ classification_NN of_IN vestibular_NN schwannomas_NNS is_BEZ by_IN size_NN , location_NN , and_CC growth_NN rate_NN however_RB , tumors_NNS tend_VB to_TO enlarge_VB unpredictably_JJ some_DTI do_DO not_XNOT change_VB in_IN size_NN for_IN many_AP years_NNS , while_CS others_APS may_MD grow_VB at_IN a_AT rate_NN of_IN up_RP to_IN 20_CD mm_UH in_IN diameter_NN per_NNU year_NN currently_RB , the_ATI best_JJT method_NN to_TO monitor_NN tumor_NN growth_NN is_BEZ with_IN gadolinium-enhanced_JJ MRI_NP to_TO facilitate_VB the_ATI interpretation_NN of_IN clinical_JJ studies_NNS , both_ABX the_ATI greatest_JJT diameter_NN of_IN the_ATI tumor_NN within_IN the_ATI posterior_JJ fossa_NN and_CC the_ATI extent_NN of_IN penetration_NN into_IN the_ATI intracanalicular_NN space_NN should_MD be_BE documented_VBN 65_CD a_AT second_OD important_JJ classification_NN is_BEZ between_IN familial_JJ and_CC sporadic_JJ cases_NNS all_ABN cases_NNS of_IN vestibular_NN schwannomas_NNS are_BER thought_VBN to_TO result_VB from_IN the_ATI functional_JJ loss_NN of_IN a_AT tumor- suppressor_NN gene_NN that_WPR has_HVZ been_BEN localized_VBN to_IN the_ATI long_JJ arm_NN of_IN chromosome_NN 22_CD in_IN at_RB least_RB 95%_NN of_IN patients_NNS , however_RB , the_ATI disease_NN is_BEZ unilateral_JJ and_CC the_ATI majority_NN of_IN these_DTS cases_NNS are_BER sporadic_JJ , resulting_JJ from_IN somatic_JJ mutations_NNS that_CS are_BER not_XNOT associated_VBN with_IN an_AT increased_JJ risk_NN for_IN other_AP tumors_NNS either_DTX in_IN the_ATI individual_JJ or_CC in_IN close_RB relatives_NNS about_IN 5%_NN of_IN patients_NNS exhibit_VB bilateral_JJ disease_NN or_CC other_AP features_NNS that_WPR define_VB NF2.=20_NP 66_CD these_DTS patients_NNS are_BER thought_VBN to_TO carry_VB a_AT single_JJ germ- line_JJ mutation_NN of_IN the_ATI chromosome_NN 22-linked_JJ gene_NN and_CC sustain_VB the_ATI loss_NN of_IN the_ATI remaining_JJ normal_JJ allele_NN as_IN a_AT somatic_JJ event_NN in_IN those_DTS cells_NNS that_WPR give_VB rise_NN to_IN the_ATI tumor_NN thus_RB , the_ATI trait_NN is_BEZ recessive_JJ at_IN the_ATI cellular_JJ level_NN but_CC exhibits_NNS a_AT dominant_JJ pattern_NN of_IN genetic_JJ transmission_NN in_IN families_NNS even_RB when_WRB a_AT thorough_JJ family_NN history_NN is_BEZ obtained_VBN , in_RP about_IN half_ABN of_IN all_ABN recognized_VBN cases_NNS of_IN NF2_NP , no_ATI evidence_NN of_IN other_AP affected_JJ family_NN members_NNS can_MD be_BE found_VBN These_NP patients_NNS may_MD represent_VB new_JJ germ-line_NN mutations_NNS and_CC are_BER at_IN risk_NN of_IN transmitting_VBG the_ATI disease_NN to_IN their_PP$ offspring_NN 67_CD 10_CD patients_NNS with_IN NF2_NP who_WPR carry_VB new_JJ mutations_NNS tend_VB to_TO be_BE more_QL severely_RB affected_VBN than_IN familial_JJ cases_NNS , and_CC some_DTI recent_JJ studies_NNS have_HV raised_VBN the_ATI possibility_NN that_CS in_IN familial_JJ cases_NNS the_ATI onset_NN of_IN symptoms_NNS may_MD be_BE earlier_RBR and_CC the_ATI severity_NN greater_JJR when_WRB the_ATI disease_NN is_BEZ inherited_VBN from_IN the_ATI mother_NN such_ABL effects_NNS can_MD arise_VB from_IN genomic_JJ imprinting_NN , and_CC although_CS the_ATI precise_JJ genetic_JJ mechanism_NN for_IN this_DT phenomenon_NN is_BEZ unknown_JJ , a_AT growing_JJ number_NN of_IN examples_NNS of_IN such_ABL parental_JJ origin_NN effects_NNS now_RN have_HV been_BEN documented_VBN if_CS confirmed_VBN , these_DTS findings_NNS could_MD have_HV practical_JJ implications_NNS for_IN the_ATI management_NN of_IN families_NNS with_IN NF2_NP 68_CD molecular_JJ studies_NNS on_IN NF2_NP and_CC on_IN unilateral_JJ tumors_NNS are_BER at_IN an_AT exciting_JJ juncture_NN the_ATI gene_NN for_IN NF2_NP should_MD soon_RB be_BE identified_VBN and_CC may_MD provide_VB molecular_JJ explanations_NNS for_IN clinical_JJ differences_NNS among_IN families_NNS with_IN NF2_NP as_QL well_RB as_CS differences_NNS in_IN the_ATI growth_NN rate_NN among_IN tumors_NNS further_JJB studies_NNS on_IN the_ATI molecular_JJ biology_NN of_IN the_ATI gene_NN may_MD suggest_VB treatments_NNS for_IN vestibular_NN schwannomas_NNS , both_ABX in_IN patients_NNS with_IN NF2_NP and_CC in_IN patients_NNS with_IN unilateral_JJ diseases_NNS 69_CD patients_NNS with_IN NF2_NP may_MD have_HV associated_JJ meningiomas_NNS and_CC spinal_JJ root_NN schwannomas_NNS as_IN well_RB as_IN cafe-au-lait_NN spots_NNS and_CC peripheral_JJ Schwann_NP cell_NN tumors_NNS and_CC often_RB develop_VB posterior_JJ subcapsular_NN cataracts_NNS at_IN an_AT early_JJ age_NN the_ATI prevalence_NN of_IN these_DTS findings_NNS varies_VBZ greatly_RB among_IN families_NNS 70_CD IN_NPT WHOM_NPT SHOULD_NPT ACOUSTIC_NPT NEUROMA_NPT BE_NPT SUSPECTED_NPT AND_NP EVALUATED_NP ? 71_CD sporadic_JJ Vestibular_NP Schwannoma_NP 72_CD the_ATI most_AP common_JJ symptom_NN , found_VBD in_IN up_RP to_IN 90%_NP of_IN individuals_NNS with_IN vestibular_NN schwannoma_NN , is_BEZ a_AT progressive_JJ , asymmetric_JJ , or_CC unilateral_JJ sensorineural_JJ hearing_NN loss_NN approximately_RB 70%_NP have_HV a_AT high-frequency_NN pattern_NN of_IN loss_NN , while_CS a_AT small_JJ number_NN of_IN patients_NNS will_MD display_VB either_DTX normal_JJ hearing_NN or_CC a_AT symmetric_JJ hearing_NN loss_NN a_AT symptom_NN sometimes_RB reported_VBN , even_RB in_IN the_ATI face_NN of_IN apparently_RB normal_JJ hearing_NN , is_BEZ distorted_VBN sound_NN perception_NN , often_RB manifested_VBN as_IN difficulty_NN in_IN using_VBG the_ATI telephone_NN or_CC perceiving_NN instruments_NNS to_TO be_BE _** off_RP key_NN _** in_IN one_CD1 ear.=20_CD 73_CD although_CS most_AP schwannoma-associated_JJ hearing_NN loss_NN is_BEZ gradual_JJ and_CC progressive_JJ , approximately_RB 10%_CD of_IN patients_NNS report_NN sudden_JJ loss_NN of_IN hearing_NN less_QL commonly_RB reported_VBN symptoms_NNS in_IN patients_NNS with_IN vestibular_NN schwannoma_NN include_VB unilateral_JJ or_CC asymmetric_JJ tinnitus_JJ (_( ringing_VBG in_IN the_ATI ears_NNS )_) with_IN or_CC without_IN complaints_NNS of_IN dizziness_NN or_CC disequilibrium_NN these_DTS symptoms_NNS are_BER generally_RB regarded_VBN as_CS _** early_JJ _** but_CC can_MD be_BE seen_VBN with_IN both_ABX small_JJ and_CC large_JJ tumors_NNS it_PP3 should_MD be_BE noted_VBN that_CS only_RB a_AT small_JJ fraction_NN of_IN patients_NNS who_WPR suffer_VB any_DTI one_CD1 of_IN the_ATI above_IN symptoms_NNS will_MD be_BE found_VBN to_TO have_HV a_AT vestibular_NN schwannoma_NN 74_CD other_AP findings_NNS , generally_RB regarded_VBN as_CS _** late_JJ _** manifestations_NNS , are_BER related_VBN to_IN compressive_JJ effects_NNS of_IN tumor_NN mass_NN on_IN neighboring_JJ structures_NNS These_NP include_VB headache_NN , ataxia_NN , cerebellar_NN signs_NNS , and_CC compressive_JJ cranial_JJ neuropathies_NNS the_ATI fifth_OD cranial_JJ (_( trigeminal_JJ )_) nerve_NN compression_NN may_MD cause_VB facial_JJ pain_NN and_or_CC numbness_NN and_CC corneal_JJ insensitivity_NN leading_JJ to_IN ulceration_NN compression_NN or_CC irritation_NN of_IN the_ATI seventh_OD (_( facial_JJ )_) cranial_JJ nerve_NN may_MD result_VB in_IN facial_JJ spasm_NN , weakness_NN , or_CC paralysis_NN infrequently_RB , involvement_NN of_IN the_ATI sixth_OD cranial_JJ nerve_NN may_MD cause_VB double_JJ vision_NN (_( diplopia_NN )_) compression_NN of_IN the_ATI 9th_OD , 10th_OD , or_CC 12th_OD cranial_JJ nerves_NNS will_MD result_VB in_IN difficulty_NN in_IN swallowing_NN and_or_CC speaking_NN when_WRB the_ATI brain_NN stem_NN is_BEZ sufficiently_RB compressed_VBN or_CC distorted_VBN by_IN a_AT large_JJ tumor_NN , the_ATI patient_NN may_MD display_VB nausea_NN , vomiting_NN , or_CC lethargy_NN , leading_JJ to_TO coma_NN , respiratory_JJ depression_NN , and_CC death_NN hydrocephalus_JJ and_CC papilledema_JJ with_IN increased_VBN intracranial_JJ pressure_NN also_RB may_MD be_BE seen_VBN with_IN increasing_JJ tumor_NN size_NN and_CC severity_NN of_IN symptoms_NNS , prompt_JJ diagnosis_NN and_CC initiation_NN of_IN treatment_NN become_VB vital_JJ 75_CD bilateral_JJ Neurofibromatosis_NN 76_CD neurofibromatosis_NN type_NN 2_CD is_BEZ a_AT complex_JJ syndrome_NN in_IN which_WDTR many_AP findings_NNS in_IN addition_NN to_IN those_DTS described_VBN above_IN may_MD occur_VB these_DTS include_VB peripheral_JJ or_CC central_JJ lenticular_NN cataracts_NNS , which_WDTR may_MD be_BE present_JJ even_RB in_IN very_QL young_JJ children_NNS (_( 80%_NP of_IN cases_NNS in_IN one_CD1 series_NN )_) ; skin_NN nodules_NNS and_CC other_AP lesions_NNS that_WPR include_VB dermal_JJ neurofibromas_NNS and_CC cafe-au-lait_NN spots_NNS (_( }60%_NP of_IN cases_NNS in_IN one_CD1 series_NN )_) ; pain_NN or_CC numbness_NN because_CS of_IN schwannomas_NNS of_IN peripheral_JJ nerves_NNS and_or_CC roots_NNS ; seizures_NNS and_CC other_AP focal_JJ neurologic_JJ symptoms_NNS ; other_AP findings_NNS related_VBN to_IN meningiomas_NNS , which_WDTR may_MD be_BE multiple_JJ , or_CC to_IN a_AT variety_NN of_IN gliomas_NNS (_( astrocytomas_NNS , ependymomas_NNS , etc_RB )_) ; and_CC similarly_RB affected_JJ relatives_NNS 77_CD once_RB the_ATI diagnosis_NN of_IN NF2_NP is_BEZ made_VBN , relatives_NNS who_WPR are_BER at_IN risk_NN should_MD be_BE screened_VBN for_IN the_ATI disease_NN bilateral_JJ neurofibromatosis_NN should_MD also_RB be_BE considered_VBN as_IN a_AT diagnostic_JJ possibility_NN in_IN patients_NNS with_IN unilateral_JJ vestibular_NN schwannomas_NNS who_WPR are_BER under_IN the_ATI age_NN of_IN 40_CD years_NNS 78_CD HOW_NPT SHOULD_NPT PATIENTS_NPT BE_NP EXAMINED_NP ? 79_CD when_WRB vestibular_NN schwannoma_NN is_BEZ suspected_VBN , the_ATI evaluation_NN must_MD begin_VB with_IN a_AT thorough_JJ clinical_JJ and_CC family_NN history_NN this_DT includes_VBZ seeking_VBG the_ATI stigmata_NN of_IN NF2_NP , schwannoma_NN , or_CC other_AP nervous_JJ system_NN tumors_NNS the_ATI physical_JJ examination_NN should_MD focus_VB on_IN the_ATI skin_NN and_CC a_AT neurologic_JJ examination_NN of_IN cranial_JJ nerve_NN function_NN additional_JJ evaluation_NN should_MD include_VB a_AT detailed_JJ examination_NN for_IN cataracts_NNS and_CC audiovestibular_NN function_NN 80_CD the_ATI initial_JJ audiologic_JJ evaluation_NN should_MD include_VB pure-tone_VB air_NN and_CC bone_NN conduction_NN thresholds_NNS , speech_NN reception_NN thresholds_NNS , and_CC speech_NN recognition_NN (_( discrimination_NN )_) scores_NNS beyond_IN these_DTS tests_NNS , two_CD other_AP diagnostic_JJ approaches_NNS are_BER commonly_RB used_VBN more_AP sophisticated_JJ audiologic_JJ tests_NNS such_IN as_IN the_ATI determination_NN of_IN acoustic_JJ reflex_NN threshold_NN , acoustic_JJ reflex_NN decay_NN tests_NNS , and_CC brain-stem_JJ auditory_JJ evoked_VBD responses_NNS (_( BAER_NP , also_RB termed_VBD ABR_NP )_) may_MD permit_VB assessment_NN of_IN the_ATI site_NN of_IN the_ATI audiologic_JJ lesion_NN The_NP other_AP approach_NN is_BEZ gadolinium-enhanced_JJ MRI_NP the_ATI decision_NN of_IN which_WDTR test_NN to_TO use_VB depends_VBZ on_IN clinical_JJ judgment_NN and_CC level_NN of_IN suspicion_NN these_DTS are_BER affected_VBN by_IN family_NN pedigree_NN , degree_NN of_IN asymmetry_RB of_IN auditory_JJ symptoms_NNS , brain-stem_NN findings_NNS , or_CC stigmata_NN of_IN NF2_NP 81_CD the_ATI advantages_NNS of_IN BAER_NP (_( ABR_NP )_) are_BER its_PP$ ability_NN to_TO measure_VB functional_JJ status_NN and_CC its_PP$ lower_JJR cost_NN recent_JJ experience_NN has_HVZ shown_VBN that_CS the_ATI sensitivity_NN of_IN BAER_NP (_( ABR_NP )_) is_BEZ 94%_JJ and_CC that_CS the_ATI specificity_NN is_BEZ greater_JJR than_IN 85%_NN for_IN the_ATI diagnosis_NN of_IN vestibular_NN schwannoma_NN auditory_JJ evoked_VBD responses_NNS , however_RB , may_MD not_XNOT be_BE possible_JJ in_IN the_ATI face_NN of_IN severe_JJ hearing_NN loss_NN 82_CD magnetic_JJ resonance_NN imaging_VBG now_RN is_BEZ regarded_VBN as_IN the_ATI most_QL definitive_JJ study_NN that_WPR can_MD be_BE performed_VBN , and_CC it_PP3 is_BEZ capable_JJ of_IN revealing_VBG vestibular_NN tumors_NNS as_QL small_JJ as_CS a_JJ few_AP millimeters_NNS in_IN diameter_NN this_DT examination_NN should_MD emphasize_VB thin-slice_VB scans_NNS in_IN the_ATI axial_JJ plane_NN with_IN gadolinium_NN enhancement_NN a_AT negative_JJ gadolinium-enhanced_JJ MRI_NP is_BEZ accepted_VBN in_IN current_JJ practice_NN as_CS effectively_RB excluding_VBG the_ATI diagnosis_NN of_IN vestibular_NN schwannoma_NN false_JJ positives_NNS are_BER rare_JJ a_AT disincentive_NN to_IN the_ATI use_NN of_IN MRI_NP as_IN a_AT screening_NN test_NN is_BEZ its_PP$ cost_NN 83_CD vestibular_NN testing_NN is_BEZ thought_VBN to_TO be_BE of_IN less_QL diagnostic_JJ value_NN than_IN the_ATI audiometric_JJ tests_NNS listed_VBN above_IN , at_RB least_RB in_IN part_NN , because_CS of_IN the_ATI compensatory_JJ ability_NN of_IN the_ATI vestibular_NN system_NN preoperative_JJ tests_NNS of_IN vestibular_NN function_NN may_MD be_BE important_JJ as_CS predictors_NNS of_IN postoperative_JJ balance_NN and_CC possible_JJ hearing_NN preservation_NN at_IN surgery_NN 84_NN computed_JJ tomography_NN is_BEZ useful_JJ in_IN certain_JJ instances_NNS for_IN screening_NN purposes_NNS , particularly_RB when_WRB MRI_NP cannot_NN be_BE obtained_VBN some_DTI surgeons_NNS stress_NN the_ATI usefulness_NN of_IN computed_JJ tomography_NN in_IN preoperative_JJ planning_NN 85_CD WHAT_NPT ARE_NPT THE_NPT TREATMENT_NPT OPTIONS_NPT FOR_NPT THOSE_NPT WITH_NPT ACOUSTIC_NP NEUROMA_NP ? 86_CD currently_RB , the_ATI ideal_JJ treatment_NN for_IN symptomatic_JJ patients_NNS with_IN vestibular_NN schwannoma_NN is_BEZ the_ATI total_JJ excision_NN of_IN the_ATI tumor_NN in_IN a_AT single_JJ stage_NN with_IN minimal_JJ morbidity_NN and_CC mortality_NN and_CC with_IN preservation_NN of_IN neurologic_JJ function_NN the_ATI other_AP options_NNS for_IN management_NN are_BER observation_NN , subtotal_JJ removal_NN , and_CC various_JJ forms_NNS of_IN radiation_NN treatment_NN , including_IN stereotaxic_JJ radiosurgery_NN selection_NN of_IN the_ATI appropriate_JJ treatment_NN option_NN should_MD be_BE based_VBN on_IN the_ATI clinical_JJ findings_NNS and_CC status_NN of_IN the_ATI patient_NN 87_CD the_ATI question_NN of_IN whether_CS and_CC when_WRB to_TO undertake_VB treatment_NN of_IN a_AT vestibular_NN schwannoma_NN is_BEZ a_AT complex_JJ issue_NN for_IN the_ATI majority_NN of_IN patients_NNS who_WPR present_JJ with_IN a_AT symptomatic_JJ tumor_NN , expeditious_JJ surgery_NN will_MD be_BE the_ATI primary_JJ treatment_NN modality_NN young_JJ patients_NNS with_IN progressive_JJ neurologic_JJ deficit_NN or_CC evidence_NN of_IN tumor_NN growth_NN clearly_RB are_BER candidates_NNS for_IN surgery_NN However_NP , there_EX are_BER groups_NNS of_IN patients_NNS for_IN whom_WPOR conservative_JJ approaches_NNS , including_IN long-term_JJB observation_NN , may_MD be_BE indicated_VBN elderly_JJ patients_NNS without_IN severe_JJ neurologic_JJ symptoms_NNS or_CC evidence_NN of_IN tumor_NN growth_NN are_BER one_CD1 such_ABL group.=20_CD 88_CD there_EX also_RB is_BEZ evidence_NN that_CS some_DTI patients_NNS with_IN unilateral_JJ vestibular_NN schwannoma_NN and_CC a_AT subgroup_NN of_IN patients_NNS with_IN NF2_NP may_MD have_HV tumors_NNS that_WPR fail_VB to_TO progress_VB rapidly_RB , resulting_JJ in_IN stable_JJ neurologic_JJ function_NN for_IN a_AT long_JJ time_NN the_ATI use_NN of_IN MRI_NP with_IN contrast_NN enhancement_NN has_HVZ resulted_VBN in_IN the_ATI identification_NN of_IN patients_NNS with_IN very_QL small_JJ , relatively_RB asymptomatic_JJ vestibular_NN schwannomas_NNS for_IN whom_WPOR the_ATI natural_JJ history_NN is_BEZ still_RB not_XNOT known_VBN Conservative_NP management_NN may_MD be_BE appropriate_JJ for_IN these_DTS patients_NNS the_ATI risk_NN of_IN neurologic_JJ deterioration_NN in_IN conservatively_RB treated_VBN patients_NNS needs_NNS to_TO be_BE recognized_VBN and_CC discussed_VBN with_IN the_ATI patient_NN 89_CD 32_CD certain_JJ preoperative_JJ findings_NNS correlate_VB with_IN treatment_NN outcome_NN When_NP a_AT patient_NN presents_VBZ with_IN a_AT mild_JJ hearing_NN loss_NN and_CC the_ATI preoperative_JJ BAER_NP (_( ABR_NP )_) recording_VBG demonstrates_VBZ normal_JJ results_NNS with_IN well-formed_JJ waves_NNS , the_ATI prognosis_NN for_IN hearing_VBG preservation_NN after_IN surgery_NN is_BEZ more_QL favorable_&FW than_IN when_WRB these_DTS conditions_NNS are_BER not_XNOT present_JJ conversely_RB , when_WRB MRI_NP shows_VBZ a_AT tumor_NN that_WPR is_BEZ larger_JJR than_IN 2_CD cm_NNU or_CC when_WRB the_ATI tumor_NN fills_VBZ the_ATI fundus_NN of_IN the_ATI internal_JJ auditory_JJ canal_NN , the_ATI likelihood_NN that_CS useful_JJ hearing_NN will_MD be_BE preserved_VBN is_BEZ far_RB lower_JJR expanding_JJ our_PP$ understanding_NN of_IN how_WRB these_DTS and_CC other_AP preoperative_JJ findings_NNS correlate_VB with_IN treatment_NN outcome_NN should_MD be_BE a_AT high_JJ priority_NN for_IN future_NN research_NN 90_CD 33_CD advances_NNS in_IN microsurgical_JJ technique_NN , anesthesia_NN , and_CC perioperative_JJ care_NN have_HV significantly_RB reduced_VBN the_ATI morbidity_NN and_CC mortality_NN for_IN vestibular_NN schwannoma_NN surgery_NN and_CC now_RN permit_VB total_JJ removal_NN in_IN a_AT majority_NN of_IN cases_NNS excellent_JJ results_NNS have_HV been_BEN reported_VBN for_IN three_CD major_JJ surgical_JJ approaches_NNS , each_DT characterized_VBN by_IN specific_JJ advantages_NNS and_CC disadvantages_NNS hearing_VBG preservation_NN should_MD be_BE a_AT goal_NN of_IN surgery_NN when_WRB tumor_NN removal_NN can_MD be_BE achieved_VBN without_IN compromising_JJ the_ATI facial_JJ nerve_NN the_ATI middle_JJB fossa_NN approach_NN provides_VBZ good_JJ extradural_JJ exposure_NN for_IN small_JJ lesions_NNS situated_VBN in_IN the_ATI internal_JJ auditory_JJ canal_NN and_CC enables_VBZ potential_JJ hearing_VBG preservation_NN , especially_RB for_IN tumors_NNS arising_VBG from_IN the_ATI superior_JJ vestibular_NN nerve.=20_CD 91_CD 34_CD this_DT approach_NN is_BEZ less_QL suitable_JJ for_IN larger_JJR tumors_NNS with_IN intracranial_JJ extension_NN the_ATI translabyrinthine_NN approach_NN sacrifices_NNS hearing_VBG but_CC facilitates_NNS ventral_JJ exposure_NN of_IN small_JJ and_CC large_JJ tumors_NNS and_CC allows_VBZ the_ATI surgeon_NN to_TO identify_VB and_CC protect_VB the_ATI facial_JJ nerve_NN the_ATI suboccipital_JJ or_CC retrosigmoid_JJ approach_NN allows_VBZ the_ATI surgeon_NN to_TO identify_VB the_ATI brain_NN stem_NN , cranial_JJ nerves_NNS , and_CC cerebral_JJ vasculature_NN through_IN a_AT wide_JJ exposure_NN in_IN patients_NNS with_IN small_JJ tumors_NNS , this_DT approach_NN facilitates_NNS hearing_VBG preservation_NN the_ATI approach_NN also_RB is_BEZ suitable_JJ for_IN large_JJ tumors_NNS Criteria_NP for_IN the_ATI selection_NN of_IN surgical_JJ approach_NN should_MD be_BE based_VBN on_IN the_ATI training_NN , experience_NN , and_CC preference_NN of_IN the_ATI surgical_JJ team_NN ; the_ATI status_NN of_IN preoperative_JJ hearing_NN ; and_CC the_ATI location_NN and_CC size_NN of_IN the_ATI lesion_NN 92_CD 35_CD there_EX is_BEZ consensus_NN that_CS intraoperative_JJ real-time_JJ neurologic_JJ monitoring_VBG improves_VBZ the_ATI surgical_JJ management_NN of_IN vestibular_NN schwannoma_NN , including_IN the_ATI preservation_NN of_IN facial_JJ nerve_NN function_NN and_CC possibly_RB improved_JJ hearing_NN preservation_NN by_IN the_ATI use_NN of_IN intraoperative_JJ auditory_JJ brain-stem_NN response_NN monitoring_NN new_JJ approaches_NNS to_IN monitoring_VBG acoustic_JJ nerve_NN function_NN may_MD provide_VB more_QL rapid_JJ feedback_JJ to_IN the_ATI surgeon_NN , thus_RB enhancing_VBG their_PP$ usefulness_NN intraoperative_JJ monitoring_NN of_IN cranial_JJ nerves_NNS V_ZZ , VI_NP , IX_NP , X_ZZ , and_CC XI_NP also_RB has_HVZ been_BEN described_VBN , but_CC the_ATI full_JJ benefits_NNS of_IN this_DT monitoring_VBG remain_VB to_TO be_BE determined_JJ 93_CD 36_CD in_IN the_ATI majority_NN of_IN cases_NNS of_IN vestibular_NN schwannoma_NN , the_ATI treatment_NN goal_NN is_BEZ complete_JJ removal_NN of_IN the_ATI tumor_NN with_IN minimum_NN morbidity_NN and_CC mortality_NN however_RB , there_EX are_BER clinical_JJ situations_NNS where_WRB the_ATI more_QL conservative_JJ goal_NN of_IN planned_VBN subtotal_JJ resection_NN of_IN the_ATI tumor_NN may_MD be_BE indicated_VBN among_IN these_DTS are_BER patients_NNS requiring_VBG decompression_NN in_IN whom_WPOR recurrence_NN is_BEZ unlikely_JJ because_CS of_IN limited_JJ life_NN expectancy_NN and_CC patients_NNS in_IN whom_WPOR hearing_VBG preservation_NN is_BEZ of_IN importance_NN because_CS of_IN diminished_VBN function_NN of_IN the_ATI contralateral_JJ ear_NN 94_CD 37_CD the_ATI best_JJT published_VBN surgical_JJ outcomes_NNS in_IN the_ATI treatment_NN of_IN vestibular_NN schwannoma_NN are_BER from_IN medical_JJ centers_NNS that_CS have_HV highly_RB organized_VBN and_CC dedicated_JJ teams_NNS with_IN a_AT specific_JJ interest_NN in_IN these_DTS tumors_NNS and_CC sufficient_JJ continuing_NN experience_NN to_TO develop_VB , refine_VB , and_CC maintain_VB proficiency_NN comprehensive_JJ surgical_JJ treatment_NN of_IN patients_NNS with_IN vestibular_NN schwannoma_NN requires_VBZ collaboration_NN between_IN health_NN care_NN providers_NNS from_IN many_AP disciplines_NNS , including_IN neuro-otology_NN , otorhinolaryngology_NN , neurosurgery_NN , anesthesiology_NN , radiology_NN , neurology_NN , audiology_NN , nursing_NN , pathology_NN , clinical_JJ neurophysiology_NN , plastic_NN surgery_NN , ophthalmology_NN , social_JJ service_NN , and_CC rehabilitation_NN medicine_NN , in_IN addition_NN to_IN a_AT strong_JJ institutional_JJ commitment_NN and_CC support_NN for_IN intensive_JJ care_NN in_IN the_ATI postoperative_JJ period_NN teamwork_NN is_BEZ necessary_JJ for_IN both_ABX planning_NN and_CC performing_VBG the_ATI primary_JJ surgical_JJ procedure_NN and_CC recognizing_VBG and_CC managing_JJ potential_JJ intraoperative_JJ and_CC postoperative_JJ complications_NNS 95_CD 38_CD radiotherapy_NN is_BEZ a_AT treatment_NN option_NN limited_VBN in_IN current_JJ practice_NN primarily_RB to_IN patients_NNS unable_JJ or_CC unwilling_JJ to_TO undergo_VB otherwise_RB indicated_VBN surgery_NN the_ATI greatest_JJT experience_NN to_TO date_VB has_HVZ been_BEN with_IN stereotaxic_JJ radiosurgery_NN , using_VBG multisource_JJ cobalt_JJ 60_CD units_NNS for_IN single-dose_NN , external_JJ gamma_NN ray_NN therapy_NN other_AP options_NNS include_VB conventional_JJ photon_NN beam_NN therapy_NN and_CC particle_NN beam_NN therapy_NN , using_VBG either_DTX single_JJ or_CC fractionated_JJ doses_NNS early_JJ reports_NNS indicate_VB that_CS retardation_NN of_IN tumor_NN growth_NN is_BEZ observed_VBN in_IN the_ATI majority_NN of_IN patients_NNS , but_CC long- term_JJB follow-up_NN from_IN multiple_JJ centers_NNS is_BEZ not_XNOT yet_RB available_JJ fully_RB to_TO assess_VB therapeutic_JJ efficacy_NN and_CC complication_NN rates_NNS 96_CD 39_CD patient_NN follow-up_NN is_BEZ an_AT important_JJ component_NN of_IN management_NN whether_CS the_ATI primary_JJ treatment_NN is_BEZ surgery_NN , irradiation_NN , or_CC observation_NN The_NP program_NN for_IN monitoring_VBG patients_NNS includes_VBZ obtaining_VBG a_AT history_NN of_IN new_JJ findings_NNS , following_JJ the_ATI progression_NN of_IN known_JJ signs_NNS and_CC symptoms_NNS , repeated_VBN neurologic_JJ examination_NN , audiologic_JJ assessment_NN , and_CC radiographic_JJ imaging_NN follow-up_NN intervals_NNS may_MD range_VB from_IN every_AT 3_CD months_NNS initially_RB to_TO every_AT 1_CD1 to_IN 2_CD years_NNS , depending_VBG on_IN the_ATI patient's_NN$ clinical_JJ course_NN the_ATI interval_NN between_IN follow-up_NN evaluations_NNS may_MD be_BE shorter_JJR initially_RB and_CC longer_RBR with_IN the_ATI passage_NN of_IN time_NN , if_CS there_EX is_BEZ no_ATI evidence_NN of_IN recurrent_JJ disease_NN or_CC progression_NN the_ATI duration_NN of_IN patient_NN follow-up_NN may_MD be_BE lifelong_JJ , particularly_RB in_IN patients_NNS with_IN NF2_NP 97_CD 40_CD management_NN of_IN bilateral_JJ vestibular_NN schwannomas_NNS in_IN patients_NNS with_IN NF2_NP must_MD take_VB into_IN account_NN the_ATI risk_NN of_IN hearing_VBG impairment_NN in_IN both_ABX ears_NNS and_CC the_ATI disabling_JJ consequences_NNS of_IN acquired_JJ deafness_NN one_CD1 side_NN may_MD progress_VB more_QL rapidly_RB and_CC dictate_VB the_ATI need_NN and_CC priority_NN of_IN treatment_NN The_NP previous_JJ loss_NN of_IN functional_JJ hearing_NN in_IN one_CD1 ear_NN raises_VBZ additional_JJ management_NN issues_NNS for_IN treatment_NN of_IN the_ATI tumor_NN on_IN the_ATI side_NN with_IN better_JJR hearing_NN more_AP conservative_JJ approaches_NNS , such_IN as_IN subtotal_JJ intracapsular_NN resection_NN or_CC simple_JJ observation_NN of_IN the_ATI patient's_NN$ progress_NN , may_MD be_BE indicated_VBN 98_NN 41_CD rational_JJ selection_NN of_IN specific_JJ treatment_NN options_NNS is_BEZ impeded_VBN by_IN the_ATI absence_NN of_IN standardized_JJ terminology_NN in_IN the_ATI medical_JJ literature_NN in_IN future_NN reports_NNS , audiometric_JJ assessment_NN should_MD be_BE classified_VBN according_IN to_IN levels_NNS of_IN residual_JJ hearing_NN , with_IN specific_JJ objective_JJ definitions_NNS for_IN each_DT level_NN such_ABL categories_NNS might_MD include_VB mild_JJ , moderate_JJ , severe_JJ , and_CC profound_JJ hearing_NN loss_NN , as_CS determined_VBN by_IN combinations_NNS of_IN pure-tone_NN averages_NNS and_CC speech_NN recognition_NN scores_NNS imaging_VBG of_IN vestibular_NN schwannomas_NNS by_IN gadolinium-enhanced_JJ MRI_NP allows_VBZ tumors_NNS to_TO be_BE classified_VBN according_IN to_TO volume_NN and_CC tumor_NN location.=20_CD 99_CD 42_CD specific_JJ size_NN categories_NNS should_MD be_BE developed_VBN to_TO facilitate_VB comparison_NN of_IN patient_NN populations_NNS and_CC treatment_NN results_NNS facial_JJ nerve_NN function_NN should_MD be_BE reported_VBN according_IN to_IN a_AT standardized_JJ grading_NN scale_NN , such_IN as_IN the_ATI House- Brackmann_NP classification_NN system_NN more_AP sophisticated_JJ methods_NNS of_IN assessing_VBG functional_JJ speech_NN recognition_NN and_CC facial_JJ animation_NN also_RB may_MD be_BE useful_JJ in_IN monitoring_VBG outcomes_NNS and_CC evaluating_VBG management_NN options_NNS patient_NN age_NN groups_NNS should_MD also_RB be_BE standardized_VBN , with_IN numerical_JJ definition_NN of_IN specific_JJ age_NN groups_NNS studies_NNS suggest_VB that_CS three_CD or_CC more_QL age_NN groups_NNS may_MD be_BE useful_JJ 100_CD 43_CD WHAT_NPT ARE_NPT POSSIBLE_NPT ADVERSE_NPT CONSEQUENCES_NPT OF_NPT TREATMENT_NPT AND_NP WHAT_NP ARE_NPT THE_NPT MANAGEMENT_NPT OPTIONS_NPT FOR_NP EACH_NP ? 101_CD 44_CD both_ABX the_ATI vestibular_NN schwannoma_NN itself_PPL and_CC its_PP$ management_NN can_MD result_VB in_IN significant_JJ morbidity_NN requiring_VBG intensive_JJ rehabilitative_JJ (_( and_CC sometimes_RB reconstructive_JJ )_) therapy_NN it_PP3 is_BEZ therefore_RB vital_JJ that_CS the_ATI health_NN care_NN team_NN provide_VB to_IN patients_NNS and_CC their_PP$ families_NNS sufficient_JJ verbal_JJ and_CC written_JJ materials_NNS so_CS that_CS they_PP3AS have_HV realistic_JJ expectations_NNS of_IN treatment_NN outcomes_NNS when_WRB appropriate_JJ , referral_JJ to_IN a_AT former_AP patient_NN or_CC to_IN a_AT peer_NN support-information_NN group_NN can_MD be_BE most_QL helpful_JJ 102_CD 45_CD the_ATI most_AP serious_JJ perioperative_JJ complications_NNS occur_VB in_IN the_ATI first_OD 72_CD hours_NNS these_DTS include_VB air_NN embolism_NN , intracranial_JJ hemorrhage_NN , and_CC stroke_NN prompt_JJ recognition_NN by_IN the_ATI operative_JJ team_NN can_MD result_VB in_IN decreased_VBD mortality_NN and_CC morbidity_NN cerebrospinal_JJ fluid_NN leak_NN and_CC meningitis_NN can_MD occur_VB in_IN a_AT delayed_JJ fashion_NN and_CC also_RB require_VB immediate_JJ therapy_NN 103_CD 46_CD loss_NN of_IN hearing_VBG in_IN the_ATI operated-on_NN ear_NN is_BEZ the_ATI most_QL common_JJ adverse_JJ consequence_NN and_CC can_MD be_BE a_AT serious_JJ handicap_NN these_DTS patients_NNS have_HV difficulty_NN hearing_VBG in_IN even_RB modestly_RB noisy_JJ environments_NNS and_CC do_DO not_XNOT have_HV directional_JJ hearing_NN young_JJ children_NNS are_BER at_IN an_AT educational_JJ disadvantage_NN There_NP are_BER a_AT number_NN of_IN devices_NNS that_DT can_MD be_BE used_VBN to_TO allow_VB for_IN partial_JJ compensation_NN to_TO make_VB the_ATI acoustic_JJ signal_NN louder_JJR than_IN the_ATI background_NN noise_NN or_CC bring_VB sound_NN from_IN the_ATI impaired_VBN ear_NN to_IN the_ATI hearing_NN ear_NN these_DTS devices_NNS can_MD be_BE used_VBN by_IN both_ABX children_NNS and_CC adults_NNS 104_CD 47_CD total_JJ loss_NN of_IN hearing_VBG occurs_VBZ in_IN many_AP patients_NNS with_IN NF2_NP and_CC in_IN a_AT small_JJ number_NN of_IN patients_NNS with_IN unilateral_JJ tumors_NNS who_WPR have_HV had_HVD hearing_VBG loss_NN in_IN the_ATI nontumor_NN ear_NN from_IN other_AP causes_NNS these_DTS are_BER among_IN the_ATI most_QL seriously_RB handicapped_JJ of_IN all_ABN patients_NNS there_EX are_BER a_AT number_NN of_IN rehabilitation_NN strategies_NNS that_DT can_MD be_BE used_VBN to_TO restore_VB communication_NN Many_NP of_IN these_DTS are_BER visually_RB based_VBN , such_IN as_IN lipreading_VBG (_( speech_NN )_) , use_NN of_IN captions_NNS , or_CC sign_NN language_NN sign_NN language_NN would_MD be_BE more_QL useful_JJ if_CS families_NNS were_BED also_RB instructed_VBN patients_NNS with_IN visual_JJ defects_NNS , common_NN in_IN NF2_NP , will_MD have_HV added_VBN difficulty_NN in_IN visual_JJ communication_NN modes_NNS tactile_JJ systems_NNS are_BER somewhat_RB effective_JJ for_IN the_ATI deaf- blind_NN 105_CD 48_CD electroprostheses_NNS are_BER being_BEG developed_VBN and_CC may_MD be_BE of_IN potential_JJ benefit_NN in_IN selected_JJ patients_NNS with_IN postlingual_JJ total_JJ deafness_NN , secondary_JJ to_IN loss_NN of_IN both_ABX statoacoustic_JJ nerves_NNS 106_CD 49_CD abnormal_JJ vestibular_NN function_NN occurs_VBZ in_IN almost_RB all_ABN patients_NNS Unilateral_NP loss_NN for_IN usual_JJ life_NN situations_NNS has_HVZ little_JJ morbidity_NN and_CC is_BEZ compensated_VBD rapidly_RB vestibular_NN dysfunction_NN becomes_VBZ significant_JJ when_WRB it_PP3 is_BEZ bilateral_JJ or_CC occurs_VBZ in_IN conjunction_NN with_IN other_AP central_JJ nervous_JJ system_NN or_CC sensory_JJ impairment_NN patients_NNS with_IN bilateral_JJ vestibular_NN dysfunction_NN are_BER at_IN increased_JJ risk_NN for_IN drowning_NN when_WRB swimming_NN , diving_JJ , or_CC even_RB bathing_NN 107_CD 50_CD one_CD1 distressing_JJ complication_NN of_IN surgery_NN is_BEZ disfiguring_VBG facial_JJ nerve_NN weakness_NN or_CC paralysis_NN , with_IN consequent_JJ physical_JJ , emotional_JJ , psychosocial_JJ , and_CC possibly_RB professional_JJ dysfunction_NN treatment_NN approaches_NNS to_TO _** reanimation_JJ _** of_IN the_ATI face_NN include_VB surgery_NN (_( muscle_NN or_CC nerve_NN grafting_VBG or_CC rerouting_VBG )_) and_CC physical_JJ and_CC occupational_JJ therapy_NN (_( exercise_NN , biofeedback_NN )_) as_CS yet_RB , none_PN of_IN these_DTS can_MD restore_VB normal_JJ function_NN and_CC appearance_NN strong_JJ support_NN from_IN family_NN , friends_NNS , the_ATI health_NN care_NN team_NN , and_CC patient_NN advocacy-support_NN groups_NNS is_BEZ needed_VBN 108_CD 51_CD when_WRB complete_JJ closure_NN of_IN the_ATI eye_NN is_BEZ compromised_VBN , dryness_NN , irritation_NN , excessive_JJ tearing_NN , blurred_JJ vision_NN , corneal_JJ abrasions_NNS , ectropion_NN , entropion_NN , and_CC loss_NN of_IN vision_NN can_MD occur_VB surgical_JJ reanimation_NN techniques_NNS can_MD restore_VB nearly_RB normal_JJ function_NN other_AP cranial_JJ nerves_NNS can_MD be_BE involved_VBN , but_CC the_ATI particular_JJ combination_NN of_IN the_ATI fifth_OD and_CC seventh_OD nerves_NNS places_VBZ the_ATI cornea_NN at_IN greater_JJR risk_NN and_CC must_MD be_BE treated_VBN vigorously_RB The_NP combined_JJ involvement_NN of_IN 9th_OD , 10th_OD , and_CC 12th_OD nerves_NNS creates_VBZ difficulty_NN swallowing_NN and_CC places_VBZ the_ATI patient_NN at_IN risk_NN for_IN aspiration_NN 109_CD 52_CD headache_NN may_MD be_BE a_AT common_JJ and_CC often_RB debilitating_JJ complication_NN of_IN surgery_NN its_PP$ intensity_NN can_MD range_VB from_IN moderate_JJ to_TO excruciatingly_VB severe_JJ , and_CC while_CS most_QL headaches_NNS eventually_RB resolve_NN , they_PP3AS can_MD last_AP for_IN months_NNS and_CC sometimes_RB years_NNS evaluation_NN of_IN the_ATI true_JJ incidence_NN of_IN postoperative_JJ headache_NN , its_PP$ etiology_NN , and_CC possible_JJ treatment_NN are_BER needed_VBN 110_CD 53_CD recurrence_NN can_MD occur_VB in_IN cases_NNS where_WRB tumors_NNS were_BED apparently_RB either_DTX totally_RB or_CC partially_RB removed_VBN ; thus_RB , all_ABN cases_NNS need_NN to_TO be_BE followed_VBN up_RP by_IN imaging_NN those_DTS that_CS have_HV recurred_VBD may_MD be_BE managed_VBN by_IN either_DTX reoperation_NN or_CC stereotaxic_JJ or_CC fractionated_JJ irradiation_NN the_ATI results_NNS are_BER modestly_RB satisfactory_JJ for_IN surgery_NN and_CC marginally_RB satisfactory_JJ for_IN fractionated_JJ radiotherapy_NN 111_CD 54_CD complications_NNS of_IN irradiation_NN occur_VB late_JJ as_CS opposed_VBN to_IN the_ATI immediate_JJ complications_NNS of_IN surgery_NN stereotaxic_JJ radiosurgery_NN , a_AT newer_JJR modality_NN , has_HVZ the_ATI benefit_NN of_IN a_AT low_JJ early_JJ complication_NN rate_NN , but_CC it_PP3 has_HVZ unknown_JJ long-term_JJB complications_NNS the_ATI limited_JJ data_NNS available_JJ indicate_VB that_CS there_EX is_BEZ a_AT high_JJ rate_NN of_IN hearing_VBG loss_NN within_IN 1_CD1 year_NN after_IN therapy_NN There_NP may_MD be_BE delayed_VBN transient_JJ dysfunction_NN of_IN the_ATI fifth_OD and_CC seventh_OD cranial_JJ nerves_NNS comparison_NN of_IN the_ATI complication_NN rate_NN with_IN surgical_JJ techniques_NNS cannot_NN be_BE done_VBN until_CS there_EX are_BER proper_JJ long- term_JJB data_NNS available_JJ if_CS surgery_NN is_BEZ required_VBN after_IN radiotherapy_NN , it_PP3 may_MD be_BE more_QL difficult_JJ and_CC complication_NN prone_JJ 112_CD 55_CD the_ATI emotional_JJ and_CC interpersonal_JJ consequences_NNS of_IN vestibular_NN schwannoma_NN on_IN the_ATI patient_NN and_CC family_NN must_MD be_BE anticipated_VBN appropriate_JJ and_CC early_JJ intervention_NN must_MD be_BE made_VBN by_IN a_AT team_NN of_IN professionals_NNS and_CC must_MD include_VB advance_NN preparation_NN of_IN the_ATI patient_NN and_CC family_NN , emotional_JJ support_NN , aggressive_JJ physical_JJ and_CC rehabilitative_JJ therapy_NN , and_CC a_AT carefully_RB coordinated_JJ program_NN of_IN follow-up_NN focusing_VBG on_IN medical_JJ and_CC psychosocial_JJ needs_NNS the_ATI support_NN team_NN should_MD consist_VB of_IN physicians_NNS , audiologists_NNS , nurses_NNS , social_JJ workers_NNS , physical_JJ and_CC occupational_JJ therapists_NNS , and_CC behavioral_JJ counselors_NNS 113_CD 56_CD many_AP complications_NNS would_MD be_BE deemed_VBN far_RB less_QL problematic_JJ , certainly_RB less_QL devastating_JJ , if_CS patient_NN needs_NNS and_CC expectations_NNS were_BED addressed_VBN preoperatively_RB with_IN precise_JJ knowledge_NN of_IN possibilities_NNS for_IN the_ATI future_NN the_ATI patients_NNS should_MD be_BE educated_JJ to_IN the_ATI degree_NN that_CS they_PP3AS understand_VB the_ATI decision_NN they_PP3AS must_MD ultimately_RB make_VB and_CC any_DTI potential_JJ consequences_NNS they_PP3AS will_MD face_VB in_IN accordance_NN with_IN that_DT decision_NN this_DT may_MD include_VB referral_JJ to_IN specialized_JJ facilities_NNS that_CS deal_NN with_IN their_PP$ particular_JJ problem_NN complete_JJ and_CC realistic_JJ written_VBN and_CC audiovisual_JJ information_NN should_MD be_BE presented_VBN at_IN the_ATI time_NN of_IN diagnosis_NN , hospitalization_NN and_CC operation_NN , discharge_NN , and_CC follow-up_NN referral_JJ should_MD be_BE made_VBN to_TO peer_VB support_NN groups_NNS and_or_CC positive_JJ former_AP patients_NNS early_RB in_IN the_ATI process_NN 114_CD fear_NN of_IN the_ATI unknown_JJ exacerbates_NNS any_DTI threatening_JJ situation_NN the_ATI more_AP knowledge_NN imparted_VBN to_IN patients_NNS , the_ATI more_QL they_PP3AS participate_VB in_IN a_AT decision_NN , the_ATI better_JJR they_PP3AS will_MD be_BE able_JJ to_TO live_VB with_IN any_DTI possible_JJ aftereffects_NNS 115_CD WHAT_NPT ARE_NPT APPROPRIATE_NPT AREAS_NPT FOR_NPT FUTURE_NP RESEARCH_NP ? 116_CD two_CD recent_JJ advances_NNS , the_ATI development_NN of_IN gadolinium- enhanced_JJ MRI_NP and_CC the_ATI mapping_NN of_IN the_ATI gene_NN for_IN NF2_NP , have_HV opened_VBN major_JJ new_JJ areas_NNS of_IN needed_VBN research_NN 117_CD the_ATI ability_NN to_TO diagnose_VB vestibular_NN schwannoma_NN with_IN unprecedented_JJ accuracy_NN and_CC to_TO recognize_VB much_RB smaller_JJR tumors_NNS has_HVZ enhanced_VBN dramatically_RB the_ATI potential_JJ for_IN the_ATI preservation_NN of_IN hearing_NN there_EX is_BEZ an_AT urgent_JJ need_NN for_IN the_ATI development_NN of_IN protocols_NNS to_TO collect_VB carefully_RB standardized_VBN preoperative_JJ and_CC postoperative_JJ data_NNS on_IN unbiased_JJ patient_NN samples_NNS so_CS that_CS the_ATI influence_NN of_IN relevant_JJ variables_NNS on_IN treatment_NN outcomes_NNS can_MD be_BE objectively_RB assessed_VBN 118_CD the_ATI establishment_NN of_IN an_AT international_JJ vestibular_NN schwannoma_NN registry_NN also_RB could_MD yield_VB valuable_JJ epidemiologic_JJ and_CC demographic_JJ data_NNS on_IN the_ATI distribution_NN of_IN the_ATI disease_NN this_DT could_MD provide_VB the_ATI basis_NN for_IN studies_NNS of_IN diagnostic_JJ method_NN , treatment_NN and_CC rehabilitative_JJ modalities_NNS , and_CC complication_NN rates_NNS , and_CC for_IN case-control_JJ studies_NNS of_IN possible_JJ environmental_JJ factors_NNS that_DT might_MD influence_VB tumor_VB development_NN 119_CD now_RN that_CS the_ATI chromosomal_JJ location_NN of_IN the_ATI NF2_NP gene_NN has_HVZ been_BEN determined_JJ , its_PP$ successful_JJ cloning_NN can_MD be_BE anticipated_VBN in_IN the_ATI near_IN future_NN this_DT achievement_NN may_MD provide_VB immediate_JJ insight_NN into_IN the_ATI pathogenesis_NN of_IN the_ATI disease_NN , the_ATI extent_NN of_IN the_ATI genetic_JJ heterogeneity_NN that_CS exists_VBZ among_IN families_NNS , and_CC the_ATI cause_NN for_IN the_ATI associated_JJ findings_NNS in_IN NF2_NP these_DTS studies_NNS would_MD be_BE greatly_RB facilitated_VBN by_IN the_ATI establishment_NN of_IN a_AT cell_NN repository_NN and_CC tissue_NN bank_NN 120_CD there_EX also_RB is_BEZ an_AT urgent_JJ need_NN for_IN careful_JJ longitudinal_JJ studies_NNS of_IN families_NNS with_IN NF2_NP to_TO document_NN the_ATI natural_JJ history_NN of_IN the_ATI disease_NN little_JJ is_BEZ known_VBN about_IN the_ATI control_NN of_IN Schwann_NP cell_NN growth_NN in_IN humans_NNS and_CC the_ATI factors_NNS that_DT may_MD contribute_VB to_IN formation_NN of_IN vestibular_NN schwannomas_NNS Research_NP to_TO define_VB the_ATI specific_JJ factors_NNS that_CS control_NN growth_NN could_MD have_HV important_JJ therapeutic_JJ implications_NNS for_IN example_NN , evidence_NN suggests_VBZ that_CS angiogenic_JJ factors_NNS may_MD play_VB a_AT role_NN in_IN tumor_NN growth_NN , and_CC their_PP$ pharmacologic_JJ inhibition_NN could_MD provide_VB an_AT exciting_JJ approach_NN to_TO treatment_NN of_IN this_DT disease_NN the_ATI evidence_NN that_CS hormones_NNS influence_VB the_ATI growth_NN of_IN schwannomas_NNS is_BEZ inconclusive.=20_CD 121_CD because_CS the_ATI target_NN is_BEZ so_PN small_JJ , vestibular_JJB schwannoma_NN conceivably_RB could_MD become_VB a_AT candidate_NN for_IN somatic_JJ gene_NN therapy_NN other_AP approaches_NNS to_TO the_ATI control_NN of_IN tumor_NN growth_NN by_IN the_ATI manipulation_NN of_IN specific_JJ growth_NN factors_NNS would_MD be_BE greatly_RB enhanced_VBN by_IN the_ATI availability_NN of_IN cells_NNS from_IN schwannomas_NNS and_CC from_IN normal_JJ human_JJ nerves_NNS to_TO study_VB the_ATI growth_NN of_IN Schwann_NP cells_NNS in_IN vitro_NN finally_RB , the_ATI cloning_NN of_IN the_ATI gene_NN for_IN NF2_NP could_MD ultimately_RB lead_NN to_IN the_ATI development_NN of_IN animal_JJ models_NNS of_IN the_ATI disease_NN in_IN transgenic_JJ mice_NNS 122_CD RECOMMENDATIONS_NP 123_CD future_NN activities_NNS and_CC research_NN efforts_NNS should_MD include_VB establishment_NN of_IN a_AT registry_NN for_IN all_ABN patients_NNS with_IN vestibular_NN schwannoma_NN , including_IN those_DTS undergoing_VBG observation_NN rather_RB than_IN active_JJ treatment_NN ; descriptive_JJ and_CC analytic_JJ epidemiologic_JJ studies_NNS targeting_VBG potential_JJ environmental_JJ causes_NNS of_IN vestibular_NN schwannoma_NN ; development_NN of_IN a_AT tissue_NN repository_NN and_CC greater_JJR use_NN of_IN cell_NN cultures_NNS and_CC animal_NN models_NNS for_IN studies_NNS of_IN the_ATI factors_NNS that_CS influence_NN tumor_NN growth_NN ; 124_CD refinement_NN of_IN surgical_JJ techniques_NNS with_IN a_AT focus_NN on_IN lowering_VBG morbidity_NN ; improved_JJ communication_NN between_IN health_NN care_NN providers_NNS , patient_NN advocate_NN groups_NNS , and_CC patients_NNS about_IN diagnosis_NN , treatment_NN options_NNS , prognosis_NN , side_NN effects_NNS , and_CC available_JJ support_NN ; improved_JJ documentation_NN of_IN long-term_JJB outcome_NN in_IN relation_NN to_TO treatment_NN modality_NN ; and_CC increased_VBN research_NN on_IN and_CC reimbursement_NN for_IN rehabilitation_NN , that_CS involves_VBZ hearing_VBG deficits_NNS , facial_JJ nerve_NN dysfunction_NN , eye_NN disorders_NNS , and_CC the_ATI psychological_JJ impact_NN of_IN vestibular_NN schwannoma_NN 125_CD estrogen_NN Replacement_NPT Therapy_NPT In_NPT Breast_NPT Cancer_NP Survivors_NP : a_AT Time_NP for_IN Change_NP 126_CD postmenopausal_JJ women_NNS often_RB experience_NN annoying_JJ and_CC sometimes_RB debilitating_JJ menopausal_JJ symptoms_NNS , and_CC breast_NN cancer_NN survivors_NNS are_BER no_ATI exception_NN hot_JJ flashes_NNS , dyspareunia_NN , atrophic_JJ vaginitis_NN with_IN attendant_JJ urinary_NN tract_NN symptoms_NNS , sleep_NN disturbance_NN , and_CC mood_NN change_NN are_BER among_IN these_DTS symptoms_NNS coronary_JJ artery_NN disease_NN and_CC osteoporosis_NN may_MD be_BE more_QL insidious_JJ , but_CC potentially_RB fatal_JJ consequences_NNS of_IN menopausal_JJ estrogen_NN decline_NN estrogen_NN replacement_NN therapy_NN (_( ERT_NP )_) has_HVZ been_BEN shown_VBN to_TO ameliorate_VB these_DTS problems_NNS , and_CC as_CS informed_JJ consumers_NNS , breast_NN cancer_NN survivors_NNS are_BER increasingly_RB inquiring_JJ about_IN and_or_CC requesting_VBG ERT_NP 127_CD there_EX are_BER more_AP breast_NN cancer_NN survivors_NNS alive_JJ now_RN than_IN ever_RB before_CS , so_QL their_PP$ nononcologic_JJ health_NN problems_NNS are_BER a_AT growing_JJ concern_NN a_AT dramatic_JJ rise_NN in_IN the_ATI incidence_NN rates_NNS of_IN breast_NN cancer_NN occurred_VBD in_IN the_ATI United_NP States_NP between_IN 1982_CD and_CC 1987_CD , presumably_RB because_CS of_IN increased_JJ screening_NN the_ATI incidence_NN of_IN noninvasive_JJ and_CC of_IN small_JJ , invasive_JJ , axillary_JJB node-negative_JJ breast_NN cancers_NNS rose_VBD concurrently_RB five-year_JJB survival_NN rates_NNS for_IN breast_NN cancer_NN patients_NNS also_RB have_HV been_BEN rising_VBG since_IN 1979_CD 128_CD ERT_NP is_BEZ increasingly_RB prescribed_VBN for_IN menopausal_JJ women_NNS the_ATI magnitude_NN of_IN the_ATI reduction_NN of_IN coronary_JJ heart_NN disease_NN reported_VBN in_IN ERT_NP users_NNS who_WPR undergo_VB natural_JJ menopause_NN is_BEZ large_JJ and_CC in_IN general_JJ ranges_NNS from_IN 30%_NP to_IN 70%_NP likewise_RB , bone_NN mineral_NN density_NN is_BEZ maintained_VBN in_IN women_NNS receiving_VBG ERT_NP , and_CC reduction_NN in_IN the_ATI rate_NN of_IN subsequent_JJ fracture_NN in_IN ERT_NP users_NNS has_HVZ been_BEN reported_VBN to_TO range_VB from_IN 30%_NP to_IN 60%_NP 129_CD the_ATI prohibition_NN of_IN ERT_NP may_MD diminish_VB quality_NN of_IN life_NN in_IN breast_NN cancer_NN survivors_NNS furthermore_RB , it_PP3 is_BEZ possible_JJ that_CS the_ATI prohibition_NN of_IN ERT_NP could_MD reduce_VB overall_JJB survival_NN in_IN such_ABL women_NNS by_IN leaving_VBG them_PP3OS at_IN increased_JJ risk_NN of_IN coronary_JJ heart_NN disease_NN and_CC osteoporotic_JJ fracture_NN 130_CD of_IN greater_JJR concern_NN is_BEZ the_ATI precipitation_NN of_IN premature_JJ menopause_NN in_IN women_NNS treated_VBN for_IN breast_NN cancer_NN along_RP with_IN the_ATI increasing_JJ incidence_NN of_IN small_JJ , prognostically_RB favorable_&FW cancers_NNS , the_ATI indications_NNS for_IN adjuvant_NN therapy_NN have_HV expanded_VBN in_IN 1989_CD , the_ATI results_NNS of_IN four_CD major_JJ , prospective_JJ , randomized_VBN clinical_JJ trials_NNS were_BED published_VBN they_PP3AS compared_VBD treatment_NN with_IN no_ATI treatment_NN and_CC documented_VBN the_ATI benefit_NN of_IN adjuvant_NN therapy_NN in_IN women_NNS with_IN node-negative_JJ , invasive_JJ breast_NN cancers_NNS larger_JJR than_IN 1_CD1 cm_NNU sup_VB 6-9_NN Chemotherapy_NP was_BEDZ the_ATI intervention_NN used_VBN in_IN three_CD of_IN the_ATI studies_NNS since_CS then_RN , chemotherapy_NN is_BEZ increasingly_RB prescribed_VBN for_IN this_DT favorable_&FW subset_JJ of_IN breast_NN cancer_NN patients_NNS 131_CD adjuvant_NN chemotherapy_NN causes_NNS premature_JJ ovarian_NN failure_NN the_ATI incidence_NN of_IN amenorrhea_NN is_BEZ age_NN and_CC drug_NN dependent_JJ for_IN CMF_NP , the_ATI combination_NN of_IN cyclophosphamide_NN , methotrexate_NN , and_CC fluorouracil_NN , the_ATI most_QL commonly_RB prescribed_JJ adjuvant_NN chemotherapy_NN regimen_NNS for_IN breast_NN cancer_NN , amenorrhea_NN occurs_VBZ in_IN 53%_CD of_IN women_NNS younger_JJR than_IN 35_CD years_NNS , in_IN 84%_JJ of_IN those_DTS aged_JJ 35_CD through_IN 44_CD years_NNS , and_CC in_IN 94%_NN of_IN those_DTS aged_JJ 45_CD years_NNS or_CC more_QL among_IN those_DTS who_WPR experience_NN amenorrhea_NN , ovarian_NN failure_NN is_BEZ permanent_JJ in_IN 86%_NN of_IN women_NNS younger_JJR than_IN 40_CD years_NNS and_CC in_IN 96%_NN of_IN women_NNS 40_CD years_NNS of_IN age_NN or_CC older_JJR 132_CD this_DT is_BEZ of_IN concern_NN , since_CS most_QL studies_NNS that_CS have_HV examined_VBN the_ATI role_NN of_IN premature_JJ menopause_NN on_IN coronary_JJ heart_NN disease_NN have_HV found_VBN an_AT increased_VBN risk_NN in_IN women_NNS with_IN early_JJ menopause_NN evidence_NN that_CS ERT_NP can_MD reduce_VB this_DT effect_NN of_IN early_JJ menopause_NN comes_VBZ from_IN the_ATI Harvard_NP Nurses'_NNS$ Health_NP Study_NP , where_WRB nurses_NNS who_WPR underwent_JJ surgical_JJ menopause_NN and_CC received_VBD ERT_NP had_HVD a_AT significantly_RB lower_JJR risk_NN of_IN cardiovascular_NN disease_NN compared_VBN with_IN those_DTS who_WPR underwent_JJ surgical_JJ menopause_NN and_CC did_DOD not_XNOT receive_VB ERT_NP the_ATI age-adjusted_JJ relative_JJ risk_NN of_IN major_JJ coronary_JJ disease_NN for_IN ERT_NP users_NNS was_BEDZ 0.40_CD (_( 95%_NN confidence_NN interval_NN , 0.22_NP to_IN 0.73_NP )_) 133_CD death_NN from_IN nonneoplastic_JJ conditions_NNS is_BEZ common_JJ among_IN node- negative_JJ breast_NN cancer_NN survivors_NNS cardiovascular_NN disease_NN is_BEZ the_ATI most_QL common_JJ nonneoplastic_JJ cause_NN these_DTS data_NNS are_BER derived_VBN from_IN patients_NNS who_WPR did_DOD not_XNOT receive_VB chemotherapy_NN and_CC thus_RB did_DOD not_XNOT undergo_VB premature_JJ menopause_NN as_CS more_AP node-negative_JJ women_NNS receive_VB adjuvant_NN chemotherapy_NN , the_ATI possibility_NN exists_VBZ that_CS early_JJ chemotherapy- mediated_JJ gains_NNS in_IN survival_NN from_IN breast_NN cancer_NN may_MD be_BE overshadowed_VBN by_IN higher_JJR mortality_NN from_IN cardiovascular_NN and_CC osteoporotic_JJ events_NNS later_RBR on_RP that_DT is_BEZ , women_NNS may_MD survive_VB their_PP$ breast_NN cancers_NNS , only_RB to_TO succumb_VB to_IN these_DTS other_AP more_QL common_JJ , but_CC delayable_JJ afflictions_NNS 134_CD concern_NN for_IN quality_NN of_IN life_NN as_IN well_RB as_IN longevity_NN in_IN our_PP$ patients_NNS justifies_VBZ a_AT trial_NN of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS members_NNS of_IN the_ATI Breast_NPT Cancer_NP Committees_NP of_IN the_ATI Eastern_NPT Cooperative_NPT Oncology_NP Group_NP have_HV been_BEN struggling_JJ with_IN the_ATI subject_NN of_IN ERT_NP for_IN 4_CD years_NNS here_RN we_PP1AS address_VB the_ATI issue_NN for_IN the_ATI breast_NN cancer_NN survivors_NNS of_IN the_ATI future_NN 135_CD we_PP1AS have_HV performed_VBN a_AT literature_NN review_NN of_IN MEDLINE_NP and_CC CANCERLINE_NP (_( CancerLit_NP )_) through_IN the_ATI National_NP Library_NPL of_IN Medicine_NP the_ATI search_NN included_VBN Medical_NPT Subject_NP Heading_NP (_( MESH_NP )_) terms_NNS such_IN as_IN estrogen_NN replacement_NN therapy_NN , breast_NN neoplasms_NNS , mammography_NN , and_CC tamoxifen_NN Further_NP references_NNS were_BED retrieved_VBD from_IN bibliographies_NNS of_IN manuscripts_NNS abstracted_VBN from_IN the_ATI search_NN of_IN these_DTS on-line_NN databases_NNS 136_CD the_ATI Standard_NP of_IN Care_NP 137_CD the_ATI standard_NN of_IN care_NN in_IN the_ATI United_NP States_NP is_BEZ to_TO discourage_VB prescription_NN of_IN ERT_NP to_TO breast_NN cancer_NN survivors_NNS although_CS there_EX are_BER theoretical_JJ justifications_NNS for_IN this_DT position_NN , the_ATI limited_JJ number_NN of_IN studies_NNS offer_VB little_JJ support_NN for_IN such_ABL concern_NN (_( vide_&FW infra_NN )_) this_DT lack_NN of_IN study_NN is_BEZ not_XNOT because_CS of_IN indifference_NN ; physicians_NNS are_BER increasingly_RB calling_VBG for_IN clinical_JJ trials_NNS , and_CC some_DTI have_HV published_JJ guidelines_NNS for_IN administration_NN of_IN ERT_NP to_TO breast_NN cancer_NN survivors_NNS further_JJB , we_PP1AS know_NN of_IN many_AP clinicians_NNS who_WPR will_MD treat_VB breast_NN cancer_NN survivors_NNS with_IN ERT_NP in_IN the_ATI absence_NN of_IN evidence_NN showing_VBG a_AT harmful_JJ effect_NN a_AT distinguished_JJ investigator_NN has_HVZ stated_VBN , _** It_NP is_BEZ no_RB longer_RBR justifiable_JJ to_TO deprive_VB those_DTS women_NNS who_WPR have_HV received_JJ treatment_NN for_IN breast_NN cancer_NN of_IN hormonal_JJ treatment_NN which_WDTR can_MD relieve_VB symptoms_NNS which_WDTR are_BER making_VBG their_PP$ lives_NNS intolerable_JJ _** nonetheless_RB , practicing_VBG physicians_NNS who_WPR treat_VB breast_NN cancer_NN survivors_NNS currently_RB have_HV no_ATI official_JJ justification_NN to_TO offer_VB ERT_NP to_IN their_PP$ patients_NNS , as_IN the_ATI opinions_NNS of_IN many_AP professional_JJ societies_NNS are_BER either_DTX ambiguous_JJ or_CC opposed_VBN to_TO such_ABL treatment_NN 138_CD the_ATI American_JNP College_NPL of_IN Physicians_NP has_HVZ recently_RB published_VBN guidelines_NNS for_IN counseling_VBG postmenopausal_JJ women_NNS about_IN preventive_JJ hormone_NN therapy_NN they_PP3AS support_NN ERT_NP in_IN women_NNS with_IN or_CC at_IN increased_JJ risk_NN for_IN coronary_JJ heart_NN disease_NN they_PP3AS speculate_VB that_CS the_ATI risks_NNS of_IN ERT_NP in_IN women_NNS who_WPR are_BER at_IN increased_JJ risk_NN for_IN breast_NN cancer_NN might_MD outweigh_VB its_PP$ benefits_NNS For_NP other_AP women_NNS , the_ATI best_JJT course_NN of_IN action_NN is_BEZ unclear_JJ , but_CC they_PP3AS suggest_VB describing_VBG the_ATI probable_JJ risks_NNS and_CC benefits_NNS of_IN ERT_NP 139_CD the_ATI American_JNP College_NPL of_IN Obstetricians_NNS and_CC Gynecologists_NNS supports_VBZ the_ATI use_NN of_IN ERT_NP in_IN postmenopausal_JJ women_NNS but_CC considers_VBZ breast_NN cancer_NN a_AT contraindication_NN the_ATI American_JNP College_NPL of_IN Cardiology_NP has_HVZ no_ATI official_JJ policy_NN regarding_IN ERT_NP , nor_CC does_DOZ the_ATI Endocrine_NP Society_NP 140_CD ERT_NP and_CC Mammographic_NP Detection_NN of_IN Breast_NP Cancer_NP 141_CD ERT_NP can_MD increase_VB breast_NN density_NN and_CC thus_RB potentially_RB delay_NN diagnosis_NN of_IN breast_NN cancer_NN unfortunately_RB , the_ATI literature_NN on_IN the_ATI subject_NN is_BEZ limited_JJ most_AP studies_NNS were_BED retrospective_JJ the_ATI duration_NN and_CC type_NN of_IN ERT_NP varied_JJ , and_CC baseline_NN studies_NNS were_BED often_RB unavailable_JJ radiologists_NNS were_BED not_XNOT blinded_VBN as_CS to_IN the_ATI ERT_NP status_NN of_IN the_ATI patients_NNS technique_NN varied_JJ ; some_DTI women_NNS underwent_JJ radiographic_JJ screening_NN , others_APS xeromammography_NN 142_CD ERT_NP probably_RB causes_VBZ increased_VBN parenchymal_JJ density_NN in_IN a_AT minority_NN of_IN women_NNS parenchymal_JJ density_NN was_BEDZ increased_VBN in_IN 17%_CD of_IN 30_CD women_NNS in_IN one_CD1 study_NN and_CC in_IN 24%_NN of_IN 50_CD in_IN another_DT increased_VBN parenchymal_JJ density_NN has_HVZ not_XNOT been_BEN uniformly_RB observed_VBN a_AT matched_JJ cohort_NN study_NN of_IN 405_NP women_NNS who_WPR underwent_NN screening_NN xeromammography_NN demonstrated_VBN no_ATI increase_NN in_IN breast_NN density_NN among_IN ERT_NP users_NNS 143_CD there_EX is_BEZ conflicting_JJ information_NN on_IN duration_NN of_IN ERT_NP and_CC parenchymal_JJ patterns_NNS significant_JJ differences_NNS in_IN the_ATI proportion_NN of_IN high-risk_NN and_CC low-risk_JJ parenchymal_JJ patterns_NNS were_BED not_XNOT observed_VBN as_IN the_ATI duration_NN of_IN ERT_NP increased_VBN in_IN one_CD1 study_NN however_RB , duration_NN of_IN ERT_NP did_DOD matter_NN in_IN another_DT high-risk_NN patterns_NNS were_BED observed_VBN significantly_RB more_QL often_RB among_IN 194_CD women_NNS who_WPR had_HVD taken_VBN ERT_NP for_IN more_AP than_IN 5_CD years_NNS compared_VBN with_IN 216_CD nonusers_NNS 144_CD clearly_RB , any_DTI clinical_JJ trial_NN evaluating_VBG ERT_NP in_IN breast_NN cancer_NN survivors_NNS must_MD include_VB a_AT controlled_JJ study_NN of_IN mammographic_JJ parenchymal_JJ changes_NNS mammography_NN before_CS and_CC after_IN treatment_NN evaluated_VBN by_IN an_AT observer_NN blinded_VBD to_IN the_ATI assigned_JJ treatment_NN (_( placebo_NN vs_IN ERT_NP )_) would_MD provide_VB valuable_JJ prospective_JJ information_NN 145_CD ERT_NP and_CC Second_NPT Breast_NP Cancers_NP 146_CD concern_NN over_IN ERT-induced_NP new_JJ breast_NN cancers_NNS must_MD be_BE addressed_VBN in_IN any_DTI trial_NN of_IN ERT_NP for_IN breast_NN cancer_NN survivors_NNS a_AT personal_JJ history_NN of_IN breast_NN cancer_NN is_BEZ a_AT strong_JJ risk_NN factor_NN for_IN subsequent_JJ development_NN of_IN primary_JJ breast_NN cancers_NNS the_ATI annual_JJ incidence_NN of_IN new_JJ primary_JJ breast_NN cancers_NNS among_IN breast_NN cancer_NN survivors_NNS is_BEZ 14_CD per_NNU 1000_CD women_NNS , compared_VBD with_IN an_AT incidence_NN of_IN two_CD per_NNU 1000_CD women_NNS in_IN the_ATI general_JJ population_NN 147_CD the_ATI association_NN between_IN ERT_NP and_CC risk_NN of_IN breast_NN cancer_NN remains_VBZ controversial_JJ , although_CS 24_CD studies_NNS and_CC three_CD meta-analyses_NNS have_HV been_BEN published_VBN since_IN 1980_CD (_( Table_NP 1_CD1 )_) collectively_RB , the_ATI studies_NNS do_DO not_XNOT consistently_RB demonstrate_VB an_AT increased_JJ risk_NN of_IN breast_NN cancer_NN among_IN women_NNS who_WPR have_HV ever_RB used_VBN ERT_NP studies_NNS that_CS controlled_VBN for_IN screening_NN showed_VBD no_ATI difference_NN in_IN relative_JJ risk_NN between_IN cases_NNS and_CC controls_NNS this_DT suggests_VBZ that_CS there_EX may_MD be_BE a_AT detection_NN bias_NN operating_VBG in_IN some_DTI studies_NNS that_CS have_HV reported_VBN an_AT increased_JJ risk_NN of_IN breast_NN cancer_NN among_IN ERT_NP users_NNS Importantly_NP , use_NN of_IN low-dose_NN (_( 0.625_NP mg_d_NN )_) conjugated_VBN ERT_NP for_IN several_AP years_NNS did_DOD not_XNOT appreciably_RB increase_VB the_ATI risk_NN of_IN breast_NN cancer_NN 148_CD although_CS having_HVG ever_RB used_VBN ERT_NP does_DOZ not_XNOT appear_VB to_TO substantially_RB increase_VB the_ATI risk_NN of_IN breast_NN cancer_NN , there_EX remains_VBZ a_AT concern_NN that_CS selected_JJ subgroups_NNS of_IN the_ATI population_NN will_MD be_BE adversely_RB affected_VBN by_IN the_ATI use_NN of_IN ERT_NP for_IN example_NN , some_DTI studies_NNS have_HV suggested_VBN that_CS long- term_JJB estrogen_NN use_NN (_( 10_CD to_IN 15_CD years_NNS or_CC more_QL )_) does_DOZ increase_VB the_ATI risk_NN of_IN breast_NN cancer_NN in_IN women_NNS using_VBG replacement_NN doses_NNS although_CS these_DTS results_NNS are_BER based_VBN on_IN small_JJ numbers_NNS of_IN cases_NNS (_( since_CS relatively_RB few_AP women_NNS have_HV used_VBN ERT_NP for_IN 15_CD or_CC more_QL years_NNS )_) these_DTS findings_NNS are_BER of_IN concern_NN 149_CD despite_IN the_ATI preponderance_NN of_IN evidence_NN that_CS short-term_JJB (_( less_AP than_IN 10_CD years_NNS )_) use_NN of_IN ERT_NP does_DOZ not_XNOT cause_VB breast_NN cancer_NN in_IN healthy_JJ women_NNS , it_PP3 is_BEZ possible_JJ that_CS women_NNS with_IN a_AT personal_JJ history_NN of_IN breast_NN cancer_NN may_MD be_BE more_QL susceptible_JJ to_TO tumor-promoting_VB effects_NNS of_IN estrogen_NN tamoxifen_NN reduces_VBZ the_ATI risk_NN of_IN contralateral_JJ breast_NN cancers_NNS in_IN women_NNS with_IN a_AT history_NN of_IN breast_NN cancer_NN among_IN eight_CD prospective_JJ randomized_JJ trials_NNS of_IN tamoxifen_NN vs_IN no_ATI therapy_NN , the_ATI relative_JJ risk_NN reduction_NN was_BEDZ 35%_CD for_IN women_NNS receiving_VBG tamoxifen_NN thus_RB , it_PP3 is_BEZ possible_JJ that_CS tamoxifen_NN , if_CS administered_VBN with_IN ERT_NP , may_MD attenuate_VB any_DTI potential_JJ cancer-promoting_JJ effect_NN of_IN estrogen_NN on_IN breast_NN cells_NNS 150_CD ERT_NP and_CC Breast_NPT Cancer_NP Relapse_Survival_NP 151_CD a_AT major_JJ concern_NN over_IN prescribing_VBG ERT_NP for_IN women_NNS with_IN a_AT history_NN of_IN breast_NN cancer_NN is_BEZ that_CS dormant_JJ tumor_NN cells_NNS might_MD be_BE activated_VBN there_EX is_BEZ surprisingly_RB little_JJ clinical_JJ information_NN to_TO substantiate_VB such_ABL concern_NN If_NP endogenous_JJ estrogen_JJ stimulated_JJ breast_NN cancer_NN growth_NN , women_NNS diagnosed_VBN with_IN breast_NN cancer_NN after_IN menopause_NN should_MD have_HV a_AT better_JJR prognosis_NN than_IN women_NNS diagnosed_VBN premenopausally_RB this_DT is_BEZ not_XNOT the_ATI case_NN instead_RB , there_EX is_BEZ rapid_JJ prognostic_JJ deterioration_NN in_IN breast_NN cancers_NNS diagnosed_VBN after_IN menopause_NN such_ABL deterioration_NN could_MD be_BE explained_VBN by_IN an_AT interaction_NN between_IN endogenous_JJ hormones_NNS and_CC the_ATI metastatic_JJ process_NN Counterintuitive_NP though_CS it_PP3 may_MD seem_VB , endogenous_JJ hormones_NNS might_MD somehow_RB inhibit_VB microscopic_JJ tumor_NN deposits_NNS 152_CD if_CS ERT_NP were_BED injurious_JJ for_IN patients_NNS with_IN breast_NN cancer_NN , one_CD1 would_MD expect_VB that_CS women_NNS who_WPR developed_JJ breast_NN cancer_NN while_CS taking_VBG estrogen_NN would_MD have_HV a_AT worse_JJR prognosis_NN in_IN fact_NN , the_ATI prognosis_NN of_IN women_NNS with_IN breast_NN cancer_NN who_WPR took_VBD ERT_NP before_CS diagnosis_NN is_BEZ better_JJR than_IN that_DT of_IN women_NNS with_IN no_ATI recorded_JJ exposure_NN , and_CC women_NNS who_WPR were_BED diagnosed_VBN within_IN a_AT year_NN of_IN taking_VBG ERT_NP enjoy_VB a_AT longer_RBR relative_JJ survival_NN than_IN women_NNS with_IN no_ATI recorded_JJ exposure_NN or_CC those_DTS whose_WP$R exposure_NN has_HVZ been_BEN more_AP than_IN a_AT year_NN from_IN diagnosis_NN (_( Table_NP 2_CD )_) 153_CD bergkvist_NN et_&FW al_APS studied_JJ survival_NN among_IN women_NNS with_IN breast_NN cancer_NN in_IN a_AT cohort_NN exposed_VBN to_IN ERT_NP before_IN diagnosis_NN these_DTS women_NNS were_BED then_RN compared_VBN with_IN women_NNS of_IN the_ATI background_NN population_NN diagnosed_VBN with_IN breast_NN cancer_NN during_IN the_ATI same_AP time_NN women_NNS with_IN a_AT history_NN of_IN ERT_NP exposure_NN had_HVD significantly_RB better_JJR observed_VBN and_CC relative_JJ survival_NN rates_NNS compared_VBN with_IN those_DTS who_WPR had_HVD no_ATI recorded_JJ history_NN of_IN ERT_NP 154_CD Gambrell_NP conducted_VBD a_AT prospective_JJ study_NN of_IN postmenopausal_JJ breast_NN cancer_NN patients_NNS and_CC evaluated_VBN the_ATI effect_NN of_IN ERT_NP on_IN breast_NN cancer_NN survival_NN at_IN the_ATI time_NN of_IN the_ATI analysis_NN , 102_CD of_IN 256_CD women_NNS had_HVD died_VBN the_ATI mortality_NN rate_NN was_BEDZ 22%_NN among_IN those_DTS diagnosed_VBN with_IN breast_NN cancer_NN while_CS using_VBG hormones_NNS and_CC 46%_NN among_IN those_DTS not_XNOT using_VBG hormones_NNS (_( P{_NP .002_NP )_) Fifty-seven_NP percent_NNU of_IN the_ATI hormone_NN users_NNS had_HVD negative_JJ nodes_NNS ; 42%_NN of_IN the_ATI nonusers_NNS were_BED node- negative_JJ within_IN this_DT node-negative_JJ group_NN , the_ATI mortality_NN rate_NN was_BEDZ 8%_NN for_IN hormone_NN users_NNS and_CC 25%_NN for_IN nonusers_NNS (_( P{.05_NP )_) 155_CD hunt_NN et_&FW al_APS reported_VBN on_IN mortality_NN from_IN breast_NN cancer_NN among_IN 4544_NN ERT_NP users_NNS their_PP$ cohort_NN experienced_JJ a_AT relative_JJ risk_NN of_IN 0.55_NP compared_VBD with_IN national_JJ rates_NNS screening_NN mammography_NN was_BEDZ rarely_RB if_CS ever_RB used_VBN to_TO diagnose_VB breast_NN cancer_NN 156_CD a_AT final_JJ study_NN confirms_VBZ these_DTS reports_NNS Henderson_NP et_&FW al_APS observed_VBN a_AT 19%_CD reduction_NN in_IN the_ATI mortality_NN from_IN breast_NN cancer_NN among_IN 4988_NN ERT_NP users_NNS vs_IN 3865_CD nonusers_NNS who_WPR subsequently_RB developed_JJ breast_NN cancer_NN 157_CD there_EX are_BER potential_JJ confounding_NN variables_NNS that_DT might_MD explain_VB these_DTS protective_JJ findings_NNS , including_IN the_ATI supposition_NN that_CS ERT_NP might_MD promote_VB development_NN of_IN estrogen-dependent_NN breast_NN cancers_NNS that_WPR wither_VB upon_IN estrogen_NN withdrawal_NN nevertheless_RB , the_ATI data_NNS are_BER coherent_JJ in_IN that_DT they_PP3AS suggest_VB that_CS ERT_NP prior_RB to_TO diagnosis_NN may_MD have_HV a_AT beneficial_JJ effect_NN on_IN survival_NN of_IN women_NNS with_IN breast_NN cancer_NN 158_CD other_AP Supporting_NP Information_NN 159_CD some_DTI natural_JJ experiments_NNS suggest_VB that_CS ERT_NP will_MD not_XNOT adversely_RB influence_NN breast_NN cancer_NN outcome_NN hormone_NN levels_NNS are_BER very_QL high_JJ during_IN pregnancy_NN however_RB , pregnancy_NN after_IN breast_NN cancer_NN does_DOZ not_XNOT affect_VB survival_NN or_CC recurrence_NN when_WRB stage_NN and_CC age_NN are_BER controlled_VBN further_JJB , use_NN of_IN oral_JJ contraceptive_JJ pills_NNS (_( OCPs_NP )_) before_CS development_NN of_IN breast_NN cancer_NN does_DOZ not_XNOT appear_VB to_TO have_HV a_AT negative_JJ effect_NN on_IN survival_NN 160_CD Spencer_NP et_&FW al_APS found_VBN no_ATI evidence_NN of_IN a_AT worse_JJR prognosis_NN in_IN 44_CD women_NNS who_WPR took_VBD OCPs_NP during_IN the_ATI year_NN preceding_JJ a_AT diagnosis_NN of_IN breast_NN cancer_NN Matthews_NP et_&FW al_APS studied_VBN 93_CD breast_NN cancer_NN patients_NNS whose_WP$R history_NN included_VBN OCP_NP use_NN they_PP3AS were_BED matched_VBN by_IN age_NN and_CC parity_NN with_IN a_AT control_NN group_NN who_WPR had_HVD no_ATI history_NN of_IN OCP_NP use_NN and_CC presented_VBD during_IN a_AT similar_JJ period_NN the_ATI OCP_NP group_NN had_HVD significantly_RB better_JJR differentiated_JJ tumors_NNS and_CC were_BED significantly_RB more_QL likely_JJ to_TO be_BE node- negative_JJ among_IN node-negative_JJ patients_NNS , survival_NN was_BEDZ significantly_RB better_JJR for_IN OCP_NP users_NNS 161_CD an_AT Argument_NP for_IN Prescribing_NP Tamoxifen_NP and_CC ERT_NP Together_NP 162_CD a_AT discussion_NN of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS must_MD consider_VB the_ATI increasing_JJ prescription_NN of_IN tamoxifen_NN the_ATI window_NN of_IN opportunity_NN to_TO study_VB the_ATI effect_NN of_IN ERT_NP on_IN the_ATI natural_JJ history_NN of_IN breast_NN cancer_NN , independent_JJ of_IN tamoxifen_NN , has_HVZ closed_VBN 163_CD tamoxifen_NN is_BEZ recommended_JJ adjuvant_NN therapy_NN for_IN an_AT increasing_JJ number_NN of_IN women_NNS with_IN breast_NN cancer_NN a_AT recent_JJ worldwide_NN overview_NN suggested_VBN that_CS all_ABN women_NNS with_IN invasive_JJ tumors_NNS might_MD benefit_VB from_IN tamoxifen_NN and_CC that_CS longer_RBR durations_NNS of_IN treatment_NN may_MD be_BE superior_JJ to_IN shorter_JJR durations_NNS Currently_NP , adjuvant_NN tamoxifen_NN , when_WRB prescribed_VBN for_IN invasive_JJ breast_NN cancer_NN , is_BEZ given_VBN for_IN 5_CD or_CC more_QL years_NNS trials_NNS evaluating_VBG 5_CD vs_IN 10_CD years_NNS of_IN adjuvant_NN tamoxifen_NN are_BER under_IN way_NN trials_NNS evaluating_VBG the_ATI worth_IN of_IN tamoxifen_NN in_IN women_NNS with_IN node-negative_JJ , invasive_JJ cancers_NNS less_AP than_IN 1_CD1 cm_NNU and_CC trials_NNS evaluating_VBG the_ATI worth_IN of_IN tamoxifen_NN among_IN women_NNS with_IN noninvasive_JJ breast_NN cancer_NN are_BER ongoing_NN 164_CD in_IN the_ATI future_NN , tamoxifen_NN may_MD also_RB be_BE widely_RB used_VBN not_XNOT only_RB in_IN breast_NN cancer_NN survivors_NNS , but_CC also_RB in_IN women_NNS who_WPR are_BER considered_VBN at_IN risk_NN for_IN breast_NN cancer_NN three_CD breast_NN cancer_NN prevention_NN trials_NNS evaluating_VBG tamoxifen_NN prophylaxis_NN in_IN healthy_JJ women_NNS at_IN high_JJ risk_NN for_IN breast_NN cancer_NN are_BER currently_RB under_IN way_NN , one_CD1 in_IN the_ATI United_NP States_NP and_CC Canada_NP , one_CD1 in_IN Italy_NP , and_CC one_CD1 in_IN the_ATI United_NP Kingdom_NPL and_CC Australia_NP if_CS the_ATI results_NNS of_IN these_DTS trials_NNS are_BER encouraging_JJ , tamoxifen_JJB may_MD be_BE recommended_VBN as_IN a_AT preventive_JJ agent_NN for_IN large_JJ numbers_NNS of_IN women_NNS 165_CD ERT_NP and_CC tamoxifen_NN have_HV been_BEN administered_VBN simultaneously_RB to_TO postmenopausal_JJ patients_NNS , apparently_RB without_IN ill_JJ effect_NN in_IN the_ATI British_JNP Breast_NP Cancer_NP Prevention_NN Trial_NP , which_WDTR uses_VBZ tamoxifen_NN as_IN the_ATI preventive_JJ agent_NN , postmenopausal_JJ women_NNS who_WPR experience_NN hot_JJ flashes_NNS are_BER given_VBN ERT_NP for_IN relief_NN however_RB , carefully_RB controlled_JJ studies_NNS have_HV not_XNOT been_BEN performed_VBN 166_CD because_CS of_IN its_PP$ estrogenic_JJ properties_NNS , tamoxifen_NN maintains_VBZ bone_NN mass_NN and_CC reduces_VBZ death_NN from_IN heart_NN attack_NN by_RP about_IN 20%_NP in_IN postmenopausal_JJ women_NNS ERT_NP also_RB maintains_VBZ bone_NN mass_NN and_CC reduces_VBZ the_ATI rate_NN of_IN coronary_JJ heart_NN disease_NN in_IN postmenopausal_JJ women_NNS the_ATI risk_NN of_IN fracture_NN has_HVZ not_XNOT been_BEN assessed_VBN among_IN tamoxifen_NN users_NNS , and_CC tamoxifen_NN has_HVZ not_XNOT been_BEN approved_VBN by_IN the_ATI Food_NP and_CC Drug_NP Administration_NN (_( FDA_NP )_) for_IN this_DT indication_NN in_IN comparison_NN , the_ATI FDA_NP has_HVZ approved_VBN ERT_NP for_IN the_ATI prevention_NN of_IN osteoporosis_NN It_NP is_BEZ possible_JJ that_CS these_DTS heart_NN and_CC bone_NN benefits_NNS may_MD be_BE accentuated_VBN by_IN combined_JJ tamoxifen_NN and_CC ERT_NP 167_CD tamoxifen_NN slightly_RB increases_VBZ the_ATI risk_NN of_IN vascular_NN thrombosis_NN among_IN breast_NN cancer_NN patients_NNS ; however_RB , there_EX is_BEZ no_ATI epidemiologic_JJ evidence_NN of_IN estrogen-mediated_JJ hypercoagulability_NN among_IN ERT_NP users_NNS thus_RB , combining_VBG ERT_NP and_CC tamoxifen_NN is_BEZ not_XNOT expected_VBN to_TO exacerbate_VB this_DT toxicity_NN both_ABX tamoxifen_NN and_CC ERT_NP with_IN unopposed_JJ estrogen_NN increase_VB the_ATI risk_NN of_IN endometrial_JJ cancer_NN combining_VBG these_DTS treatments_NNS , especially_RB with_IN unopposed_JJ estrogen_NN , might_MD increase_VB this_DT risk_NN because_CS of_IN this_DT , it_PP3 is_BEZ necessary_JJ to_TO use_VB progestogens_NNS in_IN women_NNS with_IN an_AT intact_JJ uterus_JJ 168_CD the_ATI safety_NN of_IN combined_JJ tamoxifen_NN and_CC endogenous_JJ estrogen_NN has_HVZ been_BEN demonstrated_VBN in_IN clinical_JJ trials_NNS premenopausal_JJ women_NNS receiving_VBG tamoxifen_NN do_DO not_XNOT experience_VB a_AT higher_JJR incidence_NN of_IN vascular_NN or_CC endometrial_JJ events_NNS compared_VBN with_IN postmenopausal_JJ women_NNS receiving_VBG tamoxifen_NN this_DT is_BEZ true_JJ despite_IN the_ATI fact_NN that_CS premenopausal_JJ women_NNS receiving_VBG tamoxifen_NN develop_VB hyperestrogenemia_NN (_( Table_NP 3_CD )_) 169_CD as_IN the_ATI 21st_OD century_NN approaches_NNS , an_AT era_NN in_IN which_WDTR tamoxifen_NN may_MD be_BE prescribed_VBN for_IN nearly_RB all_ABN breast_NN cancer_NN survivors_NNS and_CC for_IN women_NNS at_IN high_JJ risk_NN (_( all_ABN women_NNS ? )_) , it_PP3 is_BEZ reasonable_JJ to_TO ask_VB whether_CS tamoxifen_NN and_CC ERT_NP together_RB can_MD be_BE administered_VBN safely_RB furthermore_RB , it_PP3 is_BEZ reasonable_JJ to_TO study_VB the_ATI combined_JJ effect_NN of_IN ERT_NP and_CC tamoxifen_NN on_IN menopausal_JJ disease_NN , menopausal_JJ symptoms_NNS , and_CC breast_NN cancer_NN outcome_NN 170_CD potential_JJ Antagonism_NPT Between_NP ERT_NP and_CC Tamoxifen_NP on_IN Breast_NP Cancer_NP Growth_NP 171_CD a_AT logical_JJ concern_NN over_IN administration_NN of_IN estrogen_NN and_CC tamoxifen_NN together_RB is_BEZ that_CS estrogen_NN might_MD antagonize_VB the_ATI effect_NN of_IN tamoxifen_NN on_IN breast_NN cells_NNS or_CC on_IN tumor_NN cells_NNS however_RB , premenopausal_JJ women_NNS have_HV high_JJ levels_NNS of_IN estradiol_NN circulating_VBG bound_VBN to_TO sex_NN hormone-binding_NN globulin_NN , yet_RB they_PP3AS respond_VB to_TO tamoxifen_VB ; therefore_RB , postmenopausal_JJ women_NNS receiving_VBG ERT_NP should_MD also_RB 172_CD postmenopausal_JJ women_NNS receiving_VBG ERT_NP have_HV serum_NN concentrations_NNS of_IN estradiol_NN that_CS are_BER not_XNOT significantly_RB different_JJ from_IN estradiol_NN levels_NNS in_IN premenopausal_JJ women_NNS during_IN the_ATI follicular_JJ phase_NN of_IN the_ATI menstrual_JJ cycle_NN Premenopausal_NP patients_NNS have_HV much_RB higher_JJR levels_NNS through_IN the_ATI rest_NN of_IN their_PP$ cycle_NN (_( Table_NP 3_CD )_) 173_CD tamoxifen_NN stimulates_VBZ estrogen_NN secretion_NN in_IN premenopausal_JJ women_NNS The_NP rise_NN in_IN sex_NN hormone-binding_NN globulin_NN observed_VBN in_IN these_DTS women_NNS , a_AT normal_JJ hepatic_JJ response_NN to_TO hyperestrogenemia_VB , suggests_VBZ that_CS premenopausal_JJ women_NNS experience_NN a_AT physiologically_RB hyperestrogenemic_JJ state_NN corresponding_JJ to_IN their_PP$ high_JJ estrogen_NN levels_NNS mean_VB estradiol_NN levels_NNS in_IN tamoxifen-treated_JJ premenopausal_JJ patients_NNS are_BER two_CD to_IN three_CD times_NNS those_DTS seen_VBN throughout_IN a_AT normal_JJ menstrual_JJ cycle_NN despite_IN such_ABL high_JJ levels_NNS of_IN estradiol_NN , these_DTS premenopausal_JJ women_NNS respond_VB to_TO tamoxifen_VB 174_CD tamoxifen's_NP$ mechanism_NN of_IN action_NN was_BEDZ initially_RB thought_VBN to_TO be_BE mediated_VBN solely_RB through_IN the_ATI estrogen_NN receptor_NN if_CS this_DT were_BED true_JJ , high_JJ levels_NNS of_IN endogenous_JJ estrogen_NN should_MD competitively_RB inhibit_VB binding_NN of_IN tamoxifen_NN to_IN the_ATI estrogen_NN receptor_NN , thereby_RB diminishing_VBG or_CC eliminating_VBG the_ATI drug's_NP$ effectiveness_NN in_IN premenopausal_JJ women_NNS 175_CD more_AP recent_JJ research_NN has_HVZ shown_VBN that_CS tamoxifen_NN influences_NNS other_AP physiological_JJ processes_NNS for_IN example_NN , tamoxifen_NN decreases_VBZ secretion_NN of_IN stimulatory_NN growth_NN factors_NNS , such_IN as_IN transforming-cell_NN growth_NN factor- alpha_NN , insulin-like_NN growth_NN factor-II_NN , and_CC platelet-derived_JJ growth_NN factor_NN , and_CC increases_NNS secretion_NN of_IN inhibitory_NN growth_NN factors_NNS such_IN as_IN transforming-cell_NN growth_NN factor-beta_NN it_PP3 inhibits_VBZ the_ATI mitogenic_JJ effect_NN of_IN growth_NN factors_NNS on_IN breast_NN cancer_NN cells_NNS in_IN the_ATI total_JJ absence_NN of_IN estrogens_NNS tamoxifen_NN can_MD block_VB protein_NN kinase_NN C_ZZ and_CC calmodulin_NN activation_NN , alter_VB cell_NN membrane_NN permeability_NN , and_CC modulate_VB immunoregulatory_NN function_NN it_PP3 is_BEZ reasonable_JJ to_TO presume_VB that_CS these_DTS effects_NNS would_MD be_BE independent_NN of_IN serum_NN estrogen_NN levels_NNS 176_CD 52_CD observations_NNS that_WPR suggest_VB that_CS ERT_NP will_MD not_XNOT reduce_VB tamoxifen's_NP$ therapeutic_JJ effect_NN include_VB its_PP$ efficacy_NN in_IN premenopausal_JJ women_NNS with_IN metastatic_JJ and_CC operable_JJ breast_NN cancer_NN premenopausal_JJ women_NNS with_IN metastatic_JJ breast_NN cancer_NN experience_NN remission_NN when_WRB treated_VBN with_IN tamoxifen_NN it_PP3 is_BEZ possible_JJ that_CS the_ATI increased_JJ estradiol_NN levels_NNS seen_VBN in_IN premenopausal_JJ women_NNS taking_VBG tamoxifen_NN may_MD have_HV a_AT pharmacologically_RB equivalent_JJ effect_NN to_TO diethylstilbestrol_VB use_NN for_IN treatment_NN of_IN metastatic_JJ disease_NN for_IN most_AP physicians_NNS , tamoxifen_NN has_HVZ replaced_VBN oophorectomy_NN as_IN the_ATI initial_JJ treatment_NN of_IN choice_NN for_IN premenopausal_JJ women_NNS with_IN metastatic_JJ breast_NN cancer_NN in_IN whom_WPOR a_AT hormonal_JJ manipulation_NN is_BEZ indicated_VBN the_ATI FDA_NP has_HVZ approved_VBN the_ATI use_NN of_IN tamoxifen_NN in_IN premenopausal_JJ women_NNS 177_CD adjuvant_NN therapy_NN trials_NNS comparing_VBG tamoxifen_JJ alone_JJ with_IN placebo_NN also_RB show_VB that_CS tamoxifen_NN benefits_NNS premenopausal_JJ and_CC postmenopausal_JJ women_NNS in_IN the_ATI largest_JJT trial_NN with_IN that_DT design_NN , National_NP Surgical_NPT Adjuvant_NP Breast_NP Project_NP B-14_CD-CD , node-negative_JJ , estrogen_JJ receptor-positive_JJ breast_NN cancer_NN patients_NNS were_BED randomly_RB assigned_VBN to_TO receive_VB 5_CD years_NNS of_IN tamoxifen_NN or_CC placebo_NN in_IN that_DT trial_NN , premenopausal_JJ women_NNS derived_VBN a_AT greater_JJR benefit_NN from_IN tamoxifen_NN than_IN postmenopausal_JJ women_NNS , suggesting_VBG that_CS the_ATI combination_NN of_IN endogenous_JJ estrogen_NN and_CC tamoxifen_NN is_BEZ not_XNOT antithetical_JJ and_CC may_MD be_BE beneficial_JJ yet_RB when_WRB these_DTS same_AP premenopausal_JJ women_NNS undergo_VB menopause_NN they_PP3AS will_MD be_BE denied_VBN ERT_NP 178_CD clinical_JJ Trials_NNS of_IN ERT_NP in_IN Breast_NPT Cancer_NP Survivors_NP 179_CD proponents_NNS of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS bolster_VB their_PP$ argument_NN by_IN stating_VBG that_CS estrogen_NN has_HVZ been_BEN and_CC is_BEZ used_VBN as_IN a_AT treatment_NN for_IN breast_NN cancer_NN however_RB , it_PP3 must_MD be_BE remembered_VBN that_CS the_ATI doses_NNS of_IN estrogen_NN used_VBN for_IN treatment_NN of_IN breast_NN cancer_NN are_BER pharmacologic_JJ , not_XNOT physiological_JJ , and_CC in_IN vitro_NN studies_NNS show_VB that_CS low-dose_NN estrogen_NN stimulates_VBZ and_CC high-dose_NN estrogen_NN inhibits_VBZ breast_NN cancer_NN cell_NN growth_NN however_RB , contradictory_JJ human_JJ evidence_NN exists_VBZ 180_CD Stoll_NP treated_VBD postmenopausal_JJ breast_NN cancer_NN patients_NNS with_IN an_AT OCP_NP containing_VBG estrogen_NN (_( 17-alpha-ethynylestradiol_CD-CD , 0.15_CD mg_NNU )_) and_CC a_AT progestin_NN (_( 17-alpha-ethynyl-estrenol_CD-CD , 5_CD mg_NNU )_) patients_NNS had_HVD measurable_JJ soft-tissue_NN metastases_NNS nearly_RB complete_JJ resolution_NN of_IN disease_NN was_BEDZ observed_VBN in_IN a_AT significant_JJ proportion_NN of_IN patients_NNS a_AT dose_NN response_NN was_BEDZ not_XNOT observed_VBN One_NP tablet_NN daily_JJ (_( the_ATI normal_JJ OCP_NP dose_NN )_) was_BEDZ as_QL effective_JJ as_IN three_CD or_CC six_CD tablets_NNS per_NNU day_NN menopausal_JJ symptoms_NNS were_BED relieved_JJ 181_CD three_CD clinical_JJ series_NN of_IN ERT_NP use_NN in_IN breast_NN cancer_NN survivors_NNS have_HV been_BEN published_VBN none_PN demonstrated_VBN a_AT striking_JJ adverse_JJ outcome_NN however_RB , these_DTS reports_NNS were_BED essentially_RB anecdotal_JJ and_CC not_XNOT formal_JJ clinical_JJ trials_NNS with_IN clearly_RB defined_JJ objectives_NNS , eligibility_NN criteria_NNS , and_CC end_NN points_NNS 182_CD Stoll_NP gave_VBD women_NNS 0.625_NP mg_NNU of_IN conjugated_VBN equine_JJ estrogens_NNS and_CC 0.15_CD mg_NNU of_IN norgestrel_CD per_NNU day_NN the_ATI women_NNS were_BED suffering_VBG severe_JJ sweats_NNS or_CC hot_JJ flashes_NNS , unrelieved_JJ by_IN clonidine_NN patients_NNS were_BED followed_VBN up_RP for_IN 2_CD years_NNS ; no_ATI relapses_NNS occurred_VBD 183_CD Wile_NP et_&FW al_APS conducted_VBN a_AT case-control_JJ study_NN of_IN 25_CD breast_NN cancer_NN survivors_NNS who_WPR received_VBD ERT_NP the_ATI average_JJ duration_NN between_IN diagnosis_NN and_CC beginning_NN ERT_NP was_BEDZ 2_CD years_NNS each_DT patient_NN was_BEDZ matched_VBN with_IN two_CD non-ERT_NN users_NNS for_IN stage_NN , age_NN , and_CC duration_NN of_IN observation_NN the_ATI average_JJ duration_NN of_IN observation_NN of_IN patients_NNS receiving_VBG ERT_NP was_BEDZ 2_CD years_NNS there_EX was_BEDZ one_CD1 cancer-related_JJ death_NN in_IN the_ATI treated_VBN group_NN and_CC two_CD in_IN the_ATI control_NN group_NN A_ZZ subsequent_JJ report_NN by_IN these_DTS authors_NNS revealed_VBN that_CS the_ATI type_NN of_IN ERT_NP varied_JJ at_IN the_ATI time_NN of_IN the_ATI second_OD report_NN , patients_NNS had_HVD been_BEN observed_VBN for_IN a_AT mean_NN of_IN 35_CD months_NNS three_CD women_NNS who_WPR received_VBD ERT_NP had_HVD relapsed_VBN 184_CD in_IN a_AT final_JJ case-control_JJ study_NN of_IN 901_CD breast_NN cancer_NN survivors_NNS , 90_CD of_IN whom_WPOR took_VBD combined_VBN , continuous_JJ estrogen_NN and_CC moderate-dose_NN progesterone_NN for_IN relief_NN of_IN menopausal_JJ symptoms_NNS , Eden_NP et_&FW al_APS reported_VBN significantly_RB fewer_AP tumor_NN recurrences_NNS in_IN the_ATI HRT_NP group_NN matching_JJ criteria_NNS included_VBN age_NN at_IN disease-free_NN interval_NN prior_RB to_IN starting_VBG HRT_NP 185_CD R.V._NP sellin_NN and_CC colleagues_NNS (_( written_JJ communication_NN , December_NR 1_CD1 , 1993_CD )_) are_BER currently_RB conducting_VBG a_AT prospective_JJ clinical_JJ trial_NN of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS eligibility_NN criteria_NNS for_IN the_ATI trial_NN include_VB a_AT disease-free_JJ interval_NN of_IN 2_CD years_NNS for_IN women_NNS with_IN estrogen_NN receptor- negative_JJ tumors_NNS and_CC 10_CD years_NNS for_IN those_DTS with_IN estrogen_NN receptor-positive_JJ tumors_NNS this_DT groundbreaking_VBG trial_NN is_BEZ an_AT important_JJ step_NN in_IN the_ATI study_NN of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS however_RB , it_PP3 cannot_NN detect_VB less_AP than_IN a_AT 10%_CD increase_NN in_IN relapse_NN rate_NN that_WPR could_MD be_BE caused_VBN by_IN ERT_NP in_IN a_AT disease_NN as_IN common_JJ as_IN breast_NN cancer_NN , even_RB a_AT small_JJ difference_NN in_IN outcome_NN can_MD affect_VB many_AP lives_NNS additionally_RB , the_ATI women_NNS in_IN the_ATI trial_NN are_BER not_XNOT receiving_VBG tamoxifen_NN thus_RB , the_ATI results_NNS cannot_NN be_BE generalized_JJ to_IN women_NNS receiving_VBG tamoxifen_NN 186_CD conclusions_NNS 187_CD we_PP1AS believe_VB it_PP3 is_BEZ time_NN for_IN a_AT change_NN and_CC the_ATI time_NN is_BEZ right_JJ to_TO study_VB the_ATI effects_NNS of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS women_NNS rely_VB on_IN their_PP$ oncologists_NNS for_IN advice_NN on_IN this_DT issue_NN , and_CC oncologists_NNS must_MD be_BE broad-minded_JJ and_CC consider_VB all-cause_NN mortality_NN , not_XNOT just_RB mortality_NN from_IN breast_NN cancer_NN , when_WRB designing_VBG clinical_JJ trials_NNS there_EX are_BER no_ATI published_VBN controlled_VBN clinical_JJ trials_NNS of_IN the_ATI effect_NN of_IN ERT_NP on_IN breast_NN cancer_NN survival_NN 188_CD clinical_JJ trials_NNS of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS have_HV been_BEN hindered_VBN in_IN part_NN by_IN the_ATI maxim_NN primum_NN non_&FW nocere_NN (_( first_OD do_DO no_ATI harm_NN )_) such_ABL moralizing_VBG prevents_VBZ moral_JJ reflection_NN the_ATI task_NN of_IN moral_JJ reflection_NN is_BEZ to_TO assess_VB whether_CS something_PN is_BEZ right_JJ or_CC wrong_JJ in_IN light_NN of_IN the_ATI lack_NN of_IN evidence_NN of_IN a_AT detrimental_JJ effect_NN of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS and_CC in_IN light_NN of_IN the_ATI potential_JJ positive_JJ effects_NNS of_IN ERT_NP on_IN the_ATI health_NN of_IN women_NNS , we_PP1AS suggest_VB a_AT new_JJ maxim_NN , primum_NN certior_NN fi_NN , tunc_NN mone_NN (_( first_OD understand_VB , then_RN advise_VB )_) this_DT review_NN supports_VBZ the_ATI ethics_NN of_IN a_AT clinical_JJ trial_NN of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS 189_CD ultimately_RB , the_ATI question_NN of_IN effect_NN on_IN overall_JJB survival_NN can_MD only_RB be_BE answered_VBN by_IN a_AT prospective_JJ randomized_JJ trial_NN requiring_VBG thousands_CDS of_IN women_NNS Many_NP questions_NNS regarding_IN such_ABL a_AT trial_NN exist_VB , and_CC it_PP3 is_BEZ premature_JJ to_TO mount_NN one_CD1 without_IN pilot_NN data_NNS 190_CD for_IN example_NN , it_PP3 will_MD be_BE important_JJ to_TO know_VB if_CS breast_NN cancer_NN survivors_NNS will_MD participate_VB in_IN trials_NNS of_IN ERT_NP what_WDT are_BER the_ATI baseline_NN quality-of-life_NN measurements_NNS in_IN these_DTS women_NNS and_CC how_WRB are_BER they_PP3AS changed_VBN by_IN ERT_NP ? in_IN order_NN to_TO ascertain_VB this_DT information_NN , a_AT well- defined_JJ questionnaire_NN that_CS measures_VBZ the_ATI frequency_NN and_CC severity_NN of_IN symptoms_NNS of_IN menopause_NN or_CC a_AT quality-of-life_NN assessment_NN tool_NN must_MD be_BE developed_VBN what_WDT is_BEZ the_ATI interaction_NN between_IN ERT_NP and_CC tamoxifen_NN on_IN breast_NN , endometrium_NN , mammographic_JJ patterns_NNS , menopausal_JJ symptoms_NNS , bone_NN mineral_NN density_NN , lipid_NN profiles_NNS , and_CC coagulation_NN ? will_MD ERT_NP relieve_VB menopausal_JJ symptoms_NNS in_IN women_NNS taking_VBG tamoxifen_NN ? these_DTS are_BER only_RB a_AP few_AP of_IN the_ATI questions_NNS that_DT should_MD be_BE answered_VBN before_CS large-scale_JJB trials_NNS begin_VB 191_CD a_AT series_NN of_IN pilot_NN studies_NNS would_MD lay_VBD the_ATI groundwork_NN for_IN larger_JJR definitive_JJ trials_NNS while_CS we_PP1AS favor_NN the_ATI study_NN of_IN ERT_NP in_IN women_NNS taking_VBG tamoxifen_NN , we_PP1AS think_VB that_CS many_AP interventions_NNS may_MD be_BE appropriate_JJ , given_VBN the_ATI current_JJ lack_NN of_IN information_NN 192_CD we_PP1AS are_BER encouraged_VBN that_CS the_ATI Division_NP of_IN Cancer_NP Prevention_NN and_CC Control_NP of_IN the_ATI National_NP Cancer_NP Institute_NPL hosted_VBN a_AT multidiciplinary_NN conference_NN on_IN hormone_NN replacement_NN therapy_NN on_IN November_NR 2_CD , 1993_CD the_ATI National_NP Cancer_NP Institute_NPL will_MD now_RN consider_VB supporting_VBG clinical_JJ trials_NNS of_IN ERT_NP in_IN breast_NN cancer_NN survivors_NNS through_IN the_ATI cooperative_JJ group_NN mechanism_NN 193_CD the_ATI Management_NP of_IN Cancer_NP Metastatic_NP to_IN Bone_NP 194_CD a_AT 61-year-old_JJB woman_NN with_IN a_AT 4-year_JJ history_NN of_IN breast_NN cancer_NN and_CC known_VBN metastatic_JJ bone_NN disease_NN presented_VBN with_IN bilateral_JJ hip_NN pain_NN for_IN 3_CD months_NNS roentgenograms_NNS of_IN the_ATI left_JJ hip_NN revealed_VBN a_AT destructive_JJ lesion_NN involving_VBG the_ATI intertrochanteric_JJ region_NN of_IN the_ATI left_NN proximal_JJ femur_&FW the_ATI left_VBN femoral_JJ lesion_NN measured_VBN approximately_RB 2_CD by_IN 3_CD cm_NNU and_CC involved_VBN 60%_NP of_IN the_ATI cortex_NN right_JJ hip_NN roentgenograms_NNS demonstrated_VBN an_AT acetabular_NN lesion_JJ of_IN unknown_JJ extent_NN bone_NN scan_NN revealed_VBN no_ATI other_AP lesions_NNS the_ATI patient_NN subsequently_RB underwent_JJ irradiation_NN of_IN both_ABX hips_NNS with_IN excellent_JJ pain_NN relief_NN on_IN the_ATI left_NN but_CC continued_VBD symptoms_NNS on_IN the_ATI right_JJ Orthopedic_NP consultation_NN was_BEDZ requested_VBN to_TO evaluate_VB the_ATI patient's_NN$ risk_NN for_IN pathological_JJ fracture_NN on_IN the_ATI left.=20_CD 195_CD computed_JJ tomography_NN (_( CT_NP )_) of_IN the_ATI pelvis_NN demonstrated_VBN a_AT pathological_JJ fracture_NN of_IN the_ATI right_JJ acetabulum_NN since_IN the_ATI patient_NN was_BEDZ free_JJ of_IN pain_NN on_IN the_ATI left_JJ hip_NN , a_AT cemented_JJ total-hip_NN arthroplasty_NN was_BEDZ performed_VBN on_IN the_ATI right_JJ hip_NN the_ATI patient_NN did_DOD well_RB postoperatively_RB with_IN complete_JJ relief_NN of_IN right_JJ hip_NN pain_NN and_CC improved_JJ ambulation_NN requiring_VBG the_ATI occasional_JJ use_NN of_IN a_AT cane_NN close_RB follow-up_NN of_IN the_ATI left_NN femoral_JJ lesion_NN demonstrated_VBN gradual_JJ reossification_NN during_IN the_ATI course_NN of_IN a_AT year_NN because_CS the_ATI patient_NN demonstrated_VBN continued_VBD progression_NN of_IN her_PP$ disease_NN on_IN chemotherapy_NN , she_PP3A was_BEDZ considered_VBN for_IN and_CC placed_VBN on_IN a_AT paclitaxel_NN protocol_NN 196_CD DISCUSSION_NP 197_CD metastasis_NN to_TO bone_NN is_BEZ a_AT significant_JJ problem_NN for_IN a_AT large_JJ number_NN of_IN cancer_NN patients_NNS : up_RP to_TO 85%_NN of_IN patients_NNS dying_VBG from_IN breast_NN , prostate_NN , or_CC lung_NN carcinoma_NN primaries_NNS demonstrate_VB bone_NN involvement_NN at_IN autopsy_NN bone_NN involvement_NN routinely_RB results_VBZ in_IN pain_NN , difficulty_NN in_IN ambulation_NN , and_CC an_AT overall_JJB compromise_NN in_IN the_ATI patient's_NN$ quality_NN of_IN life_NN pathological_JJ fractures_NNS are_BER extremely_RB debilitating_JJ and_CC often_RB result_NN in_IN diminished_VBN survival_NN for_IN otherwise_RB stable_JJ patients_NNS patient_NN survival_NN can_MD vary_VB widely_RB in_IN patients_NNS with_IN metastatic_JJ bone_NN disease.=20_CD 198_CD patients_NNS suffering_VBG from_IN metastatic_JJ breast_NN disease_NN survive_VB 34_CD months_NNS on_IN average_JJ after_IN detection_NN of_IN the_ATI first_OD metastasis_NN , with_IN a_AT range_NN of_IN 1_CD1 to_IN 90_CD months_NNS survival_NN with_IN metastatic_JJ prostate_NN cancer_NN averages_NNS 24_CD months_NNS , and_CC lung_NN cancer_NN patients_NNS have_HV a_AT dismal_JJ prognosis_NN of_IN less_AP than_IN 1_CD1 year_NN Most_NP patients_NNS suffering_VBG from_IN metastatic_JJ bone_NN disease_NN are_BER excellent_JJ candidates_NNS for_IN treatment_NN , whether_CS it_PP3 be_BE chemotherapy_VBN , radiation_NN , or_CC surgical_JJ intervention_NN controversy_NN regarding_IN the_ATI surgical_JJ indications_NNS for_IN prophylactic_JJ fracture_NN fixation_NN can_MD lead_VB to_TO difficulty_NN when_WRB assessing_VBG patients_NNS for_IN operative_JJ intervention_NN 199_CD pathophysiology_NN 200_CD bone_NN metastasis_NN is_BEZ not_XNOT simply_RB a_AT random_JJ process_NN metastasis_NN involves_VBZ a_AT cascade_NN of_IN linked_VBN sequential_JJ steps_NNS that_DT must_MD be_BE traversed_VBN before_CS a_AT neoplastic_JJ cell_NN successfully_RB establishes_VBZ a_AT secondary_JJ tumor_NN in_IN a_AT distant_JJ bony_JJ site_NN (_( Figure_NP 1_CD1 )_) two_CD theories_NNS of_IN bone_NN metastasis_NN are_BER often_RB cited- namely_RB , the_ATI anatomic-mechanical_JJ theory_NN proposed_VBN by_IN Ewing_NP and_CC the_ATI seed_NN and_CC soil_NN hypothesis_NN of_IN Paget_NP the_ATI mechanistic_JJ approach_NN states_NNS that_CS metastasis_NN develops_VBZ in_IN the_ATI first_OD organ_NN a_AT tumor_NN cell_NN encounters_NNS this_DT approach_NN was_BEDZ graphically_RB demonstrated_VBN by_IN Batson_NP using_VBG injection_NN studies_NNS in_IN primates_NNS to_TO define_VB the_ATI valveless_JJ paravertebral_JJ venous_JJ plexus_NN emanating_VBG from_IN the_ATI pelvis.=20_CD 201_CD mapping_NN of_IN this_DT plexus_NN was_BEDZ highly_RB predictive_JJ for_IN the_ATI bony_JJ metastatic_JJ spread_NN of_IN prostate_NN carcinoma_NN in_IN addition_NN , because_CS this_DT plexus_NN is_BEZ valveless_JJ , retrograde_JJB flow_NN was_BEDZ greatly_RB increased_VBN during_IN recumbency_NN or_CC with_IN increased_VBN abdominal_JJ pressure_NN a_AT similar_JJ plexus_NN has_HVZ been_BEN identified_VBN in_IN the_ATI shoulder_NN girdle_NN and_CC correlated_VBN with_IN the_ATI bony_JJ metastatic_JJ spread_NN of_IN breast_NN carcinoma_NN however_RB , this_DT anatomic_JJ approach_NN , although_CS it_PP3 certainly_RB plays_VBZ a_AT role_NN in_IN bone_NN metastasis_NN , is_BEZ viewed_VBN as_CS oversimplified_VBN and_CC thus_RB has_HVZ given_JJ way_NN to_IN the_ATI second_OD theory-that_NN of_IN chemotaxis_NN and_CC osteotropism_NN 202_CD clearly_RB , certain_JJ cancers_NNS exhibit_VB osteotropism_NN and_CC predictably_RB metastasize_NN to_IN bone_NN more_AP than_IN 80%_NP of_IN such_ABL cancers_NNS are_BER those_DTS of_IN breast_NN , prostate_NN , lung_NN , thyroid_JJ , and_CC kidney_NN the_ATI rate_NN of_IN metastasis_NN at_IN autopsy_NN is_BEZ estimated_VBN to_TO be_BE 84%_VBN for_IN breast_NN , 84%_NN for_IN prostate_NN , 50%_NP for_IN thyroid_JJ , 44%_NN for_IN lung_NN , and_CC 37%_CD for_IN renal_JJ carcinoma_NN proponents_NNS of_IN this_DT theory_NN have_HV isolated_JJ chemotaxic_JJ factors_NNS , which_WDTR are_BER present_JJ and_CC are_BER hypothesized_VBN to_TO play_VB a_AT role_NN in_IN directing_VBG circulating_VBG tumor_NN cells_NNS to_IN bone_NN animal_NN models_NNS of_IN bone_NN metastasis_NN have_HV been_BEN developed_VBN to_TO study_VB these_DTS factors_NNS One_NP such_ABL model_NN is_BEZ the_ATI Walker_NP 256_CD murine_NN carcinoma_NN , a_AT cell_NN line_NN that_WPR is_BEZ predictably_RB metastatic_JJ to_IN bone_NN in_IN rats_NNS bone-matrix_NN proteins_NNS such_IN as_IN type_NN I_PP1A collagen_VB and_CC transforming_VBG growth_NN factor-beta_NN have_HV been_BEN reported_VBN to_TO stimulate_VB Walker_NP 256_CD cell_NN motility_NN and_CC chemotaxis_NN in_IN vitro_NN clinical_JJ reports_NNS of_IN patients_NNS suffering_VBG from_IN both_ABX Paget's_NP$ disease_NN and_CC metastatic_JJ carcinoma_NN have_HV described_VBN an_AT increased_JJ metastasis_NN rate_NN to_TO pagetoid_VB bones_NNS this_DT observation_NN of_IN increased_JJ bone_NN turnover_NN promoting_VBG metastatic_JJ deposits_NNS was_BEDZ tested_VBN using_VBG the_ATI Walker_NP carcinoma_NN rat_NN model.=20_CD 203_CD rice_NN H-500_NP Leydig-cell_NP tumor_NN cells_NNS were_BED used_VBN to_TO stimulate_VB bone_NN resorption_NN with_IN increased_JJ osteoclast_NN number_NN and_CC activity_NN in_IN Leydig_NP tumor-bearing_NN rats_NNS , metastatic_JJ deposition_NN of_IN Walker_NP 256_CD cells_NNS adjacent_JJ to_TO trabecular_VB bone_NN increased_VBN by_IN more_AP than_IN 50%_NP conversely_RB , inhibition_NN of_IN bone_NN mineralization_NN , such_IN as_IN with_IN etidronate_NN , reduces_VBZ the_ATI rate_NN of_IN bone_NN metastasis_NN in_IN this_DT model_NN in_RB vivo_RB studies_NNS using_VBG prostate_NN cancer_NN cell_NN lines_NNS have_HV reported_VBN increased_VBN cellular_JJ growth_NN in_IN response_NN to_TO growth_NN factors_NNS produced_VBN by_IN bone_NN fibroblasts_NNS in_IN this_DT study_NN , lung_NN , normal_JJ rat_NN kidney_NN , and_CC National_NP Institutes_NNS of_IN Health_NP 3T3_CD fibroblastic_JJ cell-generated_RB conditioned_VBN media_NNS were_BED not_XNOT found_VBN to_TO be_BE mitogenic_JJ , whereas_CS a_AT bone-derived_JJ fibroblast_NN growth_NN factor_NN stimulated_JJ prostate_NN cancer_NN cell_NN growth_NN by_IN 180%_CD studies_NNS have_HV also_RB reported_VBN increased_JJ prostate_NN cancer_NN cell_NN proliferation_NN in_IN response_NN to_IN conditioned_VBN media_NNS from_IN human_JJ bone_NN marrow_NN it_PP3 appears_VBZ that_CS both_ABX the_ATI anatomic-mechanistic_JJ and_CC the_ATI chemotaxic-protein_NN organ_NN theories_NNS explain_VB aspects_NNS of_IN bone_NN metastasis_NN without_IN being_BEG mutually_RB exclusive_JJ 204_CD clinical_JJ Presentation_NN and_CC Diagnosis_NP 205_CD patients_NNS with_IN bone_NN metastasis_NN generally_RB present_JJ to_IN the_ATI clinician_NN with_IN pain_NN the_ATI pain_NN is_BEZ characteristically_RB described_VBN as_CS dull_JJ in_IN character_NN , constant_NN in_IN presentation_NN , and_CC gradually_RB progressive_JJ in_IN intensity_NN night_NN pain_NN and_CC pain_NN not_XNOT relieved_VBN by_IN rest_NN are_BER especially_RB worrisome_NN spinal_JJ involvement_NN may_MD present_JJ with_IN localized_VBN back_RP pain_NN or_CC extremity_NN paresthesia_NN from_IN nerve-root_NN compression_NN ; however_RB , bladder_NN and_CC bowel_NN impairment_NN or_CC complete_JJ paralysis_NN from_IN spinal_JJ cord_NN compression_NN is_BEZ uncommon_JJ where_WRB there_EX has_HVZ been_BEN a_AT history_NN of_IN carcinoma_NN , plain_JJ roentgenograms_NNS of_IN the_ATI involved_JJ extremity_NN and_CC a_AT bone_NN scan_NN to_TO define_VB the_ATI extent_NN of_IN disease_NN are_BER indicated_VBN roentgenograms_NNS need_MD not_XNOT be_BE obtained_VBN of_IN all_ABN additional_JJ sites_NNS identified_VBN on_IN bone_NN scan_NN ; however_RB , roentgenograms_NNS should_MD be_BE obtained_VBN of_IN painful_JJ upper- extremity_NN lesions_NNS and_CC all_ABN lower-extremity_NN lesions_NNS to_TO determine_VB fracture_NN risk_NN patients_NNS with_IN polyostotic_JJ disease_NN and_CC a_AT known_VBN primary_JJ neoplasm_NN generally_RB can_MD be_BE treated_VBN without_IN obtaining_VBG a_AT biopsy.=20_CD 206_NP however_RB , careful_JJ observation_NN is_BEZ needed_VBN , with_IN needle_NN biopsy_NN being_BEG reserved_VBN for_IN patients_NNS who_WPR do_DO not_XNOT respond_VB predictably_RB to_IN treatment_NN Needle_NP biopsy_NN is_BEZ preferred_VBN to_IN open_JJ procedures_NNS , since_CS it_PP3 is_BEZ minimally_RB invasive_JJ and_CC can_MD be_BE performed_VBN on_IN an_AT outpatient_NN basis_NN lesions_NNS that_CS are_BER at_IN risk_NN for_IN fracture_NN can_MD be_BE addressed_VBN with_IN surgical_JJ stabilization_NN at_IN the_ATI time_NN of_IN biopsy_NN , if_CS the_ATI results_NNS of_IN frozen_JJ section_NN confirm_VB carcinoma_NN or_CC metastatic_JJ sarcoma_NN monostotic_JJ lesions_NNS , especially_RB in_IN patients_NNS younger_JJR than_IN 40_CD years_NNS , are_BER at_IN increased_JJ risk_NN of_IN being_BEG a_AT primary_JJ sarcoma_NN and_CC need_NN to_TO be_BE imaged_VBN before_IN biopsy_NN to_TO elucidate_VB the_ATI full_JJ extent_NN of_IN the_ATI lesion_NN for_IN proper_JJ biopsy_NN planning_NN , CT_NP or_CC magnetic_JJ resonance_NN imaging_VBG is_BEZ needed_VBN A_ZZ well-planned_JJ biopsy_NN is_BEZ critical_JJ in_IN case_NN surgical_JJ resection_NN is_BEZ necessary_JJ later_RBR biopsy_NN incisions_NNS generally_RB need_NN to_TO be_BE longitudinal_JJ and_CC planned_VBN along_IN the_ATI lines_NNS of_IN a_AT possible_JJ larger_JJR surgical_JJ resection_NN the_ATI biopsy_NN should_MD pass_VB through_IN a_AT single_JJ compartment_NN and_CC not_XNOT violate_VB any_DTI neurovascular_NN structures_NNS drains_NNS , when_WRB used_VBN , are_BER brought_VBN out_RP of_IN the_ATI incision_NN , and_CC meticulous_JJ hemostasis_NN must_MD be_BE obtained_VBN before_CS closure_NN even_RB if_CS a_AT tourniquet_NN is_BEZ used_VBN 207_CD a_AT more_AP difficult_JJ problem_NN surfaces_NNS in_IN patients_NNS who_WPR present_JJ with_IN an_AT occult_JJ primary_JJ neoplasm_NN and_CC skeletal_JJ metastasis_NN identification_NN of_IN primary_JJ neoplasms_NNS in_IN the_ATI face_NN of_IN metastasis_NN has_HVZ averaged_VBN between_IN 9%_NN and_CC 48%_NN rougraff_NN et_&FW al_APS recently_RB presented_VBN a_AT diagnostic_JJ approach_NN with_IN an_AT 85%_NN success_NN rate_NN for_IN the_ATI identification_NN of_IN primary_JJ lesions_NNS in_IN their_PP$ series_NN a_AT careful_JJ history_NN and_CC a_AT physical_JJ examination_NN , followed_VBN by_IN a_AT routine_NN chest_NN roentgenogram_NN and_CC a_AT chest_NN CT_NP scan_NN if_CS the_ATI chest_NN roentgenogram_NN is_BEZ negative_JJ , yielded_VBD a_AT 66%_JJ successful_JJ diagnosis_NN rate_NN a_AT CT_NP scan_NN of_IN the_ATI abdomen_NN and_CC pelvis_NN established_VBN the_ATI diagnosis_NN in_IN an_AT additional_JJ 13%_CD of_IN cases_NNS it_PP3 is_BEZ interesting_JJ that_CS skeletal_JJ biopsy_NN was_BEDZ diagnostic_VBN in_IN only_RB 8%_JJ of_IN the_ATI cases_NNS , though_CS confirmatory_JJ in_IN an_AT additional_JJ 28%_NN of_IN cases_NNS this_DT type_NN of_IN standardized_JJ approach_NN to_IN the_ATI diagnosis_NN of_IN such_ABL lesions_NNS provides_VBZ the_ATI clinician_NN with_IN reliable_JJ results_NNS while_CS preventing_VBG unnecessary_JJ tests_NNS or_CC surgical_JJ procedures_NNS 208_NP treatment_NN 209_NP treatment_NN of_IN bone_NN metastasis_NN is_BEZ aimed_VBN at_IN relieving_VBG pain_NN , preventing_VBG development_NN of_IN pathological_JJ fractures_NNS , enhancing_VBG mobility_NN and_CC function_NN , and_CC thereby_RB improving_VBG survival_NN bone_NN pain_NN is_BEZ due_JJ to_TO either_DTX direct_JJ tumor_NN progression_NN and_CC subsequent_JJ destruction_NN or_CC biomechanical_JJ weakness_NN from_IN bone_NN loss_NN radiation_NN is_BEZ extremely_RB effective_JJ in_IN alleviating_VBG bone_NN pain_NN from_IN tumor_NN progression_NN irradiation_NN is_BEZ generally_RB the_ATI first_OD treatment_NN used_VBN , especially_RB for_IN solitary_JJ metastasis_NN approximately_RB 90%_NP of_IN patients_NNS experience_NN at_RB least_RB minimal_JJ relief_NN of_IN pain_NN , with_IN 54%_NN to_TO 66%_VB obtaining_VBG complete_JJ relief_NN the_ATI reason_NN for_IN this_DT response_NN is_BEZ unknown_JJ but_CC has_HVZ been_BEN hypothesized_VBN to_TO be_BE secondary_JJ to_TO tumor_VB shrinkage_NN or_CC to_IN inhibition_NN of_IN the_ATI release_NN of_IN chemical_JJ pain_NN mediators_NNS from_IN normal_JJ bone_NN cells.=20_CD 210_CD hormonal_JJ or_CC chemotherapeutic_JJ treatments_NNS can_MD provide_VB excellent_JJ relief_NN , especially_RB in_IN breast_NN or_CC prostate_NN cancer_NN patients_NNS a_AT problem_NN arises_VBZ when_WRB attempting_VBG to_TO clinically_RB evaluate_VB response_NN to_TO chemotherapy_VB in_IN patients_NNS suffering_VBG from_IN widespread_JJ bony_JJ metastasis_NN since_IN a_AT primary_JJ goal_NN of_IN chemotherapy_NN is_BEZ to_TO diminish_VB pain_NN , an_AT improvement_NN in_IN bone_NN pain_NN is_BEZ a_AT good_JJ clinical_JJ indicator_NN of_IN response_NN pathological_JJ fractures_NNS in_IN the_ATI upper_JJB extremity_NN , which_WDTR heal_JJ without_IN radiation_NN when_WRB adequately_RB immobilized_VBN , are_BER indicative_NN of_IN tumor_NN response_NN finally_RB , a_AT stable_JJ bone_NN scan_NN performed_VBN at_IN regular_JJ intervals_NNS after_IN chemotherapy_NN can_MD also_RB prove_VB helpful_JJ in_IN gauging_NN chemotherapeutic_JJ response_NN 211_CD diphosphonates_NNS , which_WDTR bind_VB to_TO hydroxyapatite_VB crystals_NNS , block_NN bone_NN resorption_NN , and_CC are_BER used_VBN routinely_RB for_IN Paget's_NP$ disease_NN and_CC hypercalcemia_NN secondary_JJ to_IN metastatic_JJ bone_NN disease_NN , have_HV been_BEN reported_VBN by_IN some_DTI authors_NNS to_TO reduce_VB bone_NN pain_NN in_IN a_AT randomized_JJ study_NN of_IN 131_CD patients_NNS with_IN metastatic_JJ bone_NN cancers_NNS , diphosphonates_NNS were_BED found_VBN to_TO demonstrate_VB a_AT significant_JJ decrease_NN in_IN fractures_NNS , hypercalcemia_NN , and_CC bone_NN pain_NN when_WRB compared_VBN with_IN controls_NNS in_IN addition_NN , a_AT study_NN of_IN 34_CD patients_NNS with_IN osteolytic_JJ breast_NN cancer_NN were_BED randomly_RB assigned_VBN to_IN either_DTX diphosphonates_NNS or_CC a_AT control_NN a_AT decrease_NN in_IN analgesic_JJ requirements_NNS was_BEDZ reported_VBN in_IN 88%_JJ of_IN patients_NNS receiving_VBG diphosphonates_NNS vs_IN 27%_NN of_IN controls_NNS however_RB , a_AT more_QL recent_JJ randomized_JJ study_NN consisting_VBG of_IN 57_CD patients_NNS suffering_VBG from_IN metastatic_JJ prostate_NN cancer_NN demonstrated_VBN no_ATI significant_JJ analgesic_JJ effects_NNS from_IN intravenous_JJ or_CC oral_JJ diphosphonates_NNS when_WRB compared_VBN with_IN controls_NNS Certainly_NP , the_ATI use_NN of_IN diphosphonates_NNS for_IN bone_NN pain_NN from_IN metastatic_JJ bone_NN disease_NN needs_NNS to_TO be_BE clarified_VBN 212_CD radionuclides_NNS have_HV also_RB been_BEN used_VBN to_TO treat_VB bone_NN pain_NN secondary_JJ to_TO metastatic_JJ bone_NN disease_NN sodium_NN phosphate_NN 32_CD , which_WDTR has_HVZ been_BEN used_VBN for_IN many_AP years_NNS , has_HVZ significant_JJ hematologic_JJ toxicity_NN and_CC has_HVZ largely_RB been_BEN replaced_VBN by_IN other_AP radionuclides_NNS such_IN as_IN strontium_NN chloride_NN 89_CD strontium_NN 89_CD is_BEZ a_AT beta-emitting_NN , bone-seeking_NN radionuclide_NN , which_WDTR has_HVZ been_BEN reported_VBN to_TO reduce_VB bone_NN pain_NN a_AT multicenter_JJ study_NN of_IN 83_CD patients_NNS reported_VBN a_AT dramatic_JJ or_CC substantial_JJ improvement_NN in_IN bone_NN pain_NN in_IN 55%_NN of_IN patients_NNS with_IN prostate_NN cancer_NN however_RB , 25%_NN of_IN the_ATI patients_NNS either_DTX did_DOD not_XNOT benefit_VB or_CC deteriorated_VBD during_IN the_ATI study_NN period_NN strontium_NN 89_CD holds_VBZ promise_NN for_IN the_ATI treatment_NN of_IN bone_NN pain_NN ; however_RB , further_JJB study_NN is_BEZ needed_VBN 213_CD structural_JJ weakness_NN secondary_JJ to_IN extensive_JJ bone_NN loss_NN is_BEZ not_XNOT acutely_RB reversed_VBN with_IN medical_JJ or_CC radiation_NN treatment_NN the_ATI local_JJ effects_NNS of_IN chemotherapy_NN and_CC radiation_NN depress_VB the_ATI rate_NN of_IN bone_NN regeneration_NN in_IN compromised_VBD areas_NNS in_IN such_ABL cases_NNS , an_AT approach_NN that_CS supports_VBZ the_ATI bone_NN during_IN recovery_NN is_BEZ often_RB necessary_JJ upper-extremity_NN lesions_NNS often_RB can_MD be_BE protected_VBN with_IN orthotic_JJ devices_NNS humeral_JJ lesions_NNS residing_VBG in_IN the_ATI diaphysis_NN are_BER amenable_JJ to_TO lightweight_JJ functional_JJ bracing_JJ the_ATI lower_JJR extremity_NN is_BEZ less_QL tolerant_JJ , largely_RB because_CS of_IN the_ATI high_JJ degree_NN of_IN stress_NN experienced_JJ during_IN ambulation_NN impending_JJ fractures_NNS of_IN the_ATI lower_JJR extremity_NN generally_RB require_VB surgical_JJ stabilization_NN with_IN fracture_NN fixation_NN devices_NNS or_CC prosthetic_JJ reconstruction_NN the_ATI use_NN of_IN polymethylmethacrylate_NN to_TO reconstitute_VB large_JJ bone_NN defects_NNS permits_VBZ immediate_JJ weight_NN bearing_VBG in_IN most_QL cases_NNS polymethylmethacrylate_NN maintains_VBZ excellent_JJ rigidity_NN , especially_RB when_WRB compressively_RB loaded_VBN , and_CC is_BEZ not_XNOT adversely_RB affected_VBN by_IN radiation_NN 214_CD the_ATI indications_NNS for_IN prophylactic_JJ fixation_NN of_IN impending_JJ fractures_NNS have_HV not_XNOT been_BEN clearly_RB defined_VBN ; most_AP of_IN the_ATI criteria_NNS are_BER generated_VBN from_IN retrospective_JJ studies_NNS of_IN plain_JJ roentgenograms_NNS often-quoted_JJ roentgenographic_JJ criteria_NNS for_IN an_AT impending_JJ fracture_NN , which_WDTR have_HV been_BEN cumulated_VBN from_IN several_AP studies_NNS , are_BER given_VBN in_IN Table_NP 1_CD1 these_DTS criteria_NNS are_BER guidelines_NNS and_CC should_MD not_XNOT be_BE strict_JJ rules_NNS one_CD1 of_IN the_ATI problems_NNS with_IN plain_JJ roentgenograms_NNS is_BEZ that_CS bone_NN loss_NN must_MD approach_VB 30%_NP to_IN 50%_NP before_CS it_PP3 becomes_VBZ apparent_JJ in_IN addition_NN , in_IN metastatic_JJ lesions_NNS characterized_VBN by_IN bone_NN production_NN (_( eg_NN , prostate_NN )_) , clear_JJ evidence_NN of_IN bone_NN destruction_NN can_MD be_BE difficult_JJ to_TO assess_VB roentgenographically_RB 215_CD an_AT objective_JJ evaluation_NN of_IN these_DTS criteria_NNS was_BEDZ undertaken_VBN in_IN a_AT study_NN by_IN Keene_NP et_&FW al_APS , who_WPR focused_VBD only_RB on_IN breast_NN cancer_NN patients_NNS with_IN proximal_JJ femoral_JJ lesions_NNS in_IN their_PP$ study_NN , critical_JJ dimensions_NNS for_IN fracture_NN based_VBN on_IN lesion_NN size_NN and_CC percentage_NN of_IN cortical_JJ involvement_NN were_BED not_XNOT identifiable_JJ because_CS of_IN similar_JJ ranges_NNS between_IN patients_NNS who_WPR fractured_VBN and_CC those_DTS who_WPR did_DOD not_XNOT the_ATI reliability_NN of_IN roentgenographic_JJ evaluation_NN was_BEDZ questioned_VBN because_CS lesion_NN size_NN could_MD vary_VB on_IN any_DTI two_CD roentgenograms_NNS of_IN the_ATI same_AP patient_NN bone_NN pain_NN unresponsive_JJ to_TO radiation_NN was_BEDZ also_RB evaluated_VBN and_CC found_VBN not_XNOT to_TO correlate_VB with_IN fracture_NN risk_NN .=20_CD 216_CD to_TO address_VB these_DTS inconsistencies_NNS , Mirels_NNS proposed_VBN a_AT scoring_NN system_NN for_IN quantitating_VBG the_ATI risk_NN for_IN pathological_JJ fracture_NN (_( Table_NP 2_CD )_) this_DT system_NN assigns_VBZ a_AT numerical_JJ score_NN to_IN four_CD variables_NNS , with_IN a_AT cumulative_JJ score_NN of_IN 7_CD points_NNS or_CC less_QL indicating_VBG a_AT low_JJ risk_NN for_IN fracture_NN (_( 5%_NN )_) Scores_NP of_IN 9_CD and_CC above_IN have_HV at_RB least_RB a_AT 33%_CD risk_NN for_IN fracture_NN , while_CS a_AT score_NN of_IN 8_CD is_BEZ suggestive_JJ of_IN a_AT 15%_CD fracture_NN risk_NN this_DT type_NN of_IN scoring_NN system_NN holds_VBZ the_ATI most_QL promise_NN for_IN quantitatively_RB predicting_VBG patients_NNS at_IN risk_NN for_IN pathological_JJ fractures_NNS 217_CD once_RB a_AT pathological_JJ fracture_NN has_HVZ occurred_VBN , aggressive_JJ surgical_JJ treatment_NN should_MD be_BE undertaken_VBN in_IN most_QL cases_NNS the_ATI goals_NNS and_CC benefits_NNS of_IN rigid_JJ fixation_NN of_IN pathological_JJ fractures_NNS include_VB pain_NN relief_NN , resumption_NN of_IN ambulation_NN , enhancement_NN of_IN survival_NN , and_CC improved_JJ fracture_NN healing_NN Patients_NP who_WPR are_BER unstable_JJ medically_RB or_CC who_WPR have_HV a_AT life_NN expectancy_NN of_IN less_AP than_IN 4_CD weeks_NNS are_BER not_XNOT surgical_JJ candidates_NNS Habermann_NP found_VBD that_CS 97%_JJ of_IN patients_NNS had_HVD good_JJ to_IN excellent_JJ pain_NN relief_NN after_IN internal_JJ fixation_NN or_CC prosthetic_JJ replacement.=20_CD 218_CD regaining_VBG ambulatory_NN status_NN is_BEZ imperative_JJ for_IN patient_NN survival_NN Harrington_NP reported_VBD a_AT success_NN rate_NN of_IN 95%_NN in_IN returning_VBG his_PP$ patients_NNS to_TO prefracture_NN ambulatory_NN status_NN with_IN surgical_JJ intervention_NN aggressive_JJ fracture_NN fixation_NN with_IN current_JJ methods_NNS has_HVZ led_VBN to_IN improved_JJ patient_NN survival_NN , 24.6_NN months_NNS as_CS opposed_VBN to_IN historical_JJ controls_NNS of_IN 11.6_CD months_NNS , after_IN pathological_JJ fracture_NN it_PP3 has_HVZ been_BEN well_RB documented_VBN that_CS radiation_NN adversely_RB affects_VBZ fracture_NN healing_NN successful_JJ fracture_NN healing_NN will_MD be_BE achieved_VBN in_IN 90%_NP of_IN patients_NNS who_WPR survive_VB longer_RBR than_IN 6_CD months_NNS , are_BER surgically_RB stabilized_VBD , and_CC receive_VB a_AT radiation_NN dose_NN of_IN no_ATI more_AP than_IN 30_CD Gy_NP 219_CD the_ATI spine_NN is_BEZ the_ATI most_QL common_JJ site_NN for_IN skeletal_JJ metastasis_NN of_IN patients_NNS who_WPR die_VB from_IN cancer_NN , 70%_NP demonstrate_VB vertebral_JJ metastasis_NN on_IN postmortem_NN examination_NN initial_JJ roentgenographic_JJ evaluation_NN generally_RB includes_VBZ plain_JJ roentgenograms_NNS and_CC bone_NN scintigraphy_NN computed_JJ tomography_NN and_CC magnetic_JJ resonance_NN imaging_VBG of_IN the_ATI spine_NN are_BER reserved_VBN for_IN patients_NNS who_WPR present_JJ with_IN vertebral_JJ body_NN compression_NN of_IN 50%_NP or_CC greater_JJR or_CC who_WPR present_JJ with_IN neurological_JJ involvement_NN once_RB workup_JJ is_BEZ complete_JJ , patients_NNS can_MD generally_RB be_BE divided_VBN into_IN five_CD categories_NNS , depending_VBG on_IN the_ATI extent_NN of_IN neurological_JJ involvement_NN or_CC bone_NN destruction_NN (_( Table_NP 3_CD )_) the_ATI majority_NN of_IN patients_NNS fall_VB into_IN categories_NNS I_PP1A , II_NP , or_CC III_NP and_CC can_MD be_BE treated_VBN nonoperatively_RB with_IN either_DTX chemotherapy_NN , hormonal_JJ manipulation_NN , or_CC irradiation_NN operative_JJ treatment_NN is_BEZ reserved_VBN for_IN patients_NNS with_IN either_DTX bony_JJ collapse_NN and_CC instability_NN (_( category_NN IV_NP )_) or_CC with_IN vertebral_JJ body_NN collapse_NN that_CS results_NNS in_IN retropulsion_NN of_IN bone_NN and_CC disk_NN fragments_NNS directly_RB into_IN the_ATI cord_NN (_( category_NN V).=20_NP 220_CD the_ATI treatment_NN of_IN choice_NN is_BEZ anterior_JJ resection_NN of_IN the_ATI diseased_JJ vertebral_JJ body_NN and_CC reconstruction_NN with_IN bone_NN graft_NN or_CC methylmethacrylate_NN and_CC spinal_JJ instrumentation_NN as_IN needed_VBN recent_JJ advances_NNS in_IN spinal_JJ instrumentation_NN have_HV resulted_VBN in_IN better_JJR methods_NNS for_IN the_ATI stabilization_NN of_IN vertebral_JJ body_NN collapse_NN secondary_JJ to_IN metastatic_JJ disease_NN titanium_NN cages_NNS , anterior_JJ cervical_JJ plates_NNS , and_CC distraction_NN rods_NNS , when_WRB used_VBN in_IN conjunction_NN with_IN bone_NN graft_NN or_CC cementation_NN , have_HV found_VBN a_AT wide_JJ applicability_NN in_IN cervical_JJ and_CC thoracic_JJ reconstructions_NNS occasionally_RB , posterior_JJ instrumentation_NN is_BEZ necessary_JJ where_WRB extreme_JJ instability_NN is_BEZ apparent_JJ once_RB again_RB , the_ATI goal_NN of_IN surgery_NN is_BEZ to_TO prevent_VB neurological_JJ compromise_NN and_CC restore_VB ambulatory_NN ability_NN at_RB least_RB 62%_NN of_IN initially_RB paraplegic_JJ patients_NNS will_MD regain_VB enough_QLP neurological_JJ recovery_NN to_TO walk_VB after_IN surgical_JJ decompression_NN patients_NNS who_WPR present_JJ with_IN rapid_JJ , as_CS opposed_VBN to_IN chronic_JJ , spinal_JJ cord_NN compromise_NN and_CC paraplegia_NN exhibit_NN a_AT poor_JJ prognosis_NN for_IN recovery_NN of_IN function_NN however_RB , it_PP3 must_MD be_BE emphasized_VBN that_CS most_QL patients_NNS do_DO not_XNOT present_JJ with_IN this_DT degree_NN of_IN neurological_JJ compromise_NN and_CC respond_VB well_RB to_TO radiation_NN or_CC chemotherapy_NN without_IN surgery_NN 221_CD metastatic_JJ bone_NN disease_NN continues_VBZ to_TO be_BE a_AT difficult_JJ management_NN problem_NN further_JJB research_NN is_BEZ needed_VBN to_TO define_VB chemotaxic_JJ proteins_NNS and_CC biochemical_JJ mechanisms_NNS required_VBN for_IN the_ATI metastatic_JJ deposition_NN of_IN neoplasms_NNS in_IN bone_NN a_AT better_JJR understanding_NN of_IN these_DTS processes_NNS will_MD certainly_RB aid_NN in_IN medical_JJ prevention_NN , as_CS opposed_VBN to_IN surgical_JJ intervention_NN , for_IN patients_NNS suffering_VBG from_IN metastatic_JJ bone_NN disease_NN JDIVE_NP does_DOZ This_NN Dizzy_NPT Patient_NP Have_NP a_AT Serious_JJ Form_&FW of_IN Vertigo_NP ? 2_CD patient_NN 1_CD1 3_CD a_AT 52-year-old_JJB woman_NN was_BEDZ admitted_VBN to_IN the_ATI hospital_NN because_CS of_IN nausea_NN , a_AT constant_JJ spinning_NN sensation_NN , and_CC vomiting_NN of_IN 24_CD hours'_NNS$ duration_NN any_DTI movement_NN of_IN her_PP$ head_NN made_VBD these_DTS symptoms_NNS worse_JJR on_IN examination_NN , she_PP3A had_HVD bilateral_JJ horizontal_JJ spontaneous_JJ nystagmus_JJ two_CD days_NNS later_RBR , after_IN symptomatic_JJ improvement_NN , she_PP3A was_BEDZ dismissed_VBN at_IN follow-up_NN 2_CD weeks_NNS later_RBR , her_PP$ symptoms_NNS and_CC nystagmus_JJ had_HVD completely_RB resolved_VBN 4_CD patient_NN 2_CD 5_CD a_AT 70-year-old_JJB woman_NN had_HVD a_AT 4-month_JJ history_NN of_IN an_AT intermittent_JJ whirling_JJ sensation_NN when_WRB turning_VBG her_PP$ head_NN and_CC especially_RB when_WRB rolling_JJ over_RP in_IN bed_NN On_NP examination_NN , a_AT left-side-down_NN head-hanging_NN maneuver_JJ elicited_JJ rotatory_NN nystagmus_JJ , with_IN the_ATI fast_RB component_NN to_IN the_ATI left_JJ ear_NN (_( Figure_NP 1_CD1 )_) there_EX was_BEDZ a_AT latency_NN of_IN about_RB 3_CD seconds_NNS before_IN the_ATI onset_NN of_IN nystagmus_JJ , which_WDTR lasted_VBD approximately_RB 10_CD seconds_NNS 6_CD WHY_NPT EVALUATE_NP VERTIGO_NP ? 7_CD _** vertigo_NN _** is_BEZ defined_VBN in_IN Webster's_NP$ dictionary_NN as_IN a_AT disturbance_NN _** in_IN which_WDTR the_ATI external_JJ world_NN seems_VBZ to_TO revolve_VB around_IN the_ATI individual_JJ or_CC in_IN which_WDTR the_ATI individual_JJ seems_VBZ to_TO revolve_VB in_IN space_NN _** vertigo_NN is_BEZ an_AT illusion_NN of_IN motion_NN and_CC is_BEZ one_CD1 of_IN several_AP forms_NNS of_IN dizziness_NN the_ATI word_NN dizziness_NN is_BEZ derived_VBN from_IN the_ATI old_JJ English_JNP word_NN dysig_NN , meaning_NN foolish_JJ or_CC stupid_JJ The_NP modern_JJ usage_NN of_IN the_ATI word_NN includes_VBZ _** a_AT whirling_JJ sensation_NN in_IN the_ATI head_NN with_IN a_AT tendency_NN to_TO fall_VB , _** _** mentally_RB confused_JJ or_CC dazed_VBN , _** and_CC _** giddiness=20_CD 8_CD in_IN one_CD1 study_NN from_IN a_AT general_JJ internal_JJ medicine_NN outpatient_NN clinic_NN , dizziness_NN was_BEDZ the_ATI third_OD most_QL frequent_JJ complaint_NN of_IN patients_NNS in_IN a_AT national_JJ survey_NN reported_VBN in_IN 1989_CD , it_PP3 was_BEDZ the_ATI 13th_OD most_QL frequent_JJ reason_NN for_IN visits_NNS to_IN internists_NNS in_IN the_ATI United_NP States_NP dizziness_NN is_BEZ often_RB a_AT diagnostic_JJ problem_NN in_IN the_ATI emergency_NN department_NN among_IN patients_NNS seen_VBN in_IN an_AT emergency_NN department_NN , in_IN an_AT outpatient_NN clinic_NN , and_CC in_IN two_CD subspecialty_NN dizziness_NN clinics_NNS , vertigo_NN was_BEDZ the_ATI most_QL frequent_JJ category_NN of_IN dizziness_NN 9_CD most_AP patients_NNS with_IN dizziness_NN can_MD be_BE classified_VBN as_CS having_HVG one_CD1 of_IN the_ATI following_JJ syndromes_NNS : 10_CD impaired_VBN perfusion_NN of_IN the_ATI central_JJ nervous_JJ system_NN or_CC near_IN syncope_NN (_( eg_NN , orthostatic_JJ hypotension_NN , cardiac_JJ presyncope_NN )_) 11_CD disequilibrium_RB , a_AT sensation_NN of_IN imbalance_NN when_WRB standing_VBG or_CC walking_VBG (_( eg_NN , multiple_JJ sensory_JJ deficits_NNS )_) 12_CD psychogenic_JJ dizziness_NN (_( eg_NN , major_JJ depression_NN , anxiety_NN disorder_NN , and_CC somatization_NN disorder_NN )_) 13_CD vertigo_NN (_( eg_NN , Meniere's_NP$ disease_NN and_CC vestibular_NN neuronitis_NN ) _) 14_CD usually_RB dizziness_JJ can_MD be_BE classified_VBN on_IN the_ATI basis_NN of_IN information_NN obtained_VBN from_IN the_ATI medical_JJ history_NN and_CC physical_JJ examination_NN in_IN this_DT article_NN , we_PP1AS concentrate_VB on_IN the_ATI evaluation_NN of_IN vertigo_NN , the_ATI most_QL common_JJ category_NN of_IN dizziness_NN serious_JJ forms_NNS of_IN vertigo_NN are_BER due_JJ to_IN conditions_NNS associated_VBN with_IN increased_JJ mortality_NN or_CC long-term_JJB disability_NN vertigo_NN severe_JJ enough_QLP to_TO impair_VB daily_JJ functioning_NN and_CC lasting_JJ for_IN more_AP than_IN a_AT month_NN would_MD be_BE included_VBN as_IN a_AT serious_JJ form_NN of_IN vertigo_NN 15_CD the_ATI importance_NN of_IN recognizing_VBG a_AT patient's_NN$ complaint_NN of_IN dizziness_NN as_IN vertigo_NN is_BEZ that_CS it_PP3 narrows_VBZ the_ATI list_NN of_IN possible_JJ causes_NNS customarily_RB the_ATI causes_NNS of_IN vertigo_NN are_BER divided_VBN into_IN central_JJ causes_NNS (_( lesions_NNS of_IN the_ATI central_JJ nervous_JJ system_NN )_) and_CC peripheral_JJ causes_NNS (_( lesions_NNS of_IN the_ATI vestibular_NN labyrinth_NN or_CC nerve_NN or_CC both_ABX )_) (_( Table_NP 1_CD1 )_) because_CS of_IN the_ATI importance_NN of_IN detecting_JJ lesions_NNS or_CC diagnosing_VBG syndromes_NNS that_DT can_MD be_BE treated_VBN and_CC because_CS of_IN the_ATI need_NN to_TO determine_VB prognosis_NN , physicians_NNS should_MD attempt_VB to_TO make_VB a_AT specific_JJ diagnosis_NN for_IN patients_NNS with_IN vertigo_NN 16_CD most_AP cases_NNS of_IN vertigo_NN are_BER due_JJ to_IN lesions_NNS of_IN the_ATI vestibular_NN nerve_NN or_CC labyrinth_NN

in_IN two_CD dizziness_NN clinics_NNS , the_ATI most_QL common_JJ cause_NN of_IN vertigo_NN was_BEDZ benign_JJ paroxysmal_JJ positional_JJ vertigo_NN 17_CD PATHOPHYSIOLOGY_NPT OF_NPT VERTIGO_NPT AND_NP NYSTAGMUS_NP 18_CD origins_NNS of_IN Vertigo_NP 19_CD before_CS discussing_VBG how_WRB the_ATI medical_JJ history_NN and_CC physical_JJ examination_NN can_MD help_VB in_IN diagnosing_VBG the_ATI various_JJ disorders_NNS that_CS cause_NN vertigo_NN , a_AT brief_JJ explanation_NN of_IN the_ATI pathophysiology_NN of_IN vertigo_NN and_CC its_PP$ causes_NNS is_BEZ necessary_JJ the_ATI maintenance_NN of_IN the_ATI sense_NN of_IN balance_NN and_CC spatial_JJ orientation_NN depends_VBZ on_IN input_NN from_IN the_ATI vestibular_NN labyrinth_NN , visual_JJ system_NN , and_CC proprioceptive_JJ nerves_NNS arising_VBG from_IN tendons_NNS , muscles_NNS , and_CC joints_NNS the_ATI vestibular_NN nuclei_NNS , which_WDTR are_BER in_IN the_ATI medulla_NN and_CC lower_JJR pons_NNS , receive_VB input_NN from_IN the_ATI vestibular_NN labyrinth_NN via_IN the_ATI vestibular_JJ branch_NN of_IN cranial_JJ nerve_NN VIII_NP and_CC from_IN the_ATI cerebellum_NN the_ATI vestibular_NN nuclei_NNS , in_IN turn_VB , send_VB efferent_NN fibers_NNS to_IN the_ATI cerebellum_NN , the_ATI medial_JJ longitudinal_JJ fasciculus_JJ , and_CC the_ATI vestibulospinal_JJ tract_NN visceral_JJ manifestations_NNS of_IN vertigo_NN (_( such_IN as_IN nausea_NN and_CC vomiting_NN )_) are_BER caused_VBN by_IN altered_JJ input_NN to_IN the_ATI dorsal_JJ nucleus_NN of_IN the_ATI vagus_JJ nerve_NN from_IN the_ATI vestibular_NN nuclei_NNS conscious_JJ awareness_NN of_IN vertigo_NN resides_NNS in_IN the_ATI superior_JJ temporal_JJ gyrus_NN of_IN the_ATI cerebral_JJ cortex_NN and_CC involves_VBZ a_AT mismatch_NN between_IN input_NN to_IN the_ATI cerebral_JJ cortex_NN from_IN the_ATI visual_JJ , proprioceptive_JJ , and_CC vestibular_NN systems_NNS lesions_NNS in_IN various_JJ locations_NNS , including_IN the_ATI inner_JJB ear_NN , brain_NN stem_NN , and_CC cerebellum_NN , may_MD all_ABN be_BE manifested_VBN as_IN vertigo_NN

20_CD origins_NNS of_IN Nystagmus_JJ 21_CD nystagmus_NN is_BEZ the_ATI objective_JJ accompaniment_NN of_IN vertigo_NN and_CC is_BEZ defined_VBN best_JJT as_IN a_AT _** rhythmical_JJ oscillation_NN of_IN the_ATI eyes_NNS , with_IN a_AT fast_RB movement_NN in_IN one_CD1 direction_NN and_CC a_AT slow_JJ movement_NN in_IN the_ATI other_AP _** the_ATI fast_RB component_NN may_MD be_BE horizontal_JJ , vertical_JJ , rotatory_JJB , or_CC any_DTI combination_NN of_IN these_DTS 22_CD there_EX are_BER two_CD clinically_RB relevant_JJ kinds_NNS of_IN nystagmus_VBN in_IN evaluating_VBG vertigo:=20_CD 23_CD spontaneous_JJ nystagmus_NN is_BEZ elicited_VBN by_IN having_HVG the_ATI patient_NN look_NN straight_RB ahead_RB , up_RP , down_RP , to_IN the_ATI right_JJ , and_CC to_IN the_ATI left_NN this_DT type_NN of_IN nystagmus_NN is_BEZ not_XNOT influenced_VBN by_IN head_NN position_NN it_PP3 is_BEZ normal_JJ to_TO have_HV a_AT few_AP beats_VBZ of_IN nystagmus_JJ with_IN extreme_JJ lateral_JJ gaze_NN .=20_CD 24_CD positional_JJ nystagmus_NN is_BEZ elicited_VBN by_IN a_AT head-hanging_NN maneuver_NN (_( Figure_NP 1_CD1 )_) 25_CD altered_JJ input_NN passing_VBG from_IN the_ATI vestibular_NN nuclei_NNS to_IN the_ATI nuclei_NNS of_IN the_ATI extraocular_NN muscles_NNS through_IN the_ATI medial_JJ longitudinal_JJ fasciculus_JJ and_CC related_JJ pathways_NNS in_IN the_ATI reticular_NN formation_NN produces_VBZ nystagmus_JJ this_DT input_NN may_MD be_BE modified_VBN by_IN information_NN arising_VBG from_IN the_ATI cerebral_JJ cortex_NN and_CC the_ATI cerebellum_NN for_IN example_NN , the_ATI fast_RB component_NN of_IN spontaneous_JJ nystagmus_JJ depends_VBZ on_IN interaction_NN between_IN the_ATI vestibular_NN system_NN and_CC the_ATI cerebral_JJ cortex_NN 26_CD HOW_NPT TO_NPT ELICIT_NPT THE_NPT SYMPTOMS_NPT AND_NPT SIGNS_NPT OF_NP VERTIGO_NP 27_CD first_OD , Distinguish_NPT Vertigo_NPT From_NPT Other_NP Causes_NP of_IN Dizziness_NN 28_CD patients_NNS often_RB have_HV difficulty_NN describing_VBG symptoms_NNS of_IN dizziness_NN , and_CC even_RB those_DTS who_WPR have_HV disorders_NNS that_WPR produce_VB vertigo_NN may_MD not_XNOT clearly_RB describe_VB a_AT hallucination_NN of_IN movement_NN as_CS Olsson_NP and_CC Atkins_NNS pointed_VBD out_RP , _** A_ZZ person_NN is_BEZ so_QL rarely_RB conscious_JJ of_IN his_PP$ own_AP vestibular_NN system_NN , he_PP3A has_HVZ a_AT great_JJ deal_NN of_IN trouble_NN describing_VBG his_PP$ symptoms_NNS to_IN a_AT doctor_NN _** thus_RB , clues_NNS must_MD be_BE gathered_VBN from_IN the_ATI medical_JJ history_NN and_CC physical_JJ examination_NN to_TO classify_VB the_ATI dizziness_NN properly_RB 29_CD dizziness_NN when_WRB standing_VBG may_MD be_BE due_JJ to_TO vertigo_NN , decreased_VBD cerebral_JJ perfusion_NN , or_CC disequilibrium_NN if_CS the_ATI patient_NN reports_NNS having_HVG symptoms_NNS of_IN dizziness_NN primarily_RB while_CS standing_VBG , the_ATI blood_NN pressure_NN should_MD be_BE checked_VBN with_IN the_ATI patient_NN in_IN the_ATI supine_NN position_NN and_CC also_RB after_IN standing_VBG for_IN 5_CD minutes_NNS if_CS there_EX is_BEZ an_AT orthostatic_JJ decrease_NN in_IN blood_NN pressure_NN , the_ATI symptom_NN is_BEZ likely_JJ due_JJ to_TO impaired_VBN central_JJ nervous_JJ system_NN perfusion_NN 30_CD unsteadiness_JJ while_CS walking_VBG , especially_RB in_IN elderly_JJ patients_NNS , is_BEZ often_RB due_JJ to_TO disequilibrium_VB (_( a_AT feeling_NN of_IN imbalance_NN )_) the_ATI cause_NN is_BEZ usually_RB multifactorial_JJ on_IN examination_NN , the_ATI findings_NNS of_IN decreased_VBD visual_JJ acuity_NN and_CC signs_NNS of_IN peripheral_JJ neuropathy_NN or_CC abnormal_JJ vestibular_NN function_NN support_NN a_AT diagnosis_NN of_IN disequilibrium_NN 31_CD dizziness_NN when_WRB turning_VBG , and_CC especially_RB when_WRB rolling_JJ over_RP in_IN bed_NN , is_BEZ usually_RB due_JJ to_IN vertigo_NN 32_CD psychogenic_JJ dizziness_NN is_BEZ a_AT diagnosis_NN of_IN exclusion_NN that_WPR should_MD be_BE considered_VBN especially_RB in_IN patients_NNS with_IN psychiatric_JJ illnesses_NNS , such_IN as_IN major_JJ depression_NN , anxiety_NN disorder_NN , and_CC a_AT somatization_NN disorder_NN in_IN this_DT setting_VBG , the_ATI patient_NN should_MD be_BE asked_VBN to_TO hyperventilate_VB for_IN 2_CD minutes_NNS and_CC then_RN asked_VBD whether_CS the_ATI feeling_NN associated_VBN with_IN hyperventilation_NN is_BEZ exactly_RB the_ATI same_AP as_IN the_ATI dizzy_JJ symptom_NN the_ATI physician_NN should_MD initially_RB hyperventilate_NN along_RP with_IN the_ATI patient_NN ; this_DT approach_NN encourages_VBZ the_ATI patient_NN and_CC demonstrates_VBZ the_ATI desired_JJ rate_NN and_CC depth_NN of_IN breathing_NN for_IN the_ATI test_NN if_CS hyperventilation_NN reproduces_VBZ the_ATI symptom_NN , the_ATI dizziness_NN is_BEZ often_RB psychogenic_JJ however_RB , the_ATI usefulness_NN of_IN hyperventilation_NN in_IN diagnosing_VBG psychogenic_JJ dizziness_NN is_BEZ unclear_JJ in_IN a_AT study_NN by_IN Kroenke_NP et_&FW al_APS of_IN 100_CD ambulatory_NN patients_NNS with_IN a_AT chief_JJB complaint_NN of_IN dizziness_NN , symptoms_NNS of_IN dizziness_NN were_BED reproduced_VBN by_IN hyperventilation_NN in_IN 21_CD ; however_RB , only_RB one_CD1 of_IN these_DTS patients_NNS had_HVD hyperventilation_NN as_IN the_ATI primary_JJ cause_NN of_IN dizziness_NN most_AP of_IN them_PP3OS had_HVD dizziness_JJ inducible_NN by_IN other_AP maneuvers_NNS in_IN addition_NN to_TO hyperventilation_VB further_JJB studies_NNS of_IN the_ATI hyperventilation_NN maneuver_NN in_IN the_ATI evaluation_NN of_IN patients_NNS with_IN suspected_VBD psychogenic_JJ dizziness_NN are_BER needed_VBN in_IN this_DT study_NN of_IN 100_CD patients_NNS , only_RB 16%_CD had_HVD pure_JJ psychogenic_JJ dizziness_NN , but_CC 24%_NN had_HVD other_AP causes_NNS of_IN dizziness_NN exacerbated_VBN by_IN psychiatric_JJ illness_NN 33_CD second_OD , Take_NP a_AT Proper_NPT History_NPT From_NPT Patients_NPT With_NP Vertigo_NP 34_CD after_IN it_PP3 is_BEZ clear_JJ that_CS the_ATI patient_NN is_BEZ describing_VBG vertigo_NN , further_JJB questions_NNS help_VB elicit_VB clues_NNS about_IN its_PP$ specific_JJ cause_NN 35_CD ask_VB When_NP the_ATI Dizziness_NN Occurs_NNS it_PP3 is_BEZ probably_RB more_QL important_JJ to_TO ask_VB a_AT patient_NN about_IN the_ATI circumstances_NNS in_IN which_WDTR the_ATI dizziness_NN occurs_VBZ than_IN to_TO ask_VB for_IN a_AT description_NN of_IN the_ATI dizziness_NN dizziness_NN related_VBN to_TO early-morning_NN activities_NNS is_BEZ somewhat_RB helpful_JJ in_IN distinguishing_VBG between_IN peripheral_JJ and_CC central_JJ vertigo_NN matutinal_JJ vertigo_NN (_( vertigo_NN on_IN first_OD arising_VBG in_IN the_ATI morning_NN )_) is_BEZ usually_RB due_JJ to_IN a_AT peripheral_JJ vestibular_NN disorder_NN 36_CD ask_VB About_NPT Other_NPT Otologic_NP Symptoms-Associated_NP otologic_JJ symptoms_NNS can_MD be_BE helpful_JJ in_IN identifying_VBG a_AT peripheral_JJ cause_NN of_IN vertigo_NN hearing_VBG loss_NN and_CC vertigo_NN are_BER common_NN in_IN patients_NNS with_IN otosclerosis_NN episodes_NNS of_IN hearing_VBG loss_NN with_IN vertigo_NN , tinnitus_JJ , and_CC a_AT sensation_NN of_IN fullness_NN in_IN the_ATI ear_NN occur_VB in_IN patients_NNS with_IN Meniere's_NP$ disease_NN patients_NNS with_IN acoustic_JJ neuromas_NNS usually_RB present_JJ with_IN hearing_VBG loss_NN rather_RB than_IN vertigo_NN most_AP of_IN these_DTS patients_NNS notice_NN dizziness_NN but_CC complain_VB of_IN unsteadiness_JJ rather_RB than_IN vertigo_NN 37_CD ask_VB About_NPT Other_NPT Neurological_NP Symptoms-Symptoms_NP of_IN neurological_JJ disease_NN , such_IN as_IN weakness_NN , difficulty_NN with_IN speech_NN , or_CC diplopia_NN , in_IN addition_NN to_TO vertigo_NN suggest_VB a_AT central_JJ cause_NN 38_CD ask_VB About_NPT Symptom_NP Patterns-Patients_NP with_IN vestibular_NN neuronitis_NN (_( also_RB called_VBN _** labyrinthitis_NN _** )_) , benign_JJ paroxysmal_JJ positional_JJ vertigo_NN , and_CC recurrent_JJ vestibulopathy_NN (_( also_RB called_VBN _** benign_JJ recurrent_JJ vertigo_NN _** and_CC _** vestibular_NN Meniere's_NN$ disease_NN _** )_) have_HV normal_JJ hearing_NN patients_NNS with_IN benign_JJ paroxysmal_JJ positional_JJ vertigo_NN (_( also_RB called_VBN _** benign_JJ paroxysmal_JJ positional_JJ nystagmus_JJ _** and_CC _** cupulolithiasis_NN _** )_) have_HV intermittent_JJ episodes_NNS of_IN vertigo_NN with_IN head_NN turning_NN vestibular_NN neuronitis_NN is_BEZ characterized_VBN by_IN a_AT relatively_RB sudden_JJ onset_NN of_IN severe_JJ , constant_JJ vertigo_NN (_( made_VBN worse_JJR by_IN head_NN movement_NN )_) that_CS resolves_VBZ after_IN days_NNS or_CC weeks_NNS patients_NNS with_IN recurrent_JJ vestibulopathy_NN have_HV intermittent_JJ episodes_NNS of_IN constant_JJ vertigo_NN lasting_JJ for_IN minutes_NNS or_CC hours_NNS vertigo_NN (_( with_IN or_CC without_IN hearing_VBG loss_NN )_) in_IN a_AT patient_NN who_WPR has_HVZ recently_RB received_JJ aminoglycoside_NN antibiotics_NNS may_MD be_BE due_JJ to_IN the_ATI toxic_JJ effect_NN these_DTS agents_NNS have_HV on_IN the_ATI vestibular_NN labyrinth_NN 39_CD how_WRB to_IN Examine_NPT Patients_NPT With_NP Vertigo_NP 40_CD findings_NNS on_IN physical_JJ examination_NN can_MD help_VB physicians_NNS detect_VB abnormalities_NNS that_DT can_MD be_BE used_VBN to_TO determine_VB the_ATI cause_NN of_IN vertigo_NN 41_CD perform_VB a_AT Brief_NPT Neurological_NP Examination-Look_NP for_IN cranial_JJ nerve_NN palsies_NNS , weakness_NN , reflex_NN changes_NNS , ataxia_NN , decreased_VBD sensation_NN in_IN the_ATI feet_NNS , and_CC abnormalities_NNS of_IN gait_NN and_CC station_NN vertical_JJ nystagmus_NN is_BEZ associated_VBN with_IN lesions_NNS of_IN the_ATI vestibular_NN nuclei_NNS or_CC of_IN the_ATI cerebellar_NN vermis_NN neurological_JJ findings_NNS other_AP than_IN pathological_JJ nystagmus_JJ suggest_VB that_CS the_ATI lesion_NN is_BEZ central_JJ 42_CD examine_VB the_ATI Ears-Briefly_NP check_NN hearing_VBG sensation_NN with_IN a_AT mechanical_JJ wristwatch_NN or_CC tuning_NN fork_NN cholesteatoma_RB , a_AT complication_NN of_IN chronic_JJ otitis_NN media_NNS that_DT can_MD present_JJ with_IN hearing_VBG loss_NN , drainage_NN from_IN the_ATI ear_NN , and_CC vertigo_NN , may_MD be_BE found_VBN ; the_ATI usual_JJ treatment_NN for_IN this_DT is_BEZ surgery_NN Alternatively_NP , vesicles_NP associated_VBN with_IN herpes_NNS zoster_JJ oticus_JJ (_( also_RB called_VBN _** Ramsay_NP Hunt_NP syndrome_NN _** )_) may_MD be_BE present_JJ ; patients_NNS with_IN this_DT condition_NN often_RB have_HV facial_JJ palsy_NN and_CC deafness_NN together_RB with_IN vertigo_NN 43_CD check_NN for_IN Spontaneous_JJ Nystagmus-Patients_NP with_IN vestibular_NN neuronitis_NN usually_RB have_HV spontaneous_JJ horizontal_JJ nystagmus_JJ or_CC a_AT mixture_NN of_IN spontaneous_JJ horizontal_JJ nystagmus_JJ and_CC rotatory_JJ nystagmus_JJ patients_NNS with_IN disorders_NNS of_IN the_ATI central_JJ nervous_JJ system_NN may_MD also_RB have_HV spontaneous_JJ nystagmus_JJ in_IN most_AP of_IN the_ATI patients_NNS examined_VBN by_IN Silvoniemi_NP , Lachman_NP and_CC Stahle_NP , and_CC Aantaa_NP and_CC Virolainen_NP , nystagmus_JJ was_BEDZ readily_RB apparent_JJ , but_CC in_IN some_DTI , detection_NN required_VBN Frenzel_NP glasses_NNS or_CC electronystagmographic_JJ monitoring_VBG with_IN the_ATI patients'_NNS$ eyes_NNS closed_VBN patients_NNS with_IN vestibular_NN neuronitis_NN may_MD also_RB have_HV positional_JJ nystagmus_JJ patient_NN 1_CD1 had_HVD vestibular_NN neuronitis_NN 44_CD perform_VB a_AT Head-Hanging_NP Maneuver_NP most_AP physicians_NNS test_VB for_IN positional_JJ nystagmus_JJ with_IN a_AT method_NN first_OD outlined_VBN by_IN Dix_NP and_CC Hallpike_NP and_CC more_QL recently_RB by_IN Mohr_NP the_ATI head-hanging_NN maneuver_NN begins_VBZ with_IN the_ATI patient_NN in_IN a_AT sitting_VBG position_NN , with_IN gaze_NN fixed_VBN on_IN the_ATI examiner's_NN$ forehead_NN (_( Figure_NP 1_CD1 )_) the_ATI examiner_NN firmly_RB grasps_VBZ the_ATI patient's_NN$ head_NN and_CC has_HVZ the_ATI patient_NN quickly_RB lie_VB supine_NN , with_IN the_ATI head_NN turned_VBD about_RB 30_CD degrees_NNS to_TO one_CD1 side_NN and_CC about_RB 30_CD degrees_NNS below_IN the_ATI level_NN of_IN the_ATI examining_VBG table_NN next_AP , the_ATI patient_NN sits_VBZ up_RP , and_CC the_ATI maneuver_NN is_BEZ repeated_VBN with_IN the_ATI head_NN turned_VBD to_TO the_ATI opposite_JJ side_NN in_IN 1979_CD , Baloh_NP et_&FW al_APS observed_VBN that_CS if_CS the_ATI maneuver_NN was_BEDZ performed_VBN slowly_RB (_( during_IN a_AT period_NN of_IN 20_CD seconds_NNS )_) , nystagmus_JJ was_BEDZ not_XNOT induced_VBN ; thus_RB , they_PP3AS recommended_VBD performing_VBG the_ATI position_NN change_NN in_RP about_IN 2_CD seconds_NNS after_IN each_DT head-hanging_NN maneuver_NN , the_ATI physician_NN should_MD observe_VB the_ATI patient's_NN$ eyes_NNS for_IN 5_CD to_IN 15_CD seconds_NNS to_TO determine_VB whether_CS nystagmus_JJ has_HVZ been_BEN induced_VBN overall_JJB , it_PP3 takes_VBZ about_RB 3_CD to_IN 5_CD minutes_NNS to_TO explain_VB the_ATI head-hanging_NN maneuver_NN to_IN the_ATI patient_NN , to_TO perform_VB the_ATI position_NN changes_NNS , and_CC to_TO observe_VB for_IN nystagmus_JJ 45_CD benign_JJ paroxysmal_JJ positional_JJ vertigo_NN is_BEZ the_ATI most_QL common_JJ cause_NN of_IN vertigo_NN and_CC can_MD usually_RB be_BE suspected_VBN on_IN the_ATI basis_NN of_IN the_ATI history_NN alone_JJ Features_NNS of_IN this_DT syndrome_NN include_VB vertigo_NN that_CS occurs_VBZ only_RB with_IN positional_JJ changes_NNS and_CC an_AT associated_VBN positional_JJ nystagmus_JJ that_DT is_BEZ usually_RB rotatory_JJ , with_IN a_AT vertical_JJ or_CC horizontal_JJ component_NN also_RB , the_ATI nystagmus_JJ usually_RB begins_VBZ 5_CD to_IN 15_CD seconds_NNS after_IN the_ATI head-hanging_NN maneuver_NN , lasts_VBZ 2_CD to_IN 30_CD seconds_NNS , and_CC , if_CS the_ATI patient_NN is_BEZ repeatedly_RB returned_VBD to_IN the_ATI provocative_JJ position_NN , occurs_VBZ less_QL and_CC less_AP until_IN it_PP3 cannot_NN be_BE induced_VBN positional_JJ nystagmus_JJ cannot_NN always_RB be_BE elicited_VBN in_IN a_AT patient_NN with_IN a_AT history_NN otherwise_RB compatible_JJ with_IN the_ATI diagnosis_NN of_IN benign_JJ paroxysmal_JJ positional_JJ vertigo_NN its_PP$ occurrence_NN during_IN a_AT head-hanging_NN maneuver_NN occasionally_RB makes_VBZ a_AT vague_JJ description_NN of_IN dizziness_NN clearer_JJR Rarely_NP , patients_NNS with_IN central_JJ nervous_JJ system_NN lesions_NNS may_MD present_JJ with_IN positional_JJ vertigo_NN and_CC nystagmus_JJ and_CC with_IN no_ATI other_AP neurological_JJ abnormality_NN patient_NN 2_CD had_HVD benign_JJ paroxysmal_JJ positional_JJ vertigo_NN 46_CD learning_VBG how_WRB to_TO check_VB for_IN positional_JJ nystagmus_JJ usually_RB requires_VBZ practice_NN always_RB explain_VB to_IN the_ATI patient_NN what_WDT you_PP2 are_BER going_VBG to_TO do_DO before_CS performing_VBG a_AT head-hanging_NN maneuver_NN specifically_RB , ask_VB the_ATI patient_NN to_TO keep_VB the_ATI eyes_NNS open_JJ if_CS he_PP3A or_CC she_PP3A becomes_VBZ vertiginous_JJ ; many_AP patients_NNS close_RB their_PP$ eyes_NNS if_CS vertigo_NN develops_VBZ the_ATI head-hanging_NN maneuver_NN should_MD be_BE performed_VBN quickly_RB but_CC not_XNOT so_QL rapidly_RB as_CS to_TO injure_VB the_ATI patient_NN be_BE observant_JJ because_CS the_ATI nystagmus_JJ may_MD last_AP only_RB a_JJ few_AP seconds_NNS 47_CD ACCURACY_NPT OF_NPT THE_NPT SYMPTOMS_NPT AND_NPT SIGNS_NPT OF_NP VERTIGO_NP 48_CD data_NNS are_BER available_JJ on_IN three_CD clinically_RB relevant_JJ questions_NNS about_IN the_ATI accuracy_NN of_IN the_ATI clinical_JJ examination_NN in_IN patients_NNS with_IN vertigo_NN 49_CD can_MD positional_JJ nystagmus_JJ identify_VB patients_NNS with_IN benign_JJ paroxysmal_JJ positional_JJ vertigo?=20_CD 50_CD the_ATI answer_NN is_BEZ _** not_XNOT very_QL well_RB _** only_RB 198_CD of_IN 255_CD patients_NNS with_IN positional_JJ vertigo_NN examined_VBN in_IN a_AT dizziness_NN clinic_NN had_HVD positional_JJ nystagmus_JJ during_IN initial_JJ and_CC subsequent_JJ examinations_NNS (_( sensitivity_NN , 78%_NN )_) in_IN an_AT epidemiologic_JJ study_NN of_IN positional_JJ vertigo_NN , only_RB 13_CD of_IN 26_CD patients_NNS tested_VBN had_HVD positional_JJ nystagmus_JJ (_( sensitivity_NN , 50%_NP )_) 51_CD can_MD matutinal_JJ vertigo_NN distinguish_VB peripheral_JJ causes_NNS from_IN central_JJ causes_NNS of_IN vertigo_NN ? again_RB , the_ATI answer_NN is_BEZ _** not_XNOT very_QL well.=20_CD 52_CD in_IN a_AT study_NN of_IN 100_CD neurology_NN patients_NNS (_( 48_CD of_IN whom_WPOR had_HVD matutinal_JJ vertigo_NN )_) , matutinal_JJ vertigo_NN had_HVD a_AT sensitivity_NN of_IN 51%_CD and_CC a_AT specificity_NN of_IN 69%_NN for_IN peripheral_JJ disorders_NNS , and_CC in_IN an_AT epidemiologic_JJ study_NN , symptoms_NNS of_IN vertigo_NN when_WRB rolling_JJ over_RP in_IN bed_NN generated_VBN a_AT sensitivity_NN of_IN 40%_NP for_IN benign_JJ paroxysmal_JJ positional_JJ vertigo_NN 53_CD can_MD any_DTI set_VBN of_IN symptoms_NNS and_CC signs_NNS distinguish_VB urgent_JJ causes_NNS from_IN nonurgent_JJ causes_NNS of_IN dizziness_NN ? 54_CD symptoms_NNS and_CC signs_NNS can_MD help_VB identify_VB patients_NNS in_IN need_NN of_IN an_AT urgent_JJ evaluation_NN , as_CS shown_VBN in_IN Table_NP 2_CD and_CC Table_NP 3_CD , which_WDTR are_BER from_IN a_AT study_NN of_IN 125_CD emergency_NN department_NN patients_NNS with_IN the_ATI complaint_NN of_IN dizziness_NN Patients_NP who_WPR had_HVD the_ATI highly_RB specific_JJ cluster_NN of_IN positive_JJ results_NNS on_IN the_ATI head-hanging_NN test_NN and_CC either_DTX vertigo_NN or_CC vomiting_NN almost_RB always_RB had_HVD a_AT nonurgent_JJ peripheral_JJ vertigo_NN (_( a_AT finding_VBG with_IN high_JJ specificity_NN , if_CS positive_JJ , tends_VBZ to_TO rule_VB in_IN the_ATI target_NN disorder_NN )_) in_IN Table_NP 3_CD , the_ATI high_JJ sensitivity_NN (_( 87%_JJ )_) of_IN the_ATI absence_NN of_IN vertigo_NN or_CC age_NN older_JJR than_IN 69_CD years_NNS or_CC the_ATI presence_NN of_IN a_AT neurological_JJ deficit_NN for_IN a_AT serious_JJ cause_NN of_IN dizziness_NN meant_VBD that_CS younger_JJR patients_NNS with_IN vertigo_NN but_CC no_ATI neurological_JJ deficit_NN were_BED unlikely_JJ to_TO have_HV an_AT urgent_JJ cause_NN of_IN dizziness_NN (_( a_AT finding_VBG with_IN high_JJ sensitivity_NN , if_CS negative_JJ , tends_VBZ to_TO rule_VB out_RP the_ATI target_NN disorder_NN )_) 55_CD these_DTS reassuring_JJ results_NNS of_IN the_ATI accuracy_NN of_IN the_ATI clinical_JJ examination_NN come_VB from_IN a_AT single_JJ study_NN in_IN an_AT emergency_NN department_NN with_IN rates_NNS of_IN peripheral_JJ vertigo_NN and_CC serious_JJ disease_NN characteristic_NN of_IN such_ABL settings_NNS ; they_PP3AS need_NN independent_JJ confirmation_NN in_IN different_JJ settings_NNS although_CS the_ATI nonurgent_JJ causes_NNS of_IN dizziness_NN may_MD not_XNOT require_VB immediate_JJ hospitalization_NN , some_DTI of_IN the_ATI causes_NNS of_IN peripheral_JJ vertigo_NN (_( eg_NN , acoustic_JJ neuroma_NN )_) deserve_VB further_JJB diagnostic_JJ study_NN 56_CD the_ATI following_JJ are_BER our_PP$ recommendations_NNS on_IN useful_JJ symptoms_NNS and_CC signs_NNS in_IN the_ATI evaluation_NN of_IN patients_NNS with_IN dizziness_NN : 57_CD in_IN patients_NNS with_IN suspected_VBD vertigo_NN , ask_VB whether_CS they_PP3AS have_HV dizziness_NN when_WRB changing_VBG body_NN position_NN (_( rolling_JJ over_RP in_IN bed_NN , looking_VBG up_RP at_IN the_ATI ceiling_NN , or_CC bending_NN over_RP to_TO tie_VB shoelaces_NNS )_) and_CC perform_VB a_AT head-hanging_NN maneuver_NN to_TO check_VB for_IN positional_JJ nystagmus_JJ 58_CD in_IN combination_NN with_IN other_AP data_NNS (_( including_IN a_AT brief_JJ neurological_JJ examination_NN )_) in_IN an_AT emergency_NN department_NN setting_VBG , the_ATI presence_NN of_IN positional_JJ nystagmus_JJ can_MD be_BE useful_JJ in_IN identifying_VBG serious_JJ causes_NNS of_IN dizziness_NN 59_CD the_ATI International_NPT Normalized_NP Ratio_NP : a_AT Guide_NP to_IN Understanding_NP and_CC Correcting_NP Its_NP Problems_NP 60_CD with_IN the_ATI increasing_JJ use_NN of_IN the_ATI international_JJ normalized_JJ ratio_NN (_( INR_NP )_) to_TO monitor_NN warfarin_NN therapy_NN , a_AT number_NN of_IN problems_NNS with_IN prothrombin_NN time_NN (_( PT_NP )_) testing_NN have_HV been_BEN identified_VBN that_CS have_HV led_VBN some_DTI laboratory_NN physicians_NNS to_TO question_VB the_ATI reliability_NN of_IN the_ATI INR_NP this_DT is_BEZ ironic_JJ , because_CS it_PP3 was_BEDZ the_ATI introduction_NN of_IN the_ATI INR_NP system_NN that_WPR brought_VBD to_TO light_VB some_DTI of_IN the_ATI long-standing_JJ problems_NNS with_IN the_ATI technique_NN of_IN PT_NP monitoring_NN However_NP , these_DTS problems_NNS are_BER not_XNOT insurmountable_JJ if_CS a_AT compromise_NN can_MD be_BE reached_VBN between_IN the_ATI expectations_NNS of_IN laboratory_NN physicians_NNS and_CC of_IN clinicians_NNS thus_RB , the_ATI laboratory_NN physician_NN seeks_VBZ a_AT perfect_JJ assay_NN system_NN , which_WDTR in_IN the_ATI case_NN of_IN the_ATI INR_NP is_BEZ unattainable_JJ at_IN present_NN , because_CS of_IN differences_NNS in_IN PT_NP reagents_NNS and_CC methods.=20_CD 61_CD in_IN contrast_NN , the_ATI clinician_NN is_BEZ satisfied_JJ with_IN a_AT system_NN of_IN monitoring_VBG that_CS provides_VBZ safe_JJ and_CC effective_JJ warfarin_NN dosing_NN this_DT goal_NN can_MD be_BE achieved_VBN provided_VBN that_CS certain_JJ details_NNS of_IN PT_NP testing_NN are_BER observed_VBN in_IN this_DT communication_NN , which_WDTR is_BEZ directed_VBN to_IN practicing_VBG clinicians_NNS , the_ATI potential_JJ problems_NNS with_IN the_ATI INR_NP system_NN are_BER discussed_VBN , their_PP$ clinical_JJ relevance_NN is_BEZ critically_RB reviewed_VBN , and_CC solutions_NNS are_BER offered_VBN 62_CD warfarin_NN treatment_NN must_MD be_BE monitored_VBN closely_RB because_CS the_ATI anticoagulant_NN response_NN to_IN fixed_JJ dosages_NNS varies_VBZ among_IN individuals_NNS , and_CC the_ATI efficacy_NN and_CC safety_NN of_IN warfarin_NN are_BER highly_RB dependent_JJ on_IN maintaining_VBG the_ATI anticoagulant_NN effect_NN within_IN a_AT defined_VBN therapeutic_JJ range_NN laboratory_NN monitoring_VBG is_BEZ usually_RB accomplished_VBN by_IN measuring_VBG the_ATI PT_NP the_ATI PT_NP is_BEZ measured_VBN by_IN adding_VBG a_AT thromboplastin_JJ reagent_JJ (_( which_WDTR is_BEZ either_DTX an_AT extract_NN of_IN mammalian_NN tissue_NN rich_JJ in_IN tissue_NN factor_NN or_CC a_AT recombinant_NN preparation_NN of_IN human_JJ tissue_NN factor_NN in_IN combination_NN with_IN phospholipid_NN )_) to_TO citrated_VBN plasma_NN and_CC recording_VBG the_ATI time_NN for_IN clotting_NN to_TO occur_VB after_IN recalcification_NN the_ATI PT_NP is_BEZ responsive_JJ to_IN a_AT reduction_NN of_IN three_CD vitamin_NN K-dependent_NP clotting_NN factors_NNS (_( prothrombin_NN and_CC factors_NNS VII_NP and_CC X_ZZ )_) , the_ATI levels_NNS of_IN which_WDTR decrease_NN at_IN a_AT rate_NN that_CS depends_VBZ on_IN their_PP$ respective_JJ half-lives_NNS the_ATI major_JJ reason_NN why_WRB control_NN of_IN warfarin_NN therapy_NN using_VBG the_ATI PT_NP is_BEZ problematic_NN is_BEZ because_CS thromboplastin_NN reagents_NNS vary_VB in_IN their_PP$ responsiveness_NN to_IN warfarin-induced_JJ reduction_NN in_IN clotting_NN factors_NNS , a_AT variability_NN that_WPR is_BEZ dependent_JJ on_IN their_PP$ method_NN of_IN preparation_NN 63_CD the_ATI urgent_JJ need_NN to_TO standardize_VB PT_NP reporting_VBG was_BEDZ highlighted_VBD by_IN two_CD recent_JJ reports_NNS in_IN the_ATI United_NP States_NP that_CS demonstrated_VBN that_CS PT_NP reagents_NNS used_VBN in_IN North_NP America_NP still_RB differ_VB markedly_RB in_IN their_PP$ responsiveness_NN to_TO the_ATI anticoagulant_NN effects_NNS of_IN warfarin_NN as_IN a_AT result_NN , widely_RB divergent_JJ PT_NP ratios_NNS may_MD be_BE obtained_VBN for_IN the_ATI same_AP plasma_NN sample_NN , depending_VBG on_IN the_ATI thromboplastin_JJ reagent_JJ that_DT is_BEZ used_VBN , a_AT situation_NN that_WPR can_MD lead_VB to_TO inappropriate_JJ and_CC dangerous_JJ anticoagulant_NN dosing_NN 64_CD there_EX are_BER a_AT number_NN of_IN potential_JJ solutions_NNS to_IN this_DT problem_NN the_ATI approach_NN that_WPR is_BEZ now_RN recommended_VBN is_BEZ to_TO standardize_VB PT_NP monitoring_VBG by_IN using_VBG the_ATI INR_NP , a_AT system_NN that_CS adjusts_VBZ for_IN the_ATI variable_JJ sensitivities_NNS of_IN the_ATI different_JJ thromboplastin_NN reagents_NNS an_AT alternative_NN approach_NN would_MD be_BE to_TO use_VB thromboplastin_NN reagents_NNS that_CS have_HV a_AT similar_JJ level_NN of_IN responsiveness_NN to_IN warfarin-induced_JJ reduction_NN of_IN coagulation_NN factors_NNS a_AT third_OD possibility_NN might_MD be_BE to_TO replace_VB the_ATI PT_NP with_IN a_AT test_NN that_CS does_DOZ not_XNOT use_NN a_AT thromboplastin_JJ reagent_JJ , avoiding_JJ the_ATI limitations_NNS caused_VBN by_IN the_ATI variability_NN in_IN responsiveness_NN of_IN these_DTS materials_NNS the_ATI latter_AP two_CD approaches_NNS will_MD be_BE discussed_VBN briefly_RB before_IN the_ATI problems_NNS associated_VBN with_IN the_ATI INR_NP system_NN are_BER reviewed_VBN 65_CD STANDARDIZING_NPT THE_NPT RESPONSIVENESS_NPT OF_NP THROMBOPLASTINS_NP 66_CD this_DT potential_JJ solution_NN would_MD require_VB the_ATI cooperation_NN of_IN manufacturers_NNS to_TO produce_VB sensitive_JJ thromboplastin_NN reagents_NNS with_IN similar_JJ levels_NNS of_IN responsiveness_NN to_IN warfarin-induced_JJ reduction_NN of_IN coagulation_NN factors_NNS this_DT approach_NN has_HVZ been_BEN facilitated_VBN by_IN the_ATI availability_NN of_IN human_JJ recombinant_NN tissue_NN factor_NN , which_WDTR makes_VBZ it_PP3 easier_JJR to_TO produce_VB sensitive_JJ thromboplastin_NN reagents_NNS in_IN commercial_JJ quantities_NNS 67_CD REPLACEMENT_NPT OF_NPT THE_NPT PT_NPT WITH_NPT OTHER_NP TESTS_NP 68_CD other_AP laboratory_NN tests_NNS that_CS are_BER easier_JJR to_TO standardize_VB than_IN the_ATI PT_NP may_MD be_BE useful_JJ substitutes_NNS for_IN monitoring_VBG warfarin_NN treatment_NN the_ATI most_AP promising_JJ of_IN these_DTS is_BEZ the_ATI prothrombin_NN (_( factor_NN II_NP )_) antigen_NN assay_NN , which_WDTR was_BEDZ reported_VBN to_TO be_BE better_JJR than_IN the_ATI PT_NP ratio_NN at_IN predicting_VBG clinical_JJ events_NNS in_IN studies_NNS of_IN patients_NNS treated_VBN with_IN warfarin_NN unfortunately_RB , however_RB , an_AT insensitive_JJ thromboplastin_NN was_BEDZ used_VBN to_TO measure_VB the_ATI PT_NP ratio_NN in_IN these_DTS studies_NNS , and_CC it_PP3 remains_VBZ to_TO be_BE established_VBN whether_CS the_ATI PT_NP antigen_NN assay_NN will_MD be_BE as_CS effective_JJ and_CC safe_JJ as_IN the_ATI PT_NP ratio_NN when_WRB a_AT sensitive_JJ thromboplastin_NN is_BEZ used_VBN further_JJB randomized_JJ trials_NNS are_BER necessary_JJ to_TO settle_VB this_DT issue_NN in_IN addition_NN , the_ATI utility_NN of_IN the_ATI prothrombin_NN antigen_NN assay_NN may_MD be_BE limited_JJ because_CS it_PP3 is_BEZ more_QL expensive_JJ and_CC more_QL complicated_JJ to_TO perform_VB than_IN the_ATI PT_NP test_NN until_CS these_DTS issues_NNS are_BER settled_VBN , the_ATI PT_NP will_MD continue_VB to_TO be_BE the_ATI method_NN of_IN choice_NN for_IN monitoring_VBG warfarin_NN treatment_NN 69_CD THE_NP INR_NP 70_CD the_ATI INR_NP scheme_NN for_IN PT_NP standardization_NN was_BEDZ approved_VBN by_IN the_ATI Expert_NP Committee_NP on_IN Biological_NP Standardization_NN of_IN the_ATI World_NP Health_NP Organization_NN in_IN 1983_CD after_IN extensive_JJ and_CC prolonged_JJ study_NN the_ATI INR_NP corrects_VBZ the_ATI PT_NP ratios_NNS obtained_VBN with_IN thromboplastin_NN reagents_NNS with_IN different_JJ degrees_NNS of_IN responsiveness_NN to_IN the_ATI warfarin-induced_JJ coagulation_NN defect_NN by_IN standardizing_VBG the_ATI result_NN against_IN a_AT common_JJ international_JJ reference_NN preparation_NN standardization_NN is_BEZ achieved_VBN by_IN converting_VBG the_ATI PT_NP ratio_NN observed_VBN with_IN any_DTI local_JJ thromboplastin_NN to_IN a_AT common_JJ standard_NN , which_WDTR is_BEZ the_ATI INR_NP the_ATI INR_NP is_BEZ calculated_VBN as_IN follows_VBZ : INR_NP =3D_CD (_( Observed_NPT PT_NP Ratio_NP )_) sup_VB c_ZZ , where_WRB the_ATI PT_NP ratio_NN is_BEZ the_ATI patient's_NN$ PT_NP value_NN divided_VBD by_IN the_ATI mean_NN normal_JJ PT_NP value_NN and_CC c_ZZ indicates_VBZ the_ATI power_NN representing_VBG the_ATI International_NP Sensitivity_NP Index_&FW (_( ISI_NP )_) for_IN each_DT thromboplastin_NN the_ATI INR_NP system_NN of_IN reporting_VBG is_BEZ based_VBN on_IN a_AT logarithmic_JJ relationship_NN between_IN the_ATI PT_NP ratios_NNS of_IN the_ATI test_NN and_CC reference_NN preparation_NN the_ATI INR_NP is_BEZ the_ATI PT_NP ratio_NN that_CS would_MD be_BE obtained_VBN if_CS the_ATI international_JJ reference_NN preparation_NN , which_WDTR has_HVZ an_AT ISI_NP of_IN 1.0_CD , were_BED used_VBN to_TO perform_VB the_ATI test_NN the_ATI ISI_NP is_BEZ the_ATI correction_NN factor_NN in_IN the_ATI equation_NN that_CS relates_VBZ the_ATI PT_NP ratio_NN of_IN the_ATI local_JJ reagent_JJ to_TO the_ATI reference_NN preparation_NN and_CC is_BEZ a_AT measure_NN of_IN the_ATI responsiveness_NN of_IN a_AT given_JJ thromboplastin_NN to_IN reduction_NN of_IN the_ATI vitamin_NN K-dependent_NP coagulation_NN factors_NNS ; the_ATI lower_JJR the_ATI ISI_NP , the_ATI more_QL _** sensitive_JJ _** the_ATI reagent_JJ and_CC the_ATI closer_RBR the_ATI derived_VBN INR_NP will_MD be_BE to_IN the_ATI observed_VBN PT_NP ratio_NN 71_CD the_ATI calculation_NN of_IN the_ATI INR_NP is_BEZ relatively_RB simple_JJ and_CC can_MD be_BE performed_VBN with_IN a_AT handheld_NN calculator_NN for_IN example_NN , if_CS the_ATI PT_NP ratio_NN is_BEZ 1.5_CD and_CC the_ATI ISI_NP of_IN the_ATI thromboplastin_NN is_BEZ 1.8_CD , the_ATI INR_NP =3D_CD 1.5_CD .8_CD =3D_CD 2.07_NP the_ATI relationship_NN between_IN the_ATI INR_NP and_CC PT_NP ratio_NN over_IN a_AT range_NN of_IN ISI_NP values_NNS is_BEZ shown_VBN in_IN Table_NP 1_CD1 72_CD after_IN a_AT slow_JJ start_NN , the_ATI INR_NP system_NN of_IN PT_NP standardization_NN is_BEZ being_BEG adopted_VBN by_IN an_AT increasing_JJ number_NN of_IN hospitals_NNS in_IN North_NP America_NP thus_RB , whereas_CS two_CD reports_NNS from_IN the_ATI United_NP States_NP in_IN 1992_CD showed_VBD that_CS only_RB a_AT very_QL small_JJ proportion_NN of_IN centers_NNS were_BED reporting_VBG the_ATI PT_NP ratio_NN as_IN an_AT INR_NP , by_IN mid-1993_CD-CD , about_IN half_ABN of_IN the_ATI participants_NNS in_IN the_ATI College_NPL of_IN American_JNP Pathologists_NP proficiency_NN testing_NN program_NN were_BED doing_VBG so_QL (_( D._NP a._RB Triplett_NP , MD_NP , oral_JJ communication_NN , March_NR 2_CD , 1993_CD )_) with_IN the_ATI increasing_JJ use_NN of_IN the_ATI INR_NP system_NN to_TO replace_VB the_ATI PT_NP ratio_NN method_NN of_IN reporting_VBG , a_AT number_NN of_IN problems_NNS have_HV been_BEN identified_VBN , and_CC the_ATI INR_NP system_NN has_HVZ been_BEN criticized_VBN The_NP remainder_NN of_IN this_DT article_NN will_MD review_VB these_DTS problems_NNS with_IN the_ATI INR_NP system_NN , consider_VB their_PP$ clinical_JJ importance_NN vis-a-vis_VB the_ATI continued_VBD use_NN of_IN PT_NP system_NN of_IN reporting_VBG , and_CC suggest_VB solutions_NNS 73_CD PROBLEM_NP 1_CD1 74_CD lack_NN of_IN Reliability_NP of_IN the_ATI INR_NPT System_NPT When_NP Used_NP at_IN the_ATI Onset_NP of_IN Warfarin_NP Therapy_NP 75_CD 17_CD the_ATI PT_NP is_BEZ responsive_JJ to_IN reduction_NN in_IN three_CD of_IN the_ATI four_CD vitamin_NN K-dependent_NP procoagulants_NNS , factor_NN II_NP , factor_NN VII_NP , and_CC factor_NN X_ZZ , but_CC individual_JJ thromboplastin_NN reagents_NNS vary_VB in_IN their_PP$ sensitivity_NN to_TO decreases_VBZ in_IN these_DTS clotting_NN factors_NNS , particularly_RB factors_NNS VII_NP and_CC X._NP Since_NP the_ATI three_CD vitamin_NN K-dependent_NP clotting_NN factors_NNS have_HV varying_JJ rates_NNS of_IN plasma_NN clearance_NN , their_PP$ relative_JJ contribution_NN to_IN the_ATI prolongation_NN of_IN the_ATI PT_NP will_MD be_BE different_JJ during_IN the_ATI induction_NN phase_NN of_IN warfarin_NN therapy_NN (_( first_OD few_AP days_NNS )_) than_CS during_IN the_ATI subsequent_JJ weeks_NNS to_IN months_NNS of_IN treatment_NN thus_RB , during_IN the_ATI first_OD 2_CD to_IN 5_CD days_NNS of_IN warfarin_NN treatment_NN , the_ATI prolongation_NN of_IN the_ATI PT_NP is_BEZ mainly_RB the_ATI result_NN of_IN a_AT reduction_NN in_IN the_ATI level_JJ of_IN functional_JJ factor_NN VII_NP , with_IN some_DTI contribution_NN from_IN a_AT decrease_NN in_IN factor_NN X_ZZ levels_NNS in_IN contrast_NN , during_IN longer-term_JJR anticoagulation_NN , the_ATI prolongation_NN of_IN the_ATI PT_NP reflects_VBZ a_AT decrease_NN in_IN all_ABN three_CD vitamin_NN K-dependent_NP coagulation_NN factors_NNS , which_WDTR are_BER usually_RB reduced_VBN to_IN a_AT similar_JJ extent_NN 76_CD to_TO overcome_VB the_ATI problem_NN of_IN the_ATI variable_JJ responsiveness_NN of_IN thromboplastins_NNS to_IN factors_NNS VII_NP and_CC X_ZZ , plasma_NN samples_NNS collected_VBN during_IN the_ATI induction_NN phase_NN are_BER not_XNOT used_VBN to_TO calibrate_VB thromboplastins_NNS instead_RB , the_ATI INR_NP scheme_NN is_BEZ based_VBN on_IN ISI_NP values_NNS derived_VBN from_IN the_ATI plasma_NN of_IN patients_NNS whose_WP$R conditions_NNS have_HV stabilized_VBN while_CS receiving_VBG anticoagulant_NN treatment_NN for_IN at_RB least_RB 6_CD weeks_NNS given_VBN this_DT practice_NN , there_EX is_BEZ the_ATI potential_JJ for_IN the_ATI INR_NP to_TO be_BE unreliable_JJ early_RB in_IN the_ATI course_NN of_IN warfarin_NN therapy_NN if_CS reagents_NNS that_CS are_BER relatively_RB insensitive_JJ to_IN depletion_NN of_IN factors_NNS VII_NP and_CC X_ZZ are_BER used_VBN 77_CD this_DT problem_NN was_BEDZ investigated_VBN by_IN McKernan_NP and_CC associates_NNS , who_WPR performed_VBN serial_JJ PT_NP testing_NN for_IN 5_CD to_IN 40_CD days_NNS after_IN oral_JJ anticoagulant_NN therapy_NN was_BEDZ started_VBN in_IN 15_CD patients_NNS all_ABN plasma_NN samples_NNS were_BED tested_VBN in_IN parallel_JJ with_IN five_CD different_JJ thromboplastins_NNS (_( including_IN the_ATI international_JJ reference_NN preparation_NN )_) a_AT wide_JJ range_NN of_IN INR_NP values_NNS was_BEDZ observed_VBN when_WRB the_ATI same_AP plasma_NN was_BEDZ tested_VBN with_IN the_ATI different_JJ thromboplastins_NNS the_ATI variance_NN appeared_VBD to_TO be_BE most_QL marked_JJ during_IN the_ATI first_OD 4_CD days_NNS of_IN warfarin_NN therapy_NN but_CC persisted_VBD throughout_IN the_ATI period_NN of_IN study_NN two_CD factors_NNS explained_VBD the_ATI divergence_NN in_IN INR_NP values_NNS among_IN the_ATI different_JJ thromboplastins_NNS these_DTS were_BED (_( 1_CD1 )_) differences_NNS in_IN the_ATI responsiveness_NN of_IN the_ATI reagents_NNS to_TO decreases_VBZ in_IN individual_JJ vitamin_NN K- dependent_NP coagulation_NN factors_NNS and_CC (_( 2_CD )_) inaccurate_JJ calibration_NN of_IN reagents_NNS by_IN manufacturers_NNS although_CS the_ATI variance_NN was_BEDZ considerable_JJ , the_ATI clinical_JJ relevance_NN of_IN these_DTS differences_NNS is_BEZ uncertain_JJ , because_CS they_PP3AS would_MD have_HV resulted_VBN in_IN only_RB modest_JJ changes_NNS in_IN warfarin_NN doses_NNS during_IN the_ATI first_OD 14_CD days_NNS of_IN treatment_NN furthermore_RB , among_IN the_ATI different_JJ thromboplastins_NNS , the_ATI INR_NP values_NNS were_BED less_QL variable_JJ than_IN the_ATI PT_NP ratios_NNS during_IN the_ATI initial_JJ stages_NNS of_IN treatment_NN thus_RB , this_DT study_NN clearly_RB demonstrates_VBZ that_CS the_ATI INR_NP system_NN of_IN reporting_VBG is_BEZ superior_JJ to_IN the_ATI nonstandardized_NN PT_NP ratio_NN , even_RB when_WRB used_VBN to_IN monitor_NN patients_NNS soon_RB after_IN warfarin_NN therapy_NN has_HVZ been_BEN started_VBN 78_CD additional_JJ evidence_NN that_CS it_PP3 is_BEZ safe_JJ to_TO use_VB the_ATI INR_NP system_NN during_IN the_ATI initial_JJ stages_NNS of_IN warfarin_NN therapy_NN is_BEZ provided_VBN by_IN the_ATI results_NNS of_IN randomized_JJ trials_NNS in_IN which_WDTR the_ATI INR_NP was_BEDZ used_VBN to_TO monitor_NN treatment_NN , even_RB though_CS PT_NP reagents_NNS with_IN different_JJ sensitivities_NNS were_BED used_VBN to_TO titrate_VB warfarin_NN doses_NNS anticoagulant_NN therapy_NN monitored_VBN this_DT way_NN proved_VBN to_TO be_BE both_ABX effective_JJ and_CC safe_JJ for_IN the_ATI prevention_NN and_CC treatment_NN of_IN venous_JJ thrombosis_NN , for_IN the_ATI prevention_NN of_IN systemic_JJ embolism_NN in_IN patients_NNS with_IN prosthetic_JJ heart_NN valves_NNS , and_CC for_IN the_ATI secondary_JJ prevention_NN of_IN myocardial_JJ infarction_NN 79_CD despite_IN its_PP$ loss_NN of_IN reliability_NN in_IN the_ATI initial_JJ stages_NNS of_IN warfarin_NN therapy_NN , when_WRB thromboplastin_NN reagents_NNS with_IN different_JJ ISI_NP values_NNS are_BER used_VBN , the_ATI INR_NP system_NN is_BEZ more_QL reliable_JJ than_IN the_ATI unconverted_JJ PT_NP ratio_NN , and_CC from_IN the_ATI point_NN of_IN view_NN of_IN clinical_JJ management_NN , it_PP3 appears_VBZ to_TO be_BE an_AT effective_JJ and_CC safe_JJ method_NN of_IN monitoring_VBG warfarin_NN therapy_NN 80_CD potential_JJ Solutions_NP 81_CD on_IN the_ATI basis_NN of_IN the_ATI data_NNS described_VBN above_IN , some_DTI investigators_NNS have_HV suggested_VBN that_CS the_ATI PT_NP ratio_NN should_MD be_BE used_VBN to_IN monitor_NN patients_NNS in_IN the_ATI early_JJ stages_NNS of_IN warfarin_NN therapy_NN and_CC the_ATI INR_NP should_MD be_BE restricted_JJ to_TO monitoring_VBG patients_NNS receiving_VBG long-term_JJB anticoagulant_NN therapy_NN not_XNOT only_RB is_BEZ this_DT approach_NN impractical_JJ and_CC confusing_JJ , it_PP3 is_BEZ also_RB not_XNOT supported_VBN by_IN the_ATI evidence_NN there_EX is_BEZ evidence_NN that_CS the_ATI PT_NP ratio_NN is_BEZ less_QL reliable_JJ than_IN the_ATI INR_NP even_RB during_IN the_ATI induction_NN phase_NN of_IN warfarin_NN treatment_NN although_CS there_EX may_MD be_BE limitations_NNS of_IN the_ATI INR_NP during_IN this_DT period_NN , they_PP3AS do_DO not_XNOT adversely_RB affect_VB patient_NN treatment_NN and_CC certainly_RB do_DO not_XNOT justify_VB abandoning_VBG the_ATI INR_NP system_NN furthermore_RB , it_PP3 is_BEZ likely_JJ that_CS the_ATI problems_NNS with_IN the_ATI INR_NP during_IN the_ATI early_JJ stages_NNS of_IN warfarin_NN therapy_NN would_MD be_BE minimized_VBN if_CS sensitive_JJ thromboplastins_NNS were_BED used_VBN 82_CD PROBLEM_NP 2_CD 83_CD INR_NP System_NP Loses_NP Accuracy_NP and_CC Precision_NP When_NP Thromboplastins_NP With_NP High_NP ISI_NP Values_NP Are_NP Used_NP 84_NN 26_CD given_VBN that_CS the_ATI INR_NP is_BEZ calculated_VBN by_IN raising_VBG the_ATI PT_NP ratio_NN to_IN the_ATI power_NN of_IN the_ATI ISI_NP as_IN follows_VBZ : INR_NP =3D_CD PT_NP ratio_NN sup_VB ISI_NP , it_PP3 is_BEZ not_XNOT surprising_JJ that_CS the_ATI calculated_JJ result_NN is_BEZ less_QL accurate_JJ when_WRB the_ATI PT_NP test_NN is_BEZ performed_VBN with_IN insensitive_JJ thromboplastins_NNS that_CS have_HV high_JJ ISI_NP values_NNS for_IN the_ATI same_AP reason_NN , the_ATI inaccuracies_NNS are_BER greater_JJR with_IN higher_JJR PT_NP ratios_NNS although_CS these_DTS concepts_NNS are_BER supported_VBN by_IN a_AT number_NN of_IN studies_NNS , the_ATI study_NN by_IN Moriarty_NP and_CC associates_NNS will_MD be_BE discussed_VBN in_IN some_DTI detail_NN because_CS it_PP3 exemplifies_VBZ the_ATI problem_NN and_CC suggests_VBZ a_AT solution_NN comparing_VBG 12_CD thromboplastins_NNS against_IN a_AT secondary_JJ reference_NN thromboplastin_NN , these_DTS investigators_NNS tested_VBN 20_CD control_NN plasma_NN samples_NNS and_CC 60_CD plasma_NN samples_NNS from_IN patients_NNS who_WPR had_HVD been_BEN treated_VBN with_IN warfarin_NN for_IN at_RB least_RB 3_CD weeks_NNS The_NP ISI_NP values_NNS of_IN the_ATI thromboplastins_NNS varied_JJ from_IN approximately_RB 1.0_CD to_IN 2.2_CD the_ATI points_NNS describing_VBG the_ATI relationship_NN between_IN the_ATI observed_VBN PT_NP ratios_NNS were_BED plotted_VBN in_IN two_CD ways_NNS : as_CS INR_NP values_NNS on_IN both_ABX the_ATI horizontal_JJ and_CC vertical_JJ axes_NNS and_CC as_IN an_AT INR_NP on_IN the_ATI horizontal_JJ axis_NN and_CC PT_NP ratio_NN on_IN the_ATI vertical_JJ axis_NN representative_JJ examples_NNS of_IN the_ATI results_NNS with_IN three_CD different_JJ thromboplastins_NNS are_BER summarized_VBN here_RN : thromboplastin_NN A_ZZ , with_IN an_AT ISI_NP value_NN of_IN 0.98_NP (_( Figure_NP 1_CD1 )_) ; thromboplastin_NN B_ZZ , with_IN an_AT ISI_NP value_NN of_IN 1.3_CD (_( Figure_NP 2_CD )_) ; and_CC thromboplastin_NN C_ZZ , with_IN an_AT ISI_NP value_NN of_IN 2.2_CD (_( Figure_NP 3_CD )_) 85_CD 27_CD with_IN thromboplastin_NN A_ZZ (_( ISI_NP , 1.0_CD )_) , the_ATI regression_NN lines_NNS representing_VBG the_ATI INR_INR_NP and_CC INR_PT_NP ratio_NN plots_NNS were_BED virtually_RB identical_JJ (_( Figure_NP 1_CD1 )_) in_IN addition_NN , the_ATI variance_NN was_BEDZ minimal_JJ , and_CC virtually_RB all_ABN of_IN the_ATI data_NNS points_NNS fell_VBD on_IN the_ATI regression_NN lines_NNS , which_WDTR had_HVD a_AT slope_NN of_IN 45_CD degrees_NNS these_DTS data_NNS demonstrate_VB that_CS a_AT very_QL responsive_JJ thromboplastin_JJ (_( with_IN an_AT ISI_NP of_IN 0.98_NP , almost_RB identical_JJ to_TO that_CS of_IN the_ATI reference_NN preparation_NN )_) is_BEZ accurate_JJ and_CC precise_JJ over_IN a_AT wide_JJ range_NN of_IN INR_NP values_NNS 86_CD 28_CD when_WRB a_AT thromboplastin_NN of_IN intermediate_JJ sensitivity_NN (_( thromboplastin_NN B_ZZ ; ISI_NP , 1.3_CD )_) was_BEDZ used_VBN , there_EX was_BEDZ considerable_JJ divergence_NN between_IN the_ATI regression_NN lines_NNS representing_VBG the_ATI INR_INR_NP and_CC INR_PT_NP ratio_NN plots_NNS although_CS there_EX was_BEDZ also_RB a_AT greater_JJR scatter_NN of_IN points_NNS around_IN the_ATI regression_NN line_NN in_IN the_ATI INR_INR_NP plot_NN , the_ATI slope_NN of_IN the_ATI line_NN was_BEDZ still_RB approximately_RB 45_CD degrees_NNS (_( Figure_NP 2_CD )_) in_IN addition_NN , as_CS expected_VBN , the_ATI PT_NP ratio_NN was_BEDZ considerably_RB lower_JJR than_IN the_ATI INR_NP , and_CC this_DT difference_NN was_BEDZ increased_VBN with_IN increasing_JJ intensity_NN of_IN anticoagulation_NN these_DTS findings_NNS indicate_VB that_CS a_AT thromboplastin_JJ with_IN of_IN an_AT ISI_NP of_IN 1.3_CD is_BEZ likely_JJ to_TO produce_VB less_QL accurate_JJ INR_NP results_NNS than_IN a_AT thromboplastin_NN with_IN an_AT ISI_NP close_RB to_IN 1.0_CD regardless_RB of_IN which_WDTR thromboplastin_NN is_BEZ used_VBN , however_RB , the_ATI results_NNS are_BER more_QL accurate_JJ when_WRB expressed_VBN as_CS INR_NP values_NNS than_IN as_CS PT_NP ratios_NNS 87_CD 29_CD the_ATI results_NNS with_IN the_ATI less_QL sensitive_JJ thromboplastin_JJ C_ZZ (_( ISI_NP , 2.2_CD )_) , a_AT midrange_NN North_NP American_JNP thromboplastin_NN , are_BER shown_VBN in_IN Figure_NP 3_CD there_EX is_BEZ marked_JJ divergence_NN between_IN the_ATI regression_NN lines_NNS representing_VBG the_ATI INR_INR_NP and_CC INR_PT_NP ratio_NN plots_NNS this_DT divergence_NN is_BEZ already_RB evident_JJ at_IN an_AT INR_NP of_IN 2.0_CD , where_WRB the_ATI corresponding_JJ PT_NP ratio_NN is_BEZ approximately_RB 1.3_CD , and_CC is_BEZ extreme_JJ with_IN an_AT INR_NP of_IN 5.0_CD , where_WRB the_ATI corresponding_JJ PT_NP ratio_NN is_BEZ approximately_RB 2.0_CD in_IN addition_NN , the_ATI ability_NN to_TO discriminate_VB between_IN an_AT INR_NP of_IN 3.0_CD (_( which_WDTR is_BEZ the_ATI upper_JJB level_NN of_IN the_ATI therapeutic_JJ range_NN and_CC represents_VBZ a_AT relatively_RB safe_JJ level_NN of_IN anticoagulation_NN )_) and_CC an_AT INR_NP of_IN 5.0_CD (_( which_WDTR is_BEZ potentially_RB dangerous_JJ )_) is_BEZ poor_JJ the_ATI slope_NN of_IN the_ATI regression_NN line_NN is_BEZ less_AP than_IN 45_CD degrees_NNS , although_CS not_XNOT greatly_RB less_QL , indicating_VBG that_CS even_RB with_IN this_DT less_QL responsive_JJ thromboplastin_JJ , the_ATI INR_NP system_NN remains_VBZ valid_JJ however_RB , the_ATI scatter_NN of_IN individual_JJ points_NNS around_IN the_ATI regression_NN line_NN is_BEZ considerable_JJ , demonstrating_VBG again_RB the_ATI potential_JJ for_IN loss_NN of_IN accuracy_NN and_CC precision_NN with_IN less_QL responsive_JJ thromboplastins_NNS 88_CD 30_CD potential_JJ Solution_NN 89_CD 31_CD the_ATI problem_NN of_IN loss_NN of_IN accuracy_NN and_CC precision_NN of_IN the_ATI INR_NP system_NN can_MD be_BE solved_VBN by_IN using_VBG sensitive_JJ thromboplastins_NNS with_IN ISI_NP values_NNS close_RB to_IN 1.0_CD however_RB , even_RB with_IN poorly_RB responsive_JJ thromboplastins_NNS , conversion_NN to_IN the_ATI INR_NP system_NN provides_VBZ more_QL accurate_JJ results_NNS than_IN reporting_VBG the_ATI results_NNS as_IN a_AT PT_NP ratio_NN 90_CD 32_CD PROBLEM_NP 3_CD 91_CD 33_CD loss_NN of_IN Accuracy_NP of_IN the_ATI INR_NPT With_NPT Automated_NPT Clot_NP Detectors_NP 92_CD 34_CD the_ATI INR_NP system_NN is_BEZ based_VBN on_IN a_AT mathematical_JJ relationship_NN between_IN the_ATI PT_NP ratios_NNS obtained_VBN with_IN test_NN thromboplastin_NN and_CC the_ATI international_JJ reference_NN preparation_NN using_VBG a_AT manual_JJ method_NN of_IN clot_NN detection_NN however_RB , most_QL modern_JJ laboratories_NNS now_RN use_NN automated_JJ clot_NN detectors_NNS , introducing_VBG a_AT new_JJ variable_NN this_DT variable_NN does_DOZ affect_VB the_ATI accuracy_NN of_IN the_ATI INR_NP system_NN Studies_NP have_HV shown_VBN that_CS the_ATI observed_VBN INR_NP of_IN the_ATI same_AP plasma_NN sample_NN can_MD vary_VB even_RB when_WRB instruments_NNS of_IN the_ATI same_AP make_NN and_CC model_NN are_BER used_VBN , but_CC is_BEZ the_ATI magnitude_NN of_IN the_ATI variability_NN clinically_RB important_JJ ? this_DT issue_NN was_BEDZ addressed_VBN in_IN a_AT recent_JJ report_NN by_IN Poller_NP and_CC associates_NNS using_VBG the_ATI same_AP responsive_JJ thromboplastin_NN (_( ISI_NP , 1.12_CD )_) , over_IN 100_CD laboratories_NNS measured_VBN the_ATI PT_NP for_IN plasma_NN samples_NNS obtained_VBN from_IN warfarinized_JJ patients_NNS and_CC from_IN normal_JJ controls_NNS the_ATI PT_NP test_NN was_BEDZ performed_VBN either_DTX by_IN the_ATI manual_JJ method_NN or_CC with_IN one_CD1 of_IN three_CD different_JJ automated_JJ devices_NNS using_VBG the_ATI manual_JJ method_NN , the_ATI _** true_JJ _** INR_NP levels_NNS of_IN the_ATI three_CD thromboplastins_NNS were_BED 2.21_CD , 2.80_CD , and_CC 4.34_CD , respectively_RB with_IN all_ABN three_CD instruments_NNS , the_ATI derived_VBN INR_NP values_NNS differed_VBD from_IN those_DTS obtained_VBN with_IN the_ATI manual_JJ method_NN in_IN addition_NN , the_ATI results_NNS obtained_VBN with_IN the_ATI three_CD automated_JJ methods_NNS were_BED more_QL variable_JJ than_IN those_DTS obtained_VBN with_IN the_ATI manual_JJ method_NN the_ATI variance_NN in_IN ISI_NP determinations_NNS could_MD be_BE reduced_VBN significantly_RB by_IN calibrating_VBG the_ATI instrument_NN with_IN 20_CD lyophilized_JJ plasma_NN samples_NNS that_CS had_HVD been_BEN certified_VBN centrally_RB using_VBG the_ATI manual_JJ method_NN without_IN this_DT type_NN of_IN calibration_NN , INR_NP values_NNS with_IN automated_JJ instruments_NNS deviated_VBD by_IN a_AT mean_NN of_IN about_RB 10%_CD from_IN the_ATI true_JJ INR_NP however_RB , such_ABL differences_NNS may_MD not_XNOT be_BE clinically_RB important_JJ , provided_VBN that_CS a_AT sensitive_JJ thromboplastin_NN (_( ISI_NP value_NN close_RB to_IN 1.0_CD )_) is_BEZ used_VBN with_IN less_AP sensitive_JJ thromboplastins_NNS , the_ATI instrument_NN effect_NN is_BEZ more_QL obvious_JJ , but_CC this_DT effect_NN can_MD be_BE offset_VB and_CC a_AT reliable_JJ result_NN can_MD be_BE obtained_VBN by_IN performing_VBG local_JJ calibration_NN with_IN plasmas_NNS with_IN certified_VBN INR_NP values_NNS for_IN each_DT new_JJ batch_NN of_IN thromboplastin_JJ reagent_JJ 93_CD 35_CD potential_JJ Solution_NN 94_CD 36_CD the_ATI problem_NN resulting_JJ from_IN the_ATI use_NN of_IN automated_JJ instruments_NNS to_TO measure_VB the_ATI INR_NP can_MD be_BE minimized_VBN by_IN using_VBG sensitive_JJ thromboplastins_NNS (_( ISI_NP values_NNS close_RB to_IN 1.0_CD )_) and_CC by_IN calibrating_VBG each_DT new_JJ batch_NN of_IN thromboplastin_NN with_IN lyophilized_JJ plasmas_NNS with_IN certified_VBN INR_NP values_NNS the_ATI problem_NN cannot_NN be_BE resolved_VBN by_IN reporting_VBG the_ATI results_NNS as_IN a_AT PT_NP ratio_NN 95_CD 37_CD PROBLEM_NP 4_CD 96_CD 38_CD lack_NN of_IN Reliability_NP of_IN the_ATI ISI_NPT Result_NP Provided_NP by_IN the_ATI Manufacturer_NP 97_CD 39_CD a_AT number_NN of_IN investigators_NNS have_HV noted_VBN that_CS the_ATI ISI_NP value_NN provided_VBD by_IN the_ATI manufacturer_NN for_IN each_DT new_JJ batch_NN of_IN thromboplastin_JJ reagent_JJ may_MD be_BE incorrect_JJ the_ATI error_NN is_BEZ usually_RB suspected_VBN and_CC identified_VBN when_WRB investigators_NNS calibrate_NN a_AT new_JJ lot_NN of_IN thromboplastin_NN against_IN an_AT old_JJ lot_NN For_NP example_NN , in_IN one_CD1 recent_JJ report_NN , the_ATI inaccuracy_NN was_BEDZ identified_VBN when_WRB a_AT new_JJ lot_NN of_IN thromboplastin_JJ reagent_JJ from_IN the_ATI same_AP manufacturer_NN produced_VBN INR_NP values_NNS that_CS were_BED inconsistent_JJ with_IN those_DTS obtained_VBN with_IN the_ATI prior_RB lot_NN the_ATI manufacturer_NN was_BEDZ contacted_VBN and_CC , after_IN review_NN , revised_JJ the_ATI ISI_NP value_NN of_IN the_ATI new_JJ lot_NN from_IN 2.23_CD to_IN 2.05_NP when_WRB the_ATI INR_NP values_NNS were_BED recalculated_VBN using_VBG the_ATI revised_JJ ISI_NP , the_ATI discrepancy_NN was_BEDZ partly_RB corrected_VBN , but_CC divergent_JJ INR_NP values_NNS were_BED still_RB observed_VBN in_IN the_ATI upper_JJB range_NN a_AT local_JJ calibration_NN was_BEDZ then_RN performed_VBN using_VBG the_ATI prior_RB thromboplastin_JJ reagent_JJ as_IN the_ATI reference_NN standard_NN , and_CC a_AT local_JJ sensitivity_NN index_NN of_IN 1.75_CD was_BEDZ obtained_VBN for_IN the_ATI new_JJ thromboplastin_NN the_ATI authors_NNS concluded_VBD that_CS better_JJR standardization_NN of_IN thromboplastin_NN reagents_NNS was_BEDZ required_VBN among_IN manufacturers_NNS , preferably_RB with_IN thromboplastins_NNS restricted_JJ to_IN those_DTS with_IN an_AT ISI_NP close_RB to_IN the_ATI international_JJ reference_NN thromboplastin_NN of_IN 1.0_CD they_PP3AS also_RB suggested_VBN that_CS reliable_JJ secondary_JJ reference_NN thromboplastins_NNS calibrated_VBN against_IN the_ATI World_NP Health_NP Organization_NN preparation_NN should_MD be_BE more_QL widely_RB available_JJ for_IN distribution_NN so_CS that_CS local_JJ laboratories_NNS can_MD perform_VB their_PP$ own_AP calibrations_NNS 98_NN 40_CD it_PP3 is_BEZ clear_JJ that_CS manufacturers_NNS should_MD be_BE required_VBN to_TO provide_VB reliable_JJ ISI_NP values_NNS for_IN each_DT new_JJ lot_NN of_IN thromboplastin_JJ reagent_JJ , since_IN failure_NN to_TO do_DO so_QL leads_VBZ to_IN inaccurate_JJ warfarin_NN monitoring_VBG , with_IN the_ATI potential_JJ for_IN clinical_JJ disaster_NN the_ATI recommended_JJ calibration_NN protocol_NN for_IN calculating_VBG the_ATI ISI_NP of_IN a_AT thromboplastin_NN is_BEZ to_TO perform_VB the_ATI PT_NP test_NN with_IN a_AT reference_NN thromboplastin_NN and_CC to_TO test_VB the_ATI thromboplastin_NN on_IN plasma_NN samples_NNS from_IN 20_CD healthy_JJ individuals_NNS and_CC from_IN 60_CD patients_NNS receiving_VBG oral_JJ anticoagulant_NN therapy_NN for_IN at_RB least_RB 6_CD weeks_NNS although_CS too_QL cumbersome_JJ for_IN clinical_JJ laboratories_NNS , this_DT exercise_NN is_BEZ within_IN the_ATI capability_NN of_IN manufacturers_NNS and_CC should_MD be_BE expected_VBN by_IN consumers_NNS (_( clinical_JJ laboratories_NNS and_CC practicing_VBG physicians_NNS )_) , by_IN government_NN , and_CC by_IN medical_JJ regulatory_NN bodies_NNS alternatively_RB , an_AT independent_JJ national_JJ standards_NNS laboratory_NN could_MD be_BE established_VBN to_TO calibrate_VB each_DT lot_NN of_IN thromboplastin_NN , providing_VBG independent_JJ verification_NN for_IN clinical_JJ laboratories_NNS if_CS manufacturers_NNS could_MD be_BE relied_VBN on_RP to_TO provide_VB accurate_JJ ISI_NP values_NNS , a_AT large_JJ part_NN of_IN the_ATI problem_NN would_MD be_BE solved_VBN however_RB , as_CS already_RB discussed_VBN , some_DTI discrepancies_NNS can_MD still_RB occur_VB because_CS of_IN the_ATI effects_NNS of_IN different_JJ automated_JJ instruments_NNS on_IN the_ATI INR_NP although_CS the_ATI instrument-related_JJ problem_NN is_BEZ relatively_RB minor_JJ if_CS responsive_JJ thromboplastins_NNS are_BER used_VBN , it_PP3 can_MD be_BE troublesome_JJ with_IN less_QL responsive_JJ thromboplastins_NNS poller_NN and_CC associates_NNS have_HV reported_VBN that_CS calibrations_NNS can_MD be_BE performed_VBN locally_RB by_IN using_VBG lyophilized_JJ plasmas_NNS with_IN known_VBN INR_NP values_NNS to_TO calculate_VB an_AT instrument-specific_JJ ISI_NP for_IN each_DT new_JJ lot_NN of_IN thromboplastin_NN thus_RB , the_ATI problem_NN is_BEZ solvable_JJ 99_CD 41_CD potential_JJ Solution_NN 100_CD 42_CD the_ATI problem_NN can_MD be_BE solved_VBN by_IN ensuring_VBG that_CS manufacturers_NNS assign_VB reliable_JJ ISI_NP values_NNS to_IN their_PP$ thromboplastins_NNS clinical_JJ laboratories_NNS should_MD select_VB sensitive_JJ thromboplastins_NNS with_IN low_JJ ISI_NP values_NNS (_( {_( 2.0_CD and_CC preferably_RB {_( 1.5_CD )_) if_CS less_AP sensitive_JJ thromboplastins_NNS are_BER used_VBN , local_JJ calibrations_NNS should_MD be_BE performed_VBN with_IN certified_VBN lyophilized_JJ plasma_NN samples_NNS with_IN known_VBN INR_NP values_NNS to_TO determine_VB the_ATI instrument-specific_JJ ISI_NP 101_CD 43_CD PROBLEM_NP 5_CD 102_CD 44_CD incorrect_JJ Calculation_NN of_IN the_ATI INR_NPT Resulting_NPT From_NP Use_NP of_IN Inappropriate_NPT Control_NP Plasma_NP 103_CD 45_CD the_ATI PT_NP ratio_NN is_BEZ calculated_VBN by_IN dividing_VBG the_ATI patient's_NN$ PT_NP by_IN the_ATI mean_JJ normal_JJ plasma_NN PT_NP the_ATI mean_JJ normal_JJ plasma_NN PT_NP is_BEZ not_XNOT interchangeable_JJ with_IN a_AT laboratory_NN control_NN PT_NP , since_CS these_DTS values_NNS can_MD be_BE substantially_RB different_JJ therefore_RB , the_ATI use_NN of_IN a_AT laboratory_NN control_NN PT_NP instead_RB of_IN a_AT properly_RB defined_VBN mean_VB normal_JJ PT_NP can_MD lead_VB to_IN erroneous_JJ INR_NP calculations_NNS , particularly_RB with_IN nonresponsive_JJ reagents_NNS the_ATI mean_JJ normal_JJ PT_NP is_BEZ determined_VBN by_IN measuring_VBG the_ATI PT_NP for_IN fresh_JJ plasma_NN samples_NNS obtained_VBN from_IN at_IN least_RB 20_CD healthy_JJ individuals_NNS (_( and_CC preferably_RB a_AT larger_JJR sample_NN from_IN both_ABX sexes_NNS over_IN a_AT range_NN of_IN age_NN groups_NNS )_) since_IN the_ATI distribution_NN of_IN PT_NP values_NNS is_BEZ not_XNOT normal_JJ , log-transformation_JJB and_CC calculation_NN of_IN a_AT geometric_JJ mean_NN is_BEZ recommended_VBN alternatively_RB , the_ATI median_JJ can_MD be_BE used_VBN , since_CS this_DT is_BEZ a_AT close_RB approximation_NN of_IN the_ATI geometric_JJ mean_NN the_ATI mean_JJ normal_JJ PT_NP should_MD be_BE determined_JJ with_IN the_ATI same_AP reagent_JJ and_CC on_IN the_ATI same_AP instrument_NN as_IN the_ATI patient's_NN$ PT_NP 104_CD 46_CD potential_JJ Solution_NN 105_CD 47_CD laboratory_NN personnel_NNS should_MD be_BE educated_JJ about_IN the_ATI differences_NNS between_IN mean_NN normal_JJ PT_NP and_CC control_NN PT_NP and_CC should_MD be_BE instructed_VBN to_TO calculate_VB the_ATI mean_JJ normal_JJ PT_NP using_VBG fresh_JJ plasma_NN samples_NNS from_IN at_RB least_RB 20_CD healthy_JJ subjects_NNS 106_CD 48_CD PROBLEM_NP 6_CD 107_CD 49_CD high_JJ INR_NP Values_NNS in_IN Overanticoagulated_NPT Patients_NPT Can_NP Produce_NP Unnecessary_NP Alarm_NP 108_CD 50_CD the_ATI expanded_JJ scale_NN and_CC logarithmic_JJ relationship_NN of_IN the_ATI INR_NP system_NN results_NNS in_IN much_RB higher_JJR values_NNS in_IN overanticoagulated_JJ patients_NNS than_IN values_NNS obtained_VBN with_IN the_ATI PT_NP ratio_NN using_VBG less_QL responsive_JJ thromboplastins_NNS For_NP example_NN , if_CS a_AT thromboplastin_NN with_IN an_AT ISI_NP of_IN 2.8_CD is_BEZ used_VBN , an_AT INR_NP of_IN 21.7_CD is_BEZ equivalent_JJ to_IN a_AT PT_NP ratio_NN of_IN 3.0_CD , and_CC an_AT INR_NP of_IN 13.0_CD is_BEZ equivalent_JJ to_IN a_AT PT_NP ratio_NN of_IN 2.5_CD while_CS a_AT PT_NP ratio_NN of_IN 2.5_CD is_BEZ unlikely_JJ to_TO evoke_VB feelings_NNS of_IN panic_NN or_CC even_RB of_IN concern_NN , the_ATI inexperienced_JJ physician_NN is_BEZ likely_JJ to_TO be_BE alarmed_JJ by_IN an_AT INR_NP of_IN 13.0_CD an_AT approach_NN to_TO reversing_NN a_AT high_JJ INR_NP has_HVZ been_BEN suggested_VBN in_IN a_AT recent_JJ publication_NN and_CC is_BEZ summarized_VBN below_RI 109_CD 51_CD potential_JJ Solution_NN 110_CD 52_CD a_AT standard_NN approach_NN to_IN treating_VBG patients_NNS with_IN high_JJ INR_NP values_NNS has_HVZ been_BEN developed_VBN the_ATI following_JJ protocol_NN is_BEZ offered_VBN : 111_CD if_CS the_ATI INR_NP is_BEZ above_IN the_ATI therapeutic_JJ range_NN but_CC below_IN 6.0_CD , if_CS the_ATI patient_NN is_BEZ not_XNOT bleeding_NN , and_CC if_CS rapid_JJ reversal_NN is_BEZ not_XNOT indicated_VBN for_IN reasons_NNS of_IN surgical_JJ intervention_NN , the_ATI next_AP few_AP doses_NNS can_MD be_BE omitted_VBN , and_CC warfarin_NN therapy_NN can_MD be_BE resumed_VBN at_IN a_AT lower_JJR dose_NN when_WRB the_ATI INR_NP is_BEZ in_IN the_ATI therapeutic_JJ range_NN 112_CD if_CS the_ATI INR_NP is_BEZ above_IN 6.0_CD but_CC below_IN 10.0_CD and_CC the_ATI patient_NN is_BEZ not_XNOT bleeding_NN , or_CC if_CS rapid_JJ reversal_NN is_BEZ required_VBN because_CS the_ATI patient_NN needs_NNS elective_JJ surgery_NN , phytonadione_NN (_( vitamin_NN K_ZZ sub_NN 1_CD1 )_) can_MD be_BE given_VBN subcutaneously_RB at_IN a_AT dose_NN of_IN 0.5_CD mg_NNU to_TO 1_CD1 mg_NNU with_IN the_ATI expectation_NN that_CS a_AT demonstrable_JJ reduction_NN of_IN the_ATI INR_NP will_MD occur_VB at_IN 8_CD hours_NNS and_CC that_CS , in_IN many_AP patients_NNS , the_ATI INR_NP will_MD be_BE in_IN the_ATI therapeutic_JJ range_NN of_IN 2.0_CD to_IN 3.0_CD within_IN 24_CD hours_NNS if_CS the_ATI INR_NP is_BEZ remains_VBZ high_JJ at_IN 24_CD hours_NNS , an_AT additional_JJ dose_NN of_IN 0.5_CD mg_NNU of_IN phytonadione_NN can_MD be_BE given_VBN warfarin_NN treatment_NN can_MD then_RN be_BE resumed_VBN at_IN a_AT lower_JJR dose_NN 113_CD if_CS the_ATI INR_NP is_BEZ above_IN 10.0_CD but_CC below_IN 20.0_CD and_CC the_ATI patient_NN is_BEZ not_XNOT bleeding_NN , a_AT higher_JJR dose_NN of_IN phytonadione_NN (_( 3_CD to_IN 5_CD mg_NNU )_) should_MD be_BE given_VBN subcutaneously_RB with_IN the_ATI expectation_NN that_CS the_ATI INR_NP will_MD be_BE reduced_VBN substantially_RB at_IN 6_CD hours_NNS the_ATI INR_NP should_MD be_BE checked_VBN after_IN 6_CD hours_NNS , and_CC the_ATI dose_NN can_MD then_RN be_BE repeated_VBN if_CS necessary_JJ subcutaneous_JJ injection_NN of_IN vitamin_NN K_ZZ is_BEZ preferred_VBN over_IN intravenous_JJ injection_NN in_IN these_DTS circumstances_NNS because_CS rapid_JJ intravenous_JJ infusion_NN of_IN phytonadione_NN can_MD produce_VB anaphylactoid_NN reactions_NNS 114_CD if_CS a_AT very_AP rapid_JJ reversal_NN of_IN an_AT anticoagulant_NN effect_NN is_BEZ required_VBN because_CS of_IN serious_JJ bleeding_NN or_CC major_JJ warfarin_NN overdose_NN (_( eg_NN , INR_NP }20.0_CD )_) , phytonadione_NN at_IN a_AT dose_NN of_IN 10_CD mg_NNU should_MD be_BE given_VBN by_IN slow_JJ intravenous_JJ infusion_NN (_( eg_NN , over_IN 20_CD to_IN 30_CD minutes_NNS )_) , and_CC the_ATI INR_NP should_MD be_BE checked_VBN every_AT 6_CD hours_NNS the_ATI dose_NN of_IN phytonadione_NN may_MD have_HV to_TO be_BE repeated_VBN every_AT 12_CD hours_NNS and_CC supplemented_VBN with_IN plasma_NN transfusion_NN or_CC prothrombin_JJ complex_JJ concentrate_VB , depending_VBG on_IN the_ATI urgency_NN of_IN the_ATI situation_NN 115_CD in_IN case_NN of_IN life-threatening_NN bleeding_NN or_CC serious_JJ warfarin_NN overdose_NN , replacement_NN with_IN prothrombin_JJ complex_JJ concentrate_NN is_BEZ indicated_VBN , supplemented_VBN with_IN intravenous_JJ phytonadione_NN , 10_CD mg_NNU , which_WDTR should_MD be_BE repeated_VBN as_CS necessary_JJ depending_VBG on_IN the_ATI INR_NP 116_CD if_CS continued_VBD warfarin_NN therapy_NN is_BEZ indicated_VBN after_IN high_JJ doses_NNS of_IN phytonadione_NN have_HV been_BEN administered_VBN , heparin_NN can_MD be_BE given_VBN until_IN the_ATI effects_NNS of_IN phytonadione_NN have_HV been_BEN reversed_VBN and_CC the_ATI patient_NN becomes_VBZ responsive_JJ to_TO warfarin_VB therapy_NN 117_CD 53_CD CONCLUSIONS_NP 118_CD 54_CD historically_RB , the_ATI INR_NP system_NN , which_WDTR is_BEZ based_VBN on_IN a_AT mathematical_JJ model_NN , was_BEDZ developed_VBN to_TO normalize_VB the_ATI variability_NN in_IN PT_NP ratios_NNS that_CS results_NNS from_IN the_ATI marked_JJ differences_NNS in_IN sensitivity_NN of_IN commercial_JJ thromboplastin_NN reagents_NNS to_IN the_ATI anticoagulant_NN effects_NNS of_IN warfarin_NN the_ATI INR_NP system_NN can_MD be_BE precise_JJ and_CC valid_JJ when_WRB a_AT sensitive_JJ thromboplastin_NN and_CC a_AT manual_JJ method_NN of_IN clot_NN detection_NN are_BER used_VBN however_RB , it_PP3 loses_VBZ precision_NN and_CC accuracy_NN when_WRB used_VBN to_TO convert_VB PT_NP ratios_NNS obtained_VBN with_IN less-sensitive_JJ thromboplastin_NN reagents_NNS or_CC when_WRB automated_JJ clot_NN detection_NN systems_NNS are_BER used_VBN these_DTS problems_NNS can_MD be_BE minimized_VBN by_IN using_VBG sensitive_JJ thromboplastins_NNS with_IN low_JJ ISI_NP values_NNS and_CC calibrating_VBG automated_JJ systems_NNS with_IN well-characterized_JJ plasma_NN calibrants_NNS 119_CD 55_CD although_CS the_ATI INR_NP system_NN is_BEZ far_RB from_IN perfect_JJ , it_PP3 is_BEZ the_ATI only_AP practical_JJ solution_NN currently_RB available_JJ with_IN all_ABN of_IN its_PP$ faults_NNS , it_PP3 is_BEZ much_RB better_JJR than_IN an_AT unadjusted_JJ PT_NP system_NN although_CS the_ATI laboratory_NN physician_NN would_MD like_IN a_AT perfect_JJ system_NN with_IN little_JJ or_CC no_ATI variability_NN , this_DT goal_NN is_BEZ unattainable_JJ unless_CS a_AT standardized_VBN sensitive_JJ reagent_JJ is_BEZ universally_RB adopted_VBN in_IN contrast_NN , the_ATI clinician_NN wants_VBZ a_AT system_NN that_CS permits_VBZ safe_JJ and_CC effective_JJ warfarin_NN dosing_NN independent_NN of_IN the_ATI reagent_JJ or_CC the_ATI method_NN used_VBN to_TO perform_VB the_ATI PT_NP test_NN by_IN using_VBG sensitive_JJ thromboplastins_NNS with_IN reliable_JJ ISI_NP values_NNS and_CC reporting_VBG the_ATI results_NNS as_IN an_AT INR_NP , the_ATI laboratory_NN physician_NN can_MD allow_VB the_ATI clinician_NN to_TO achieve_VB this_DT goal_NN 120_CD laboratory_NN Monitoring_NP of_IN Children_NP With_NP Precocious_JJ Puberty_NP 121_CD it_PP3 is_BEZ necessary_JJ not_XNOT only_RB to_TO perform_VB laboratory_NN tests_NNS for_IN the_ATI correct_JJ diagnosis_NN of_IN children_NNS with_IN precocious_JJ puberty_NN , but_CC also_RB to_TO monitor_NN laboratory_NN tests_NNS to_TO ensure_VB adequacy_NN of_IN therapy_NN careful_JJ laboratory_NN testing_NN is_BEZ a_AT requisite_JJ in_IN the_ATI differentiation_NN of_IN central_JJ from_IN peripheral_JJ precocious_JJ puberty_NN it_PP3 is_BEZ also_RB required_VBN to_TO determine_VB whether_CS the_ATI patient_NN who_WPR presents_VBZ with_IN early_JJ physical_JJ changes_NNS of_IN pubertal_JJ development_NN with_IN peripheral_JJ precocious_JJ puberty_NN has_HVZ evidence_NN of_IN pubertal_JJ hormonal_JJ secretion_NN the_ATI most_AP useful_JJ single_JJ test_NN is_BEZ gonadotropin-releasing_NN hormone_NN (_( gonadorelin_NN )_) stimulation_NN of_IN luteinizing_VBG hormone_NN release_NN the_ATI same_AP stimulation_NN test_NN is_BEZ also_RB indicated_VBN to_TO verify_VB the_ATI adequacy_NN of_IN suppression_NN of_IN gonadotropin_NN secretion_NN among_IN patients_NNS with_IN central_JJ precocious_JJ puberty_NN who_WPR are_BER being_BEG treated_VBN with_IN gonadotropin-releasing_NN hormone_NN analogue_NN it_PP3 is_BEZ necessary_JJ to_TO know_VB which_WDTR gonadotropin_NN assay_NN is_BEZ being_BEG used_VBN and_CC the_ATI range_NN of_IN nomal_JJ levels_NNS to_TO correctly_RB interpret_VB the_ATI tests_NNS 122_CD left_VBN untreated_JJ , gonadotropin_JJB releasing_VBG hormone_NN (_( GnRH)- dependent_NP precocious_JJ puberty_NN , also_RB known_VBN as_IN central_JJ precocious_JJ puberty_NN (_( CPP_NP )_) , can_MD have_HV profound_JJ physical_JJ and_CC psychological_JJ effects_NNS on_IN affected_JJ children_NNS and_CC their_PP$ families_NNS the_ATI physical_JJ effects_NNS include_VB tall_JJ stature_NN and_CC large_JJ size_NN for_IN age_NN and_CC early_JJ pubertal_JJ development_NN the_ATI psychological_JJ effects_NNS relate_VB not_XNOT only_RB to_IN the_ATI response_NN of_IN the_ATI child_NN to_TO being_BEG different_JJ but_CC also_RB to_IN those_DTS of_IN adults_NNS and_CC other_AP children_NNS to_IN the_ATI child's_NN$ premature_JJ physical_JJ maturity_NN and_CC size_NN however_RB , with_IN the_ATI advent_NN of_IN GnRH_NP agonist_NN therapy_NN , these_DTS children_NNS can_MD see_VB improved_JJ final_JJ height_NN predictions_NNS and_CC experience_NN regression_NN of_IN secondary_JJ sexual_JJ characteristics_NNS however_RB , because_CS the_ATI effectiveness_NN of_IN GnRH_NP agonist_NN therapy_NN depends_VBZ on_IN adequate_JJ suppression_NN of_IN the_ATI hypothalamic-pituitary_NN axis_NN , appropriate_JJ monitoring_NN is_BEZ essential_JJ , and_CC is_BEZ the_ATI main_JJB subject_NN of_IN this_DT article_NN a_AT brief_JJ overview_NN of_IN the_ATI diagnosis_NN and_CC current_JJ treatment_NN options_NNS in_IN GnRH-dependent_NP precocious_JJ puberty_NN will_MD also_RB be_BE presented_VBN 123_CD MAKING_NP A_ZZ DIAGNOSIS_NPT OF_NP CPP_NP 124_CD by_IN definition_NN , the_ATI appearance_NN of_IN secondary_JJ sex_NN characteristics_NNS before_IN age_NN 8_CD years_NNS in_IN girls_NNS and_CC 9_CD years_NNS in_IN boys_NNS is_BEZ termed_VBN precocious_JJ puberty_NN however_RB , the_ATI initial_JJ appearance_NN of_IN physical_JJ puberty_NN , such_IN as_IN breast_NN budding_JJ or_CC pubic_JJ hair_NN , does_DOZ not_XNOT necessarily_RB herald_NN progressive_JJ puberty_NN therefore_RB , patients_NNS should_MD be_BE observed_VBN for_IN a_AT period_NN of_IN months_NNS to_TO verify_VB progression_NN or_CC lack_NN thereof_RB progressive_JJ precocious_JJ puberty_NN can_MD result_VB from_IN central_JJ causes_NNS that_CS result_NN in_IN physiologically_RB normal_JJ but_CC early_JJ episodic_JJ GnRH_NP release_NN , or_CC peripheral_JJ causes_NNS peripheral_JJ precocious_JJ puberty_NN (_( GnRH-independent_NP precocious_JJ puberty_NN )_) results_NNS from_IN gonadotropin_NN or_CC sex_NN steroid_NN stimulation_NN from_IN any_DTI source_NN other_AP than_IN physiologic_JJ GnRH- stimulated_NP pituitary_NN gonadotropin_NN release_NN while_CS CPP_NP involves_VBZ gonadarche_NN (_( pubertal_JJ hypothalamic-pituitary- gonadal_JJ activity_NN )_) , it_PP3 may_MD or_CC may_MD not_XNOT involve_VB adrenarche_NN (_( the_ATI pubertal_JJ rise_NN of_IN adrenal_JJ an_AT drogen_NN secretion_NN )_) a_AT history_NN and_CC physical_JJ and_CC laboratory_NN tests_NNS are_BER necessary_JJ to_TO make_VB the_ATI diagnosis_NN and_CC determine_VB the_ATI cause_NN (_( Table_NP 1_CD1 through_IN Table_NP 3_CD )_) 125_CD the_ATI medical_JJ history_NN should_MD make_VB note_NN of_IN the_ATI onset_NN of_IN pubic_JJ hair_NN , breast_NN development_NN , genital_JJ growth_NN as_QL well_RB as_IN any_DTI vaginal_JJ discharge_NN , the_ATI occurrence_NN of_IN menarche_NN , acne_NN , erections_NNS , and_CC aggressive_JJ behavior_NN the_ATI rate_NN of_IN progression_NN of_IN pubertal_JJ development_NN should_MD be_BE documented_VBN it_PP3 should_MD also_RB be_BE determined_JJ whether_CS exposure_NN to_IN exogenous_JJ sex_NN steroids_NNS in_IN cosmetics_NNS , food_NN , or_CC medications_NNS may_MD have_HV occurred_VBN previous_JJ heights_NNS and_CC weights_NNS should_MD be_BE carefully_RB plotted_VBN for_IN age_NN on_IN a_AT growth_NN chart_NN physical_JJ examination_NN should_MD document_NN the_ATI Tanner_NP stage_NN of_IN sexual_JJ development_NN , testicular_NN size_NN , any_DTI neurologic_JJ or_CC ophthalmologic_JJ abnormalities_NNS , and_CC any_DTI evidence_NN consistent_JJ with_IN thyroid_JJ dysfunction_NN radiological_JJ examinations_NNS of_IN the_ATI patient's_NN$ nondominant_NN hand_NN and_CC wrist_NN help_NN determine_VB the_ATI skeletal_JJ age_NN if_CS roentgenograms_NNS show_VB advanced_JJ skeletal_JJ age_NN (_( more_AP than_IN 2_CD SDs_NP above_IN the_ATI mean_NN )_) , this_DT is_BEZ evidence_NN of_IN excessive_JJ stimulation_NN of_IN bone_NN maturity_NN the_ATI sex_NN steroids_NNS secreted_VBN in_IN precocious_JJ puberty_NN can_MD cause_VB such_ABL stimulation_NN baseline_JJ hormonal_JJ levels_NNS should_MD be_BE measured_VBN , including_IN thyroid_JJ function_NN studies_NNS , estradiol_NN in_IN girls_NNS and_CC testosterone_NN in_IN boys_NNS plus_IN basal_JJ and_CC GnRH-stimulated_NP follicle- stimulating_NN hormone_NN (_( FSH_NP )_) and_CC luteinizing_VBG hormone_NN (_( LH_NP )_) human_JJ chorionic_JJ gonadotropin_NN should_MD be_BE measured_VBN in_IN boys_NNS to_TO rule_VB out_RP a_AT gonadotropin-producing_NN tumor_NN 17-Hydroxyprogesterone_CD-CD should_MD also_RB be_BE measured_VBN in_IN boys_NNS if_CS history_NN and_CC physical_JJ examination_NN are_BER consistent_JJ with_IN congenital_JJ adrenal_JJ hyperplasia_NN 126_CD imaging_VBG techniques_NNS may_MD be_BE indicated_VBN depending_VBG on_IN sex_NN and_CC presentation-ultrasound_JJ examination_NN of_IN the_ATI adrenals_NNS and_CC ovaries_NNS in_IN girls_NNS , and_CC a_AT skeletal_JJ survey_NN including_IN a_AT skull_NN roentgenogram_NN or_CC bone_NN scan_NN searching_VBG for_IN characteristic_JJ bone_NN lesions_NNS if_CS the_ATI McCune- Albright_NP syndrome_NN (_( a_AT type_NN of_IN gonadotropin-independent_JJ precocious_JJ puberty_NN characterized_VBN by_IN cafe_NN au_&FW lait_NN spots_NNS , skeletal_JJ dysplasia_NN , and_CC autonomous_JJ precocious_JJ puberty_NN )_) is_BEZ suspected_VBN in_IN both_ABX boys_NNS and_CC girls_NNS with_IN a_AT probable_JJ diagnosis_NN of_IN CPP_NP , computed_VBN tomographic_JJ or_CC magnetic_JJ resonance_NN imaging_VBG scans_NNS may_MD be_BE needed_VBN to_TO rule_VB out_RP space- occupying_NN lesions_NNS such_ABL as_CS tumors_NNS in_IN the_ATI hypothalamic_JJ region_NN , hypothalamic_JJ hamartomas_NNS (_( congenitally_RB redundant_JJ hypothalamic_JJ tissue_NN sometimes_RB detected_VBN in_IN children_NNS with_IN GnRH-dependent_NP precocious_JJ puberty_NN )_) , or_CC increased_VBN intracranial_JJ pressure_NN (_( a_AT lesion_NN that_CS causes_NNS increased_VBN intracranial_JJ pressure_NN may_MD lead_VB to_TO precocious_JJ puberty_NN )_) head_NN scanning_VBG is_BEZ indicated_VBN if_CS neurofibromatosis_NN is_BEZ suspected_VBN because_CS of_IN family_NN history_NN or_CC cutaneous_JJ manifestations_NNS that_DT may_MD include_VB neurofibromas_NNS , fibroma_NN molluscum_NN (_( soft_JJ subcutaneous_JJ tumors_NNS )_) , or_CC cafe_NN au_&FW lait_NN spots_NNS astrocytomas_NNS or_CC gliomas_NNS of_IN the_ATI optic_JJ chiasm_NN and_CC hypothalamus_JJ may_MD be_BE associated_VBN with_IN precocious_JJ puberty_NN first_OD , however_RB , the_ATI GnRH-stimulation_NN test_NN should_MD be_BE done_VBN to_TO determine_VB whether_CS the_ATI LH_NP and_CC FSH_NP responses_NNS suggest_VB a_AT central_JJ or_CC peripheral_JJ cause_NN for_IN the_ATI precocious_JJ puberty_NN 127_CD during_IN the_ATI GnRH-stimulation_NN test_NN , a_AT 100-micrograms_CD-CD intravenous_JJ bolus_NN of_IN gonadorelin_NN is_BEZ administered_VBN and_CC serial_JJ samples_NNS of_IN serum_NN LH_NP and_CC FSH_NP are_BER collected_VBN in_IN patients_NNS with_IN GnRH-independent_NP precocious_JJ puberty_NN (_( peripheral_JJ precocious_JJ puberty_NN )_) and_CC in_IN prepubertal_JJ children_NNS , the_ATI gonadorelin_JJ bolus_JJ results_NNS in_IN minimal_JJ release_NN of_IN LH_NP and_CC a_AT relatively_RB greater_JJR FSH_NP response_NN (_( Figure_NP 1_CD1 )_) 128_CD patients_NNS with_IN precocious_JJ pubarche_NN (_( early_JJ pubic_JJ hair_NN development_NN as_IN the_ATI result_NN of_IN early_JJ adrenarche_NN )_) or_CC precocious_JJ thelarche_NN (_( early_JJ breast_NN budding_JJ without_IN other_AP evidence_NN of_IN pubertal_JJ development_NN )_) also_RB show_VB a_AT prepubertal_JJ pattern_NN of_IN LH_NP secretion_NN patients_NNS with_IN both_ABX conditions_NNS have_HV essentially_RB normal_JJ height_NN patterns_NNS and_CC their_PP$ skeletal_JJ maturation_NN is_BEZ within_IN the_ATI range_NN appropriate_JJ for_IN their_PP$ chronologic_JJ age_NN since_CS they_PP3AS can_MD be_BE expected_VBN to_TO progress_VB through_IN other_AP aspects_NNS of_IN puberty_NN at_IN an_AT appropriate_JJ time_NN , no_ATI therapy_NN is_BEZ required_VBN 129_CD in_IN children_NNS with_IN gonadotropin-dependent_JJ precocious_JJ puberty_NN and_CC in_IN normal_JJ pubertal_JJ children_NNS , the_ATI LH_NP response_NN to_IN a_AT gonadorelin_JJ bolus_NN is_BEZ greater_JJR than_IN that_DT of_IN prepubertal_JJ children_NNS (_( Figure_NP 1_CD1 )_) among_IN girls_NNS particularly_RB , the_ATI increase_NN of_IN LH_NP becomes_VBZ more_QL discernible_JJ during_IN puberty_NN while_CS that_CS of_IN FSH_NP may_MD not_XNOT be_BE noticeable_JJ although_CS the_ATI rise_NN may_MD be_BE more_QL prompt_JJ thus_RB , the_ATI ratio_NN of_IN LH_NP to_IN FSH_NP is_BEZ greater_JJR during_IN puberty_NN than_IN prepuberty_NN 130_CD levels_NNS of_IN LH_NP and_CC FSH_NP may_MD be_BE measured_VBN using_VBG a_AT variety_NN of_IN assays_NNS including_IN radioimmunoassays_NNS (_( RIAs_NNS )_) , newer_JJR , more_QL sensitive_JJ immunoradiometric_JJ (_( IRMA_NP )_) , immunochemiluminometric_JJ , and_CC immunofluorimetric_JJ (_( IFMA_NP )_) assays_NNS (_( Table_NP 4_CD and_CC Table_NP 5_CD )_) before_CS values_NNS can_MD be_BE interpreted_VBN , it_PP3 is_BEZ necessary_JJ to_TO know_VB the_ATI levels_NNS and_CC responses_NNS in_IN prepubertal_JJ and_CC pubertal_JJ individuals_NNS for_IN the_ATI particular_JJ assay_NN used_VBN Using_NP RIAs_NNS in_IN girls_NNS , a_AT diagnosis_NN of_IN GnRH-dependent_NP precocious_JJ puberty_NN can_MD be_BE made_VBN in_IN almost_RB all_ABN patients_NNS if_CS a_AT peak_NN LH_NP value_NN of_IN over_IN 15_CD IU_L_NP or_CC a_AT peak_NN LH_FSH_NP ratio_NN higher_JJR than_IN 0.66_CD is_BEZ measured_VBN generally_RB the_ATI newer_JJR assays_NNS have_HV levels_NNS that_CS are_BER 40%_NP to_IN 50%_NP of_IN those_DTS using_VBG RIAs_NNS for_IN example_NN , the_ATI data_NNS shown_VBN in_IN Figure_NP 1_CD1 suggest_VB that_CS , using_VBG IFMA_NP , a_AT peak_NN LH_NP level_NN higher_JJR than_IN 6_CD IU_L_NP and_CC an_AT LH_FSH_NP ratio_NN higher_JJR than_IN 0.3_CD are_BER consistent_JJ with_IN CPP_NP in_IN boys_NNS , the_ATI criterion_NN is_BEZ a_AT maximum_JJ LH_NP peak_NN over_IN baseline_NN of_IN more_AP than_IN 25.5_CD IU_L_NP using_VBG RIA_NP or_CC more_AP than_IN 10_CD IU_L_NP using_VBG IFMA_NP (_( Figure_NP 2_CD )_) an_AT equivocal_JJ response_NN should_MD lead_VB to_IN reassessment_NN after_IN 3_CD to_IN 6_CD months_NNS , with_IN determination_NN of_IN progression_NN of_IN growth_NN and_CC development_NN and_CC repeated_VBN GnRH_NP stimulation_NN , if_CS indicated_VBN (_( Figure_NP 3_CD )_) repeated_VBN GnRH_NP testing_NN has_HVZ been_BEN found_VBN to_TO be_BE a_AT better_JJR index_NN than_IN testing_NN for_IN spontaneous_JJ gonadotropin_NN pulses_NNS with_IN nocturnal_JJ sampling_NN 131_CD TREATMENT_NP 132_CD treatment_NN of_IN precocious_JJ puberty_NN depends_VBZ on_IN the_ATI causes_NNS obviously_RB , surgical_JJ or_CC medical_JJ therapy_NN of_IN peripheral_JJ precocious_JJ puberty_NN depends_VBZ on_IN the_ATI specific_JJ cause_NN surgical_JJ or_CC radiation_NN therapy_NN may_MD be_BE indicated_VBN for_IN central_JJ nervous_JJ system_NN tumors_NNS related_VBN to_IN GnRH-dependent_NP puberty_NN among_IN patients_NNS with_IN idiopathic_JJ CPP_NP or_CC those_DTS with_IN underlying_JJ central_JJ nervous_JJ system_NN abnormalities_NNS in_IN which_WDTR therapy_NN does_DOZ not_XNOT lead_VB to_IN regression_NN of_IN pubertal_JJ gonadotropin_NN secretion_NN , GnRH_NP agonists_NNS may_MD be_BE used_VBN to_TO remove_VB the_ATI gonadotropin_NN secretion_NN that_CS stimulates_VBZ the_ATI pubertal_JJ process_NN if_CS complete_JJ suppression_NN is_BEZ not_XNOT the_ATI goal_NN , as_IN in_IN a_AT child_NN with_IN severe_JJ mental_JJ retardation_NN in_IN whom_WPOR height_NN is_BEZ not_XNOT a_AT factor_NN but_CC menses_NNS are_BER problematic_JJ , medroxyprogesterone_NN acetate_NN may_MD be_BE used_VBN to_TO provide_VB adequate_JJ suppression_NN to_TO stop_VB menses_NNS 133_CD generally_RB the_ATI medical_JJ treatment_NN of_IN gonadotropin-dependent_NN precocious_JJ puberty_NN involves_VBZ the_ATI use_NN of_IN GnRH_NP agonists_NNS these_DTS drugs_NNS (_( eg_NN , histrelin_NN , leuprolide_NN , nafarelin_NN )_) vary_VB in_IN their_PP$ potency_NN and_CC the_ATI route_NN by_IN which_WDTR they_PP3AS are_BER administered_VBN (_( eg_NN , intranasal_JJ , subcutaneous_JJ , and_CC intramuscular_NN )_) monthly_JJ depot_NN formulations_NNS , such_IN as_IN leuprolide_NN acetate_NN , may_MD have_HV advantages_NNS because_CS of_IN suppression_NN that_CS does_DOZ not_XNOT depend_VB on_IN timing_NN of_IN the_ATI daily_JJ administration_NN and_CC improved_JJ compliance_NN side_NN effects_NNS are_BER infrequent_JJ fewer_AP than_IN 5%_NN of_IN patients_NNS have_HV been_BEN reported_VBN to_TO develop_VB symptoms_NNS suggestive_JJ of_IN drug_NN sensitivity_NN including_IN urticaria_NN , rash_NN , and_CC pruritus_NN the_ATI depot_NN injections_NNS may_MD be_BE accompanied_VBN by_IN the_ATI formation_NN of_IN a_AT sterile_JJ abscess_NN at_IN the_ATI injection_NN site_NN as_CS with_IN the_ATI diagnostic_JJ tests_NNS , the_ATI cost_NN of_IN medication_NN may_MD vary_VB considerably_RB depending_VBG on_IN numerous_JJ factors_NNS cost_NN depends_VBZ on_IN dosage_NN and_CC may_MD range_VB from_IN about_IN $350_CD to_RP over_IN $2000_CD per_NNU month_NN because_CS larger_JJR doses_NNS are_BER required_VBN for_IN intranasal_JJ therapy_NN , the_ATI drug_NN may_MD cost_VB more_QL while_CS supplies_NNS for_IN injection_NN are_BER not_XNOT needed_VBN 134_CD the_ATI goal_NN of_IN treatment_NN of_IN GnRH-dependent_NP precocious_JJ puberty_NN is_BEZ to_TO ensure_VB that_CS secondary_JJ sex_NN characteristics_NNS stop_VB progressing_VBG or_CC recede_NN and_CC that_CS skeletal_JJ maturation_NN is_BEZ slowed_VBN so_CS that_CS patients_NNS can_MD preserve_VB or_CC regain_VB genetic_JJ height_NN potential_JJ therapy_NN with_IN GnRH_NP agonists_NNS in_IN the_ATI appropriate_JJ dose_NN suppresses_VBZ the_ATI hypothalamic-pituitary_NN axis_NN , resulting_JJ in_IN downregulation_NN of_IN LH_NP and_CC FSH_NP secretion_NN to_TO accomplish_VB the_ATI goal_NN of_IN halting_VBG pubertal_JJ progression_NN and_CC preserving_VBG or_CC increasing_JJ height_NN potential_JJ this_DT is_BEZ established_VBN by_IN persistent_JJ GnRH_NP levels_NNS at_IN the_ATI pituitary_NN gland_NN while_CS the_ATI initial_JJ effect_NN is_BEZ stimulation_NN of_IN gonadotropin_NN release_NN , LH_NP and_CC FSH_NP secretion_NN is_BEZ suppressed_VBN within_IN a_AT matter_NN of_IN days_NNS However_NP , if_CS too_QL small_JJ a_AT dose_NN of_IN GnRH_NP agonist_NN is_BEZ used_VBN or_CC if_CS the_ATI drug_NN is_BEZ not_XNOT given_VBN as_CS directed_VBN , the_ATI pituitary_NN gland_NN may_MD be_BE repeatedly_RB stimulated_VBN , resulting_JJ in_IN elevation_NN , not_XNOT suppression_NN , of_IN LH_NP and_CC FSH_NP secretion_NN and_CC thus_RB accelerating_VBG the_ATI process_NN of_IN puberty_NN this_DT may_MD exacerbate_VB the_ATI rapid_JJ progression_NN of_IN puberty_NN and_CC compromise_NN final_JJ height_NN prognosis_NN Appropriate_NP monitoring_VBG of_IN GnRH_NP therapy_NN by_IN close_RB clinical_JJ observation_NN and_CC timely_JJ laboratory_NN evaluation_NN is_BEZ therefore_RB crucial_JJ there_EX is_BEZ no_ATI evidence_NN of_IN any_DTI detrimental_JJ effect_NN if_CS a_AT greater_JJR amount_NN of_IN analogue_NN is_BEZ given_VBN than_IN needed_VBN ; once_RB in_IN circulation_NN , this_DT peptide_NN is_BEZ promptly_RB degraded_JJ 135_CD since_IN suppression_NN can_MD be_BE expected_VBN within_IN a_AT month_NN if_CS an_AT adequate_JJ dose_NN is_BEZ used_VBN , a_AT GnRH-stimulation_NN test_NN should_MD be_BE conducted_VBN after_IN the_ATI initial_JJ 1_CD1 or_CC 2_CD months_NNS of_IN therapy_NN if_CS suppression_NN does_DOZ not_XNOT occur_VB , the_ATI dosage_NN should_MD be_BE increased_VBN and_CC the_ATI patients_NNS restudied_VBN until_IN adequate_JJ suppression_NN is_BEZ achieved_VBN thereafter_RB , since_IN the_ATI dosage_NN needed_VBN for_IN suppression_NN may_MD increase_VB , a_AT reassessment_NN should_MD be_BE made_VBN with_IN GnRH_NP testing_NN every_AT 6_CD months_NNS for_IN the_ATI duration_NN of_IN therapy_NN an_AT algorithm_NN for_IN the_ATI care_NN of_IN these_DTS patients_NNS during_IN and_CC after_IN therapy_NN is_BEZ outlined_VBN in_IN Figure_NP 4_CD 136_CD clinical_JJ Monitoring_NP 137_CD the_ATI growth_NN rate_NN and_CC development_NN of_IN secondary_JJ sex_NN characteristics_NNS should_MD be_BE clinically_RB followed_VBN up_RP the_ATI growth_NN and_CC skeletal_JJ maturity_NN rate_NN should_MD decrease_VB within_IN 6_CD months_NNS and_CC stabilize_VB within_IN 1_CD1 year_NN with_IN successful_JJ therapy_NN this_DT can_MD be_BE documented_VBN both_ABX clinically_RB (_( by_IN plotting_VBG serial_JJ heights_NNS )_) and_CC radiologically_RB (_( with_IN roentgenography_NN of_IN the_ATI nondominant_NN hand_NN and_CC wrist_NN )_) successive_JJ Tanner_NP staging_NN should_MD show_VB stabilization_NN or_CC regression_NN of_IN secondary_JJ sex_NN characteristics_NNS , except_IN pubic_JJ hair_NN staging_NN , which_WDTR may_MD progress_VB slowly_RB in_IN the_ATI patient_NN who_WPR also_RB has_HVZ had_HVN adrenarche_JJ because_CS of_IN adrenal_JJ androgen_NN stimulation_NN progression_NN of_IN the_ATI growth_NN rate_NN or_CC secondary_JJ sexual_JJ characteristics_NNS indicates_VBZ either_DTX a_AT diagnosis_NN other_AP than_IN CPP_NP or_CC inadequate_JJ suppression_NN of_IN the_ATI hypothalamic-pituitary_NN axis_NN 138_CD laboratory_NN Follow-up_NP 139_CD assessment_NN of_IN adequacy_NN of_IN GnRH_NP agonist_NN therapy_NN involves_VBZ estimation_NN of_IN gonadotropin_NN secretion_NN using_VBG a_AT validated_JJ assay_NN such_ABL as_CS RIA_NP , IRMA_NP , immunochemiluminometric_JJ assay_NN , and_CC IFMA_NP or_CC fluoroimmunometric_JJ assay_NN (_( Table_NP 4_CD )_) luteinizing_VBG hormone_NN responses_NNS to_IN GnRH_NP testing_NN are_BER the_ATI most_QL definitive_JJ way_NN to_TO determine_VB whether_CS adequate_JJ gonadotropin_NN suppression_NN has_HVZ occurred_VBN (_( Table_NP 3_CD )_) while_CS the_ATI current_JJ data_NNS suggest_VB that_CS GnRH_NP stimulation_NN testing_NN provides_VBZ the_ATI best_JJT index_NN of_IN adequate_JJ therapy_NN , a_AT complete_JJ standard_NN test_NN may_MD not_XNOT always_RB be_BE necessary_JJ using_VBG IFMA_NP in_IN the_ATI assessment_NN of_IN GnRH_NP agonist_NN therapy_NN in_IN patients_NNS with_IN CPP_NP , an_AT abbreviated_JJ GnRH_NP stimulation_NN test_NN with_IN blood_NN samples_NNS drawn_VBN at_IN 20_CD and_CC 40_CD minutes_NNS for_IN LH_NP and_CC FSH_NP was_BEDZ adequate_JJ for_IN assessment_NN of_IN suppression_NN 140_CD another_DT study_NN using_VBG IRMA_NP suggests_VBZ that_CS a_AT single_JJ timed_VBN sample_NN following_JJ the_ATI gonadorelin_JJ bolus_JJ was_BEDZ as_CS useful_JJ in_IN distinguishing_VBG the_ATI pubertal_JJ response_NN as_IN determination_NN of_IN the_ATI peak_NN LH_NP level_NN by_IN using_VBG multiple_JJ sampling_NN that_DT study_NN compared_VBN LH_NP levels_NNS as_CS measured_VBN with_IN both_ABX RIA_NP and_CC IRMA_NP in_IN normal_JJ children_NNS after_IN GnRH_NP stimulation_NN high_JJ specificity_NN was_BEDZ needed_VBN to_TO distinguish_VB between_IN pubertal_JJ and_CC prepubertal_JJ responses_NNS the_ATI IRMA_NP assay_NN provided_VBD a_AT higher_JJR sensitivity_NN than_IN RIA_NP for_IN determining_VBG LH_NP levels_NNS at_IN 100%_CD specificity_NN , the_ATI sensitivity_NN of_IN the_ATI IRMA_NP measurement_NN of_IN peak_NN LH_NP was_BEDZ 91%_CD , while_CS the_ATI sensitivity_NN of_IN RIA_NP measurement_NN of_IN peak_NN LH_NP was_BEDZ only_RB 73%_CD sensitivity_NN of_IN IRMA_NP at_IN all_ABN time_NN points_NNS (_( 15_CD , 30_CD , 45_CD and_CC 60_CD minutes_NNS following_JJ gonadorelin_NN injection_NN )_) at_IN 100%_CD specificity_NN was_BEDZ 88%_NN , while_CS the_ATI sensitivity_NN of_IN RIA_NP was_BEDZ variable_NN , with_IN a_AT range_NN of_IN 55%_NN to_IN 70%_NP 141_CD the_ATI general_JJ understanding_NN of_IN the_ATI physiologic_JJ characteristics_NNS of_IN gonadotropin_NN secretion_NN leads_VBZ to_IN the_ATI conclusion_NN that_CS if_CS suppression_NN occurs_VBZ after_IN GnRH_NP stimulation_NN testing_NN , spontaneous_JJ gonadotropin_NN secretion_NN , as_IN reflected_VBD for_IN example_NN in_IN the_ATI random_JJ samples_NNS , urinary_NN levels_NNS , or_CC in_IN nocturnal_JJ samples_NNS , will_MD also_RB be_BE consistent_JJ with_IN suppression_NN therefore_RB , a_AT suppressed_JJ response_NN after_IN GnRH_NP testing_NN can_MD be_BE considered_VBN to_TO be_BE indicative_NN of_IN adequate_JJ suppression_NN this_DT is_BEZ at_IN variance_NN with_IN a_AT dose-finding_JJ study_NN of_IN leuprolide_NN acetate_NN depot_NN in_IN which_WDTR Cook_NP et_&FW al_APS found_VBN that_CS nocturnal_JJ LH_NP sampling_NN using_VBG RIA_NP was_BEDZ more_QL sensitive_JJ that_CS GnRH-stimulation_NN testing_JJ alone_RB in_IN assessing_VBG suppression_NN of_IN the_ATI hypothalamic-pituitary_NN axis_NN until_IN this_DT study_NN can_MD be_BE verified_VBN , nocturnal_JJ sampling_NN should_MD not_XNOT become_VB a_AT recommended_JJ tool_NN to_TO monitor_NN therapy_NN because_CS it_PP3 is_BEZ more_QL complicated_JJ , expensive_JJ , and_CC has_HVZ been_BEN found_VBN to_TO be_BE unnecessary_JJ by_IN most_QL investigators_NNS 142_CD random_JJ measurements_NNS of_IN LH_NP levels_NNS using_VBG IRMA_NP are_BER superior_JJ to_IN those_DTS made_VBN using_VBG RIA_NP in_IN identifying_VBG the_ATI onset_NN of_IN puberty_NN in_IN normal_JJ children_NNS and_CC in_IN those_DTS with_IN sexual_JJ precocity_NN using_VBG IRMA_NP and_CC IFMA_NP for_IN measuring_VBG LH_NP levels_NNS in_IN random_JJ samples_NNS provides_VBZ a_AT clearer_JJR distinction_NN between_IN pubertal_JJ and_CC prepubertal_JJ ranges_NNS than_IN does_DOZ RIA_NP this_DT is_BEZ clearly_RB a_AT function_NN of_IN increased_JJ sensitivity_NN , since_IN RIAs_NP can_MD measure_VB LH_NP in_IN concentrations_NNS as_QL low_JJ as_IN 1.8_CD IU_L_NP while_CS IRMA_NP may_MD detect_VB levels_NNS as_QL low_JJ as_IN 0.25_CD IU_L_NP 143_CD like_IN IRMA_NP , IFMAs_NP also_RB have_HV a_AT high_JJ sensitivity_NN use_NN of_IN ultrasensitive_JJ time-resolved_JJ IFMAs_NNS permits_VBZ detection_NN of_IN LH_NP at_IN a_AT level_NN of_IN about_RB 0.019_CD IU_L_NP using_VBG this_DT method_NN , a_AT prepubertal_JJ boy_NN had_HVD an_AT LH_NP level_JJ of_IN 0.02_NP IU_L_NP , while_CS the_ATI lowest_JJT LH_NP level_NN detected_VBD in_IN an_AT early_JJ pubertal_JJ boy_NN was_BEDZ 0.3_CD IU_L_NP these_DTS newer_JJR assays_NNS (_( IRMA_NP and_CC IFMA_NP )_) may_MD eventually_RB facilitate_VB the_ATI diagnosis_NN of_IN precocious_JJ puberty_NN and_CC follow-up_NN because_CS of_IN their_PP$ increased_JJ sensitivity_NN over_IN RIA_NP , but_CC now_RN the_ATI diagnosis_NN requires_VBZ GnRH-stimulation_NN testing_NN 144_CD single_JJ blood_NN sampling_NN determinations_NNS using_VBG these_DTS binding_JJ assays_NNS including_IN the_ATI monoclonal_JJ RIA_NP , urinary_NN gonadotropins_NNS as_CS measured_VBN with_IN RIA_NP , or_CC isolated_JJ estradiol_NN determinations_NNS in_IN girls_NNS are_BER not_XNOT currently_RB recommended_VBN for_IN patient_NN follow-up_NN radioimmunoassays_NNS employing_VBG monoclonal_JJ antibodies_NNS for_IN specific_JJ isoforms_NNS of_IN LH_NP are_BER not_XNOT recommended_VBN because_CS they_PP3AS may_MD provide_VB a_AT false_JJ sense_NN of_IN security_NN about_IN the_ATI suppression_NN of_IN LH_NP secretion_NN this_DT is_BEZ because_CS low_JJ levels_NNS of_IN one_CD1 isoform_NN do_DO not_XNOT necessarily_RB mean_VB that_CS the_ATI other_AP unmeasured_JJ biologically_RB active_JJ isoforms_NNS are_BER low_JJ as_IN well_RB in_IN fact_NN , many_AP bioactive_JJ isoforms_NNS of_IN LH_NP are_BER not_XNOT detected_VBN by_IN antibodies_NNS directed_VBN against_IN specific_JJ isoforms_NNS on_IN the_ATI other_AP hand_NN , the_ATI traditional_JJ RIA_NP may_MD detect_VB significant_JJ levels_NNS of_IN immunoactive_JJ LH_NP while_CS the_ATI bioactive_JJ forms_NNS are_BER suppressed_VBN giving_VBG the_ATI false_JJ impression_NN that_CS LH_NP secretion_NN is_BEZ not_XNOT suppressed_VBN in_IN the_ATI patient_NN 145_CD urinary_NN gonadotropin_NN levels_NNS have_HV been_BEN studied_VBN using_VBG a_AT polyclonal_JJ double_JJ antibody_NN RIA_NP method_NN maesaka_NN et_&FW al_APS studied_JJ urinary_NN LH_NP and_CC FSH_NP levels_NNS in_IN consecutive_JJ 30-day_JJB first_OD morning_NN voided_JJ urine_NN specimens_NNS in_IN normal_JJ children_NNS and_CC in_IN those_DTS with_IN CPP_NP they_PP3AS found_VBD that_CS in_IN normal_JJ prepubertal_JJ girls_NNS , urinary_NN LH_NP levels_NNS were_BED low_JJ and_CC varied_JJ little_JJ , while_CS FSH_NP levels_NNS were_BED higher_JJR and_CC varied_JJ episodically_RB in_IN early_JJ pubertal_JJ girls_NNS , urinary_NN LH_NP and_CC FSH_NP levels_NNS increased_VBN and_CC showed_VBD marked_JJ rhythmic_JJ fluctuations_NNS following_JJ menarche_NN , urinary_NN gonadotropins_NNS showed_VBD a_AT single_JJ high_JJ surge_NN during_IN each_DT menstrual_JJ cycle_NN prepubertal_JJ boys_NNS showed_VBD patterns_NNS similar_JJ to_IN those_DTS seen_VBN in_IN prepubertal_JJ girls_NNS but_CC with_IN less_QL variability_NN Children_NP with_IN CPP_NP showed_VBD patterns_NNS similar_JJ to_IN those_DTS seen_VBN in_IN normal_JJ children_NNS at_IN the_ATI same_AP stage_NN of_IN sexual_JJ development_NN the_ATI authors_NNS concluded_VBD that_CS testing_NN urinary_NN gonadotropin_NN levels_NNS in_IN first_OD morning_NN voided_JJ samples_NNS is_BEZ a_AT simple_JJ physiologic_JJ test_NN of_IN gonadotropin_NN function_NN however_RB , although_CS a_AT polyclonal_JJ RIA_NP was_BEDZ used_VBN , it_PP3 did_DOD not_XNOT measure_VB all_ABN bioactive_JJ gonadotropin_NN concentrations_NNS and_CC thus_RB may_MD not_XNOT accurately_RB reflect_VB the_ATI true_JJ activity_NN of_IN the_ATI reproductive_JJ unit_NN therefore_RB , until_IN further_JJB evidence_NN is_BEZ available_JJ , urinary_NN gonadotropin_NN levels_NNS by_IN RIA_NP cannot_NN be_BE recommended_VBN for_IN use_NN as_IN a_AT follow-up_NN measure_NN to_TO replace_VB GnRH- stimulation_NN testing_NN in_IN children_NNS undergoing_VBG treatment_NN for_IN CPP_NP 146_CD finally_RB , monitoring_VBG patients_NNS by_IN following_JJ only_RB sex_NN steroid_NN levels_NNS such_IN as_IN estradiol_NN with_IN RIA_NP is_BEZ considered_VBN inadequate_JJ for_IN the_ATI following_JJ reasons_NNS : (_( 1_CD1 )_) levels_NNS can_MD be_BE quite_RB variable_JJ even_RB among_IN pubertal_JJ females_NNS , and_CC in_IN many_AP cases_NNS they_PP3AS are_BER below_IN the_ATI limit_NN of_IN detection_NN of_IN the_ATI assay_NN used_VBN ; (_( 2_CD ) _) basal_JJ estradiol_NN levels_NNS may_MD be_BE no_ATI different_RB in_IN girls_NNS with_IN CPP_NP than_CS in_IN normal_JJ girls_NNS ; (_( 3_CD )_) low_JJ estrogen_NN levels_NNS (_( {_( 90_CD pmol_L_NN )_) stimulate_VB growth_NN at_IN the_ATI same_AP level_NN as_IN high_JJ estrogen_NN levels_NNS (_( at_RB least_RB 90_CD pmol_L_NN )_) ; and_CC (_( 4_CD )_) intraindividual_JJ variation_NN of_IN plasma_NN estradiol_NN level_NN is_BEZ common_NN in_IN girls_NNS with_IN CPP_NP 147_CD in_IN boys_NNS , however_RB , a_AT low_JJ blood_NN testosterone_NN level_NN in_IN a_AT patient_NN receiving_VBG GnRH_NP agonist_NN therapy_NN for_IN CPP_NP is_BEZ an_AT adequate_JJ index_NN of_IN suppression_NN a_AT value_NN below_IN 35_CD nmol_L_NN (_( {_( 10_CD ng_mL_NN )_) is_BEZ a_AT clear_JJ indication_NN that_CS the_ATI system_NN is_BEZ downregulated_VBN in_IN the_ATI patient_NN receiving_VBG the_ATI analogue_NN in_IN a_AT depot_NN form_NN if_CS daily_JJ medication_NN is_BEZ given_VBN , the_ATI timing_NN of_IN the_ATI blood_NN sample_NN in_IN relation_NN to_IN the_ATI last_AP dose_NN is_BEZ important_JJ because_CS the_ATI patient_NN who_WPR has_HVZ not_XNOT undergone_VBN complete_JJ downregulation_NN may_MD experience_VB a_AT stimulatory_NN phase_NN for_IN a_JJ few_AP hours_NNS that_CS includes_VBZ not_XNOT only_RB gonadotropin_JJ stimulation_NN but_CC also_RB testosterone_JJ secretion_NN 148_CD in_IN a_AT recent_JJ study_NN , it_PP3 was_BEDZ found_VBN that_CS therapeutic_JJ monitoring_NN was_BEDZ best_JJT achieved_VBN with_IN GnRH-stimulation_NN testing_NN , basal_JJ testosterone_NN or_CC estradiol_NN level_NN testing_NN , and_CC physical_JJ examination_NN every_AT 1_CD1 to_IN 2_CD months_NNS until_IN suppression_NN was_BEDZ achieved_VBN (_( usually_RB within_IN 1_CD1 month_NN of_IN initiating_JJ therapy_NN )_) thereafter_RB , since_IN GnRH_NP agonist_NN dosage_NN requirements_NNS may_MD change_VB , it_PP3 is_BEZ recommended_VBN that_CS patients_NNS be_BE evaluated_VBN every_AT 6_CD months_NNS while_CS GnRH-stimulation_NN testing_NN is_BEZ needed_VBN , few_AP samples_NNS for_IN gonadotropins_NNS need_NN to_TO be_BE drawn_VBN if_CS the_ATI more_QL sensitive_JJ assays_NNS are_BER used_VBN 149_CD CONCLUSION_NP 150_CD the_ATI treatment_NN of_IN CPP_NP with_IN GnRH_NP agonists_NNS requires_VBZ careful_JJ clinical_JJ and_CC laboratory_NN monitoring_NN effective_JJ treatment_NN leads_VBZ to_TO arrest_VB or_CC regression_NN of_IN secondary_JJ sexual_JJ characteristic_JJ development_NN , a_AT decrease_NN in_IN the_ATI rate_NN of_IN skeletal_JJ maturation_NN , and_CC an_AT improvement_NN in_IN the_ATI final_JJ height_NN prognosis_NN if_CS too_QL low_JJ a_AT dose_NN of_IN GnRH_NP is_BEZ used_VBN , stimulation_NN rather_RB than_IN suppression_NN results_NNS with_IN progression_NN of_IN puberty_NN and_CC a_AT decrease_NN in_IN the_ATI final_JJ height_NN prognosis_NN to_TO prevent_VB this_DT , clinical_JJ monitoring_NN supplemented_VBN by_IN laboratory_NN testing_NN must_MD be_BE done_VBN the_ATI key_NN test_NN is_BEZ GnRH_NP stimulation_NN serum_NN LH_NP and_CC FSH_NP levels_NNS can_MD be_BE determined_JJ using_VBG RIA_NP , IRMA_NP , or_CC IFMA_NP while_CS IRMA_NP and_CC IFMA_NP are_BER more_QL sensitive_JJ , RIA_NP measurements_NNS of_IN LH_NP levels_NNS can_MD still_RB be_BE used_VBN with_IN GnRH_NP stimulation_NN testing_NN 151_CD viral_JJ Imitations_NNS of_IN Host_NPT Defense_NP Proteins_NP : flattery_NN That_NP Turns_NNS to_IN Battery_NP 152_CD a_AT 40-year-old_JJB Indian_JNP woman_NN with_IN Takayasu's_NP$ arteritis_NN presented_VBN to_TO the_ATI National_NP Naval_NPT Medical_NP Center_NP with_IN chest_NN pain_NN of_IN 1_CD1 day's_NN$ duration_NN One_NP year_NN previously_RB , she_PP3A had_HVD presented_VBN with_IN malaise_NN , diminished_VBD left_VBN upper_JJB extremity_NN pulses_NNS , and_CC an_AT elevated_VBD erythrocyte_NN sedimentation_NN rate_NN A_ZZ diagnosis_NN of_IN Takayasu's_NP$ arteritis_NN had_HVD been_BEN made_VBN by_IN angiographic_JJ demonstration_NN of_IN stenosis_NN of_IN the_ATI left_NN subclavian_JJ artery_NN she_PP3A had_HVD been_BEN treated_VBN initially_RB with_IN 1_CD1 mg_kg_CD per_NNU day_NN of_IN prednisone_NN with_IN angiographically_RB evident_JJ improvement_NN , and_CC the_ATI drug_NN dosage_NN had_HVD been_BEN tapered_JJ over_IN the_ATI past_NN year_NN to_IN 10_CD mg_NNU of_IN prednisone_NN every_AT other_AP day_NN 153_CD on_IN the_ATI day_NN of_IN admission_NN she_PP3A noted_VBD constant_JJ , sharp_JJ left_JJ chest_NN pain_NN without_IN radiation_NN and_CC without_IN dyspnea_NN her_PP$ past_NN medical_JJ history_NN was_BEDZ otherwise_RB unremarkable_JJ the_ATI physical_JJ examination_NN revealed_VBN a_AT woman_NN who_WPR appeared_VBD well_RB nourished_VBN her_PP$ temperature_NN was_BEDZ 38.5_CD degrees_NNS C_ZZ orally_RB her_PP$ heart_NN rate_NN was_BEDZ 92_CD beats_VBZ per_NNU minute_NN , and_CC her_PP$ blood_NN pressure_NN was_BEDZ 126_78_CD mm_UH Hg_&FO the_ATI physical_JJ examination_NN produced_VBN entirely_RB normal_JJ results_NNS except_CS for_IN slightly_RB diminished_VBN left_VBN upper_JJB extremity_NN pulses_NNS that_CS were_BED unchanged_JJ from_IN the_ATI previous_JJ month_NN results_NNS of_IN blood_NN analysis_NN were_BED normal_JJ except_CS for_IN an_AT erythrocyte_NN sedimentation_JJ rate_NN of_IN 52_CD mm_h_NN and_CC a_AT white_JJ blood_NN cell_NN count_NN of_IN 11.3x10_CD sup_VB 9_L_NN with_IN a_AT normal_JJ differential_JJ the_ATI electrocardiogram_NN was_BEDZ normal.=20_CD 154_CD on_IN the_ATI second_OD hospital_NN day_NN , several_AP vesicles_NNS appeared_VBD in_IN the_ATI left_NN T-7_NP dermatomal_JJ distribution_NN the_ATI mucous_JJ membranes_NNS and_CC other_AP dermatomes_NNS remained_VBD normal_JJ the_ATI results_NNS of_IN a_AT Tzanck_NP test_NN were_BED positive_JJ , and_CC a_AT clinical_JJ diagnosis_NN of_IN localized_JJ varicella-zoster_NN virus_NN (_( VZV_NP )_) infection_NN was_BEDZ made_VBN since_IN the_ATI patient_NN was_BEDZ considered_VBN to_TO be_BE at_IN low_JJ risk_NN for_IN dissemination_NN , treatment_NN with_IN acyclovir_NN was_BEDZ withheld_VBN and_CC oral_JJ analgesics_NNS were_BED given_VBN for_IN pain_NN a_AT culture_NN of_IN the_ATI vesicular_NN fluid_NN confirmed_VBN the_ATI diagnosis_NN the_ATI vesicles_NNS healed_VBN during_IN the_ATI next_AP several_AP weeks_NNS 155_CD CASE_NP DISCUSSION_NP 156_CD in_IN an_AT article_NN entitled_VBN _** Viral_NP Quasispecies_NNS _** published_VBN in_IN Scientific_NP American_JNP in_IN 1993_CD , Nobel_NP laureate_NN Manfred_NP Eigen_NP wrote_VBD : _** according_IN to_TO Greek_JNP mythology_NN , when_WRB curious_JJ Pandora_NP opened_VBD a_AT forbidden_JJ box_NN she_PP3A set_VBD loose_JJ all_ABN the_ATI miseries_NNS and_CC evils_NNS known_VBN to_IN the_ATI world_NN one_CD1 of_IN them_PP3OS was_BEDZ undoubtedly_RB the_ATI virus-the_NN very_QL name_NN of_IN which_WDTR is_BEZ Latin_JNP for_IN slime_NN , poison_NN and_CC stench_NN _** later_RBR , somewhat_RB more_QL prosaically_RB , he_PP3A wrote_VBD , _** Essentially_NP , a_AT virus_NN is_BEZ a_AT genetic_JJ program_NN that_CS carries_VBZ the_ATI simple_JJ message_NN '_**' Reproduce_NP me_PP1O !_! '_**' from_IN one_CD1 cell_NN to_IN another.=20_CD 157_CD Eigen_NP has_HVZ captured_VBN the_ATI essential_JJ paradox_NN of_IN the_ATI virus_NN : how_WRB can_MD something_PN so_QL helpless_JJ and_CC dependent_JJ do_DO so_QL much_AP damage_NN to_IN its_PP$ host_NN ? the_ATI case_NN presented_VBN herein_RB illustrates_VBZ the_ATI complex_JJ relationship_NN that_CS certain_JJ viruses_NNS may_MD have_HV with_IN their_PP$ hosts_NNS varicella-zoster_NN virus_NN is_BEZ a_AT herpesvirus_VBN in_IN which_WDTR the_ATI first_OD disease_NN manifestation_NN on_IN invading_JJ the_ATI human_JJ host_NN is_BEZ varicella_JJ (_( chickenpox_NN )_) , usually_RB occurring_VBG in_IN childhood_NN The_NP virus_NN then_RN becomes_VBZ latent_JJ in_IN the_ATI ganglia_NNS , only_RB to_TO reemerge_VB most_QL commonly_RB in_IN a_AT dermatomal_JJ distribution_NN as_IN zoster_NN (_( shingles_NNS )_) later_RBR in_IN life_NN , or_CC sometimes_RB as_IN disseminated_VBN infection_NN when_WRB the_ATI immune_JJ system_NN is_BEZ severely_RB depressed_JJ how_WRB do_DO all_ABN viral_JJ pathogens_NNS elude_VB the_ATI immune_JJ system_NN initially_RB , and_CC how_WRB do_DO viruses_NNS like_IN VZV_NP survive_VB for_IN so_QL long_RB in_IN the_ATI host?=20_CD 158_CD although_CS specific_JJ mechanisms_NNS of_IN pathogenesis_NN are_BER poorly_RB understood_VBN for_IN most_QL viruses_NNS , one_CD1 particularly_RB interesting_JJ strategy_NN that_WPR may_MD have_HV general_JJ relevance_NN involves_VBZ the_ATI ability_NN of_IN viruses_NNS to_TO copy_VB key_NN host_NN genes_NNS to_TO subvert_VB host_NN functions_NNS this_DT strategy_NN , which_WDTR was_BEDZ first_OD identified_VBN for_IN the_ATI oncogenes_NNS of_IN acutely_RB transforming_VBG retroviruses_NNS by_IN J._NP Michael_NP Bishop_NPT , MD_NP , and_CC Harold_NP Varmus_JJ , MD_NP , 15_CD years_NNS ago_RB , is_BEZ now_RN known_VBN to_TO be_BE used_VBN by_IN DNA_NP viruses_NNS as_IN well_RB all_ABN of_IN the_ATI DNA_NP virus_NN examples_NNS have_HV been_BEN discovered_VBN within_IN the_ATI past_JJB 5_CD years_NNS , and_CC so_PN far_RB all_ABN of_IN them_PP3OS come_VB from_IN the_ATI poxviruses_NNS and_CC herpesviruses_NNS interestingly_RB , most_AP of_IN the_ATI products_NNS of_IN the_ATI pirated_NN genes_NNS of_IN DNA_NP viruses_NNS mimic_VB key_NN regulatory_JJ molecules_NNS of_IN the_ATI immune_JJ system_NN 159_CD among_IN all_ABN known_VBN viral_JJ protein_NN sequences_NNS , only_RB a_AT small_JJ number_NN have_HV significant_JJ sequence_NN similarity_NN to_IN cellular_JJ proteins_NNS (_( Table_NP 1_CD1 )_) of_IN these_DTS , the_ATI majority_NN are_BER proteins_NNS involved_VBN in_IN regulating_VBG cell_NN growth_NN or_CC in_IN host_NN defense_NN the_ATI former_AP are_BER found_VBN primarily_RB among_IN the_ATI oncogenic_JJ RNA_NP retroviruses_NNS , whereas_CS the_ATI latter_AP are_BER found_VBN primarily_RB among_IN the_ATI DNA_NP poxviruses_NNS and_CC herpesviruses_NNS the_ATI sequence_NN relationship_NN of_IN the_ATI host_NN and_CC viral_JJ homologues_NNS for_IN the_ATI RNA_NP viruses_NNS is_BEZ very_QL strong_JJ , generally_RB more_AP than_IN 80%_NP amino_NN acid_NN identity_NN , yet_RB for_IN the_ATI DNA_NP viruses_NNS it_PP3 is_BEZ usually_RB weak_JJ , generally_RB less_AP than_IN 40%_NP amino_NN acid_NN identity.=20_CD 160_CD in_IN most_AP cases_NNS , the_ATI protein_NN sequences_NNS discovered_VBN separately_RB by_IN virologists_NNS and_CC cell_NN biologists_NNS have_HV been_BEN connected_VBN by_IN homology_NN searches_NNS of_IN protein_NN sequence_NN databases_NNS in_IN this_DT way_NN , the_ATI databases_NNS and_CC the_ATI algorithms_NNS that_CS analyze_NN them_PP3OS have_HV served_VBN as_IN a_AT computerized_VBN dating_VBG service_NN for_IN modern_JJ biology_NN , matching_JJ fields_NNS with_IN distinct_JJ pasts_NNS to_IN the_ATI promise_NN of_IN shared_VBD discovery_NN in_IN the_ATI future_NN 161_CD BARRIERS_NPT TO_NPT VIRAL_NP REPLICATION_NP 162_CD a_AT successful_JJ virus_NN must_MD first_OD penetrate_VB the_ATI host's_NP$ defenses_NNS and_CC then_RN redirect_VB the_ATI host's_NP$ cell_NN functions_NNS to_IN its_PP$ own_AP replicative_JJ advantage_NN this_DT is_BEZ true_JJ whether_CS the_ATI virus_NN infects_NNS a_AT bacterium_NN or_CC a_AT human_JJ being_BEG in_IN the_ATI case_NN of_IN bacteria_NNS , restriction_NN enzymes_NNS are_BER a_AT primitive_JJ but_CC effective_JJ immune_JJ system_NN that_CS works_NNS by_IN chopping_JJ up_RP viral_JJ DNA_NP before_CS it_PP3 can_MD be_BE transcribed_VBN or_CC replicated_VBN however_RB , the_ATI barriers_NNS that_DT must_MD be_BE overcome_VB for_IN the_ATI reproductive_JJ success_NN of_IN an_AT animal_NN virus_NN are_BER by_IN far_RB more_QL daunting_JJ and_CC diverse_JJ the_ATI virus_NN must_MD first_OD survive_VB physical_JJ threats_NNS such_ABL as_IN heat_NN , ultraviolet_NN radiation_NN , and_CC gastric_JJ acidity_NN then_RN it_PP3 must_MD get_VB past_NN the_ATI integument_NN and_CC elude_VB extracellular_JJ immune_JJ defenses_NNS such_IN as_IN complement-mediated_JJ lysis_NN and_CC antibody_NN neutralization_NN if_CS the_ATI virus_NN is_BEZ still_RB viable_JJ at_IN this_DT point_NN , it_PP3 must_MD find_VB a_AT way_NN to_TO attach_VB to_IN a_AT suitable_JJ host_NN cell_NN , penetrate_VB the_ATI plasma_NN membrane_NN , and_CC finally_RB commandeer_VB the_ATI host's_NP$ replicative_JJ machinery.=20_CD 163_CD inside_IN the_ATI cell_NN , the_ATI virus_NN must_MD hide_VB from_IN antigen- specific_JJ cytotoxic_JJ T_ZZ lymphocytes_NNS , which_WDTR home_NR in_RP on_IN the_ATI viral_JJ peptides_NNS displayed_VBN by_IN class_NN I_PP1A major_JJ histocompatibility_JJ complex_JJ (_( MHC_NP )_) molecules_NNS on_IN the_ATI surfaces_NNS of_IN infected_JJ cells_NNS the_ATI virus_NN must_MD also_RB neutralize_VB the_ATI potent_JJ antiviral_JJ and_CC proinflammatory_JJ effects_NNS of_IN cytokines_NNS such_IN as_IN tumor_NN necrosis_NN factor_NN (_( TNF_NP )_) , interleukin_NN 1_CD1 (_( IL-1_CD-CD )_) , and_CC interferon_NN gamma_NN (_( IFN-gamma_NP )_) finally_RB , it_PP3 must_MD come_VB to_IN terms_NNS with_IN its_PP$ own_AP virulence_NN , since_IN the_ATI death_NN of_IN the_ATI host_NN before_CS its_PP$ reproduction_NN may_MD be_BE a_AT Pyrrhic_JNP victory_NN for_IN the_ATI virus_NN the_ATI host-virus_JJ relationship_NN , developed_VBD over_IN evolutionary_JJ time_NN , can_MD range_VB from_IN all-out_JJB biological_JJ warfare_NN (_( humans_NNS and_CC smallpox_NN )_) to_IN peaceful_JJ coexistence_NN (_( swine_NNS and_CC swinepox_NN )_) 164_CD VIRAL_NPT WEAPONS_NPT AGAINST_NPT IMMUNOLOGIC_NPT DEFENSESOF_NPT THE_NP HOST_NP 165_CD all_ABN prospective_JJ pathogens_NNS must_MD counteract_VB both_ABX the_ATI general_JJ and_CC antigen-specific_JJ effector_JJ mechanisms_NNS of_IN the_ATI immune_JJ system_NN (_( Table_NP 2_CD )_) Known_NP viral_JJ strategies_NNS for_IN eluding_VBG antigen-recognition_NN molecules_NNS (_( antibody_NN and_CC T-cell_NP antigen_NN receptors_NNS )_) include_VB antigenic_JJ drift_NN and_CC the_ATI sabotage_NN of_IN antigen_NN presentation_NN pathways_NNS the_ATI influenza_NN A_ZZ hemagglutinin_NN and_CC neuraminidase_NN and_CC the_ATI human_JJ immunodeficiency_NN virus_NN envelope_NN protein_NN are_BER the_ATI best-documented_JJ examples_NNS of_IN how_WRB antigenic_JJ drift_NN may_MD enable_VB a_AT virus_NN to_TO escape_VB detection_NN by_IN the_ATI immune_JJ system_NN this_DT countermeasure_NN does_DOZ not_XNOT involve_VB pirating_VBG host_NN genes_NNS , however_RB 166_CD in_IN contrast_NN , the_ATI open_JJ reading_NN frame_NN UL18_CD of_IN the_ATI human_JJ cytomegalovirus_JJ (_( HCMV_NP )_) , a_AT beta_NN herpesvirus_JJ , encodes_NNS a_AT protein_NN that_WPR is_BEZ approximately_RB 20%_NP identical_JJ in_IN amino_NN acid_NN sequence_NN to_IN the_ATI variable_NN chain_NN of_IN mammalian_NN class_NN I_PP1A MHC_NP molecules_NNS the_ATI UL18_CD product_NN binds_VBZ to_IN cellular_JJ beta_NN sub_NN 2_CD -microglobulin_NN , the_ATI invariant_JJ chain_NN of_IN the_ATI class_NN I_PP1A molecule_VB essential_JJ for_IN transporting_VBG normal_JJ class_NN I_PP1A heterodimers_NNS to_IN the_ATI plasma_NN membrane_NN in_IN this_DT way_NN , deployment_NN of_IN fully_RB assembled_JJ class_NN I_PP1A molecules_NNS on_IN the_ATI cell_NN surface_NN is_BEZ prevented_VBN in_IN cells_NNS infected_VBN with_IN HCMV_NP , thereby_RB possibly_RB resulting_JJ in_IN defective_JJ antigen_NN presentation_NN to_IN cytotoxic_JJ T_ZZ lymphocytes_NNS 167_CD as_CS for_IN antigen-nonspecific_JJ effectors_NNS of_IN the_ATI immune_JJ system_NN , various_JJ viral_JJ countermeasures_NNS that_WPR involve_VB the_ATI pirating_NN of_IN host_NN genes_NNS have_HV been_BEN identified_VBN examples_NNS for_IN cytokines_NNS , cytokine_NN receptors_NNS , chemoattractant_NN receptors_NNS , and_CC complement_NN control_NN proteins_NNS have_HV been_BEN demonstrated_VBN these_DTS viral_JJ imitators_NNS may_MD modulate_VB intracellular_VB communication_NN in_IN at_RB least_RB two_CD ways_NNS (_( Figure_NP 1_CD1 )_) the_ATI first_OD way_NN involves_VBZ the_ATI disruption_NN by_IN poxvirus_JJ products_NNS of_IN communication_NN pathways_NNS that_CS lead_NN to_TO cytolysis_VB and_CC inflammation_NN the_ATI net_JJB result_NN of_IN this_DT disruption_NN is_BEZ decreased_VBN inflammation_NN at_IN infected_JJ sites_NNS and_CC increased_JJ virulence_NN in_RB vivo_RB , as_CS shown_VBN by_IN experiments_NNS with_IN recombinant_NN poxviruses_NNS that_CS specifically_RB lack_VB the_ATI gene_NN in_IN question.=20_CD 168_CD examples_NNS of_IN this_DT type_NN of_IN disruption_NN include_VB the_ATI IL- 1_CD-CD receptor_NN homologue_NN of_IN the_ATI vaccinia_NN virus_NN , the_ATI TNF_NP receptor_JJ homologues_NNS of_IN the_ATI myxoma_NN and_CC Shope_NP fibroma_NN viruses_NNS , the_ATI IFN-gamma_NP receptor_JJ homologue_NN of_IN the_ATI myxoma_NN virus_NN , the_ATI complement_NN control_NN protein_NN homologue_NN of_IN the_ATI vaccinia_NN virus_NN , a_AT serpin_NN (_( serine_NN protease_NN inhibitor_NN )_) homologue_NN of_IN the_ATI cowpox_NN virus_NN , and_CC the_ATI eukaryotic_JJ initiation_NN factor-2alpha_JJ homologue_NN of_IN the_ATI vaccinia_NN virus_NN 169_CD the_ATI respective_JJ poxviruses_NNS have_HV redesigned_VBN all_ABN the_ATI cytokine_NN receptor_NN homologues_NNS so_CS that_CS they_PP3AS lack_NN a_AT membrane_NN anchor_NN and_CC the_ATI cytoplasmic_JJ signaling_VBG domain_NN the_ATI cytokine_NN receptor_NN homologues_NNS are_BER therefore_RB secreted_VBN , ligand-binding_NN proteins_NNS incapable_JJ of_IN transmembrane_NN signal_NN transduction_NN the_ATI homologues_NNS appear_VB to_TO act_VB by_IN binding_JJ the_ATI respective_JJ cytokine_NN before_CS it_PP3 can_MD dock_NN to_IN its_PP$ cellular_JJ receptor_NN and_CC unload_VB its_PP$ antiviral_JJ signal_NN the_ATI complement_NN control_NN protein_NN homologue_NN of_IN the_ATI vaccinia_NN virus_NN binds_VBZ to_IN C4b_NP , thereby_RB halting_VBG the_ATI complement_NN cascade_NN , whether_CS it_PP3 is_BEZ activated_VBN by_IN classical_JJ or_CC alternative_JJ pathways_NNS the_ATI serpin_JJ homologue_NN of_IN the_ATI cowpox_NN virus_NN blocks_VBZ the_ATI action_NN of_IN the_ATI IL-1beta-converting_CD-CD enzyme_NN , a_AT cysteine_NN protease_NN that_CS cleaves_NNS an_AT inactive_JJ precursor_NN into_IN mature_JJ IL-1beta_CD-CD in_IN this_DT way_NN , the_ATI convertase_NN inhibitor_NN reduces_VBZ the_ATI concentration_NN of_IN mature_JJ IL-1beta_CD-CD , a_AT key_NN immunoregulatory_NN molecule_NN 170_CD the_ATI second_OD way_NN by_IN which_WDTR DNA_NP virus_NN imitators_NNS may_MD modulate_VB intracellular_NN communication_NN is_BEZ by_IN expropriating_VBG a_AT normal_JJ cell_NN communication_NN pathway_NN the_ATI most_QL thoroughly_RB studied_JJ example_NN is_BEZ for_IN the_ATI open_JJ reading_NN frame_NN BCRF1_CD of_IN the_ATI Epstein-Barr_NP virus_NN (_( EBV_NP )_) , which_WDTR encodes_VBZ a_AT fully_RB functional_JJ homologue_NN of_IN interleukin_NN 10_CD (_( IL-10_CD-CD )_) .=20_CD 171_CD the_ATI reproductive_JJ potential_NN of_IN EBV_NP is_BEZ apparently_RB enhanced_VBN by_IN tapping_VBG into_IN the_ATI anti-inflammatory_JJ functions_NNS of_IN IL-10_CD-CD , which_WDTR are_BER mediated_VBN by_IN the_ATI cellular_JJ IL-10_CD-CD receptor_NN in_IN Herpesvirus_JJ saimiri_NN (_( HVS_NP )_) a_AT reciprocal_JJ situation_NN has_HVZ been_BEN discovered_VBN instead_RB of_IN pirating_VBG the_ATI gene_NN for_IN an_AT immunoregulatory_NN ligand_NN , HVS_NP copied_VBD the_ATI gene_NN for_IN an_AT interleukin_NN 8_CD (_( IL-8_NP )_) receptor_NN the_ATI viral_JJ IL-8_NP receptor_NN is_BEZ an_AT integral_JJ membrane_NN protein_NN that_CS , on_IN binding_JJ to_IN a_AT ligand_NN , transmits_NNS a_AT signal_NN to_IN the_ATI cytoplasm_NN this_DT property_NN distinguishes_VBZ it_PP3 from_IN the_ATI soluble_JJ cytokine_NN receptor_NN homologues_NNS of_IN poxviruses_NNS the_ATI precise_JJ biological_JJ actions_NNS of_IN IL-8_NP that_CS are_BER coveted_JJ by_IN the_ATI virus_NN are_BER not_XNOT yet_RB known_VBN , but_CC probably_RB involve_VB immune_JJ cell_NN activation_NN both_ABX EBV_NP and_CC HVS_NP are_BER closely_RB related_JJ gamma- herpesviruses_NNS with_IN highly_RB conserved_VBN genomes_NNS the_ATI HVS_NP IL-8_NP receptor_NN gene_NN and_CC the_ATI EBV_NP IL-10_CD- CD gene_NN are_BER two_CD genes_NNS not_XNOT conserved_VBN in_IN EBV_NP and_CC HVS_NP 172_CD subversion_NN of_IN the_ATI IL-1_CD-CD system_NN by_IN the_ATI vaccinia_NN virus_NN could_MD have_HV occurred_VBN either_DTX by_IN mimicking_VBG the_ATI ligands_NNS or_CC the_ATI receptors_NNS (_( Table_NP 3_CD )_) two_CD forms_NNS of_IN IL-1_CD-CD are_BER produced_VBN in_IN mammals-IL- 1alpha_CD-CD , which_WDTR is_BEZ cell_NN associated_VBN and_CC may_MD not_XNOT serve_VB a_AT signaling_VBG function_NN in_RB vivo_RB , and_CC IL- 1beta_CD-CD , the_ATI major_JJ circulating_JJ form_NN of_IN IL-1_CD-CD that_CS accounts_NNS for_IN the_ATI known_VBN biological_JJ actions_NNS of_IN IL-1_CD- CD a_AT third_OD isoform_NN , the_ATI IL-1_CD-CD receptor_NN antagonist_NN , blocks_VBZ the_ATI actions_NNS of_IN IL-1_CD-CD but_CC lacks_VBZ agonist_NN activity_NN all_ABN three_CD isoforms_NNS possess_VB about_IN 20%_NP amino_NN acid_NN sequence_NN identity_NN , which_WDTR indicates_VBZ that_CS they_PP3AS arose_VBD from_IN a_AT common_JJ ancestral_JJ gene_NN the_ATI IL-1_CD-CD receptor_NN is_BEZ also_RB complex.=20_CD 173_CD two_CD are_BER known_VBN the_ATI type_NN II_NP receptor_NN has_HVZ a_AT short_JJ cytoplasmic_JJ domain_NN and_CC has_HVZ not_XNOT been_BEN shown_VBN to_TO have_HV a_AT signaling_VBG function_NN it_PP3 may_MD reduce_VB concentrations_NNS of_IN soluble_JJ IL-1_CD-CD available_JJ to_IN the_ATI type_NN I_PP1A receptor_VB , which_WDTR in_IN contrast_NN has_HVZ a_AT long_JJ cytoplasmic_JJ domain_NN and_CC mediates_VBZ all_ABN the_ATI known_VBN signaling_VBG functions_NNS of_IN IL-1_CD-CD both_ABX receptors_NNS bind_VB all_ABN three_CD forms_NNS of_IN IL-1_CD-CD however_RB , the_ATI binding_JJ affinity_NN for_IN IL-1beta_CD-CD by_IN the_ATI type_NN II_NP receptor_NN is_BEZ about_RB 10_CD times_NNS greater_JJR than_IN that_DT of_IN the_ATI type_NN I_PP1A receptor_VB given_VBN these_DTS facts_NNS , natural_JJ selection_NN has_HVZ yielded_VBN what_WDT appears_VBZ to_TO be_BE the_ATI most_QL logical_JJ route_NN to_TO efficiently_RB subvert_VB the_ATI IL-1_CD-CD system_NN the_ATI viral_JJ IL-1_CD-CD receptor_NN corresponds_VBZ only_RB to_IN the_ATI soluble_JJ portion_NN of_IN the_ATI type_NN II_NP receptor_NN ; moreover_RB , it_PP3 binds_VBZ IL-1beta_CD-CD , the_ATI signaling_NN isoform_NN , but_CC ignores_VBZ IL-1alpha_CD-CD , the_ATI nonsignaling_NN isoform_NN 174_CD similarly_RB , natural_JJ selection_NN may_MD have_HV yielded_VBN what_WDT appears_VBZ to_TO be_BE the_ATI most_QL logical_JJ way_NN for_IN HVS_NP to_TO take_VB full_JJ advantage_NN of_IN the_ATI IL-8_NP signaling_VBG system_NN interleukin_NN 8_CD is_BEZ one_CD1 of_IN a_AT family_NN of_IN at_RB least_RB 18_CD structurally_RB and_CC functionally_RB related_VBN human_JJ molecules_NNS known_VBN as_IN chemokines-for_NN chemoattractants_NNS and_CC cytokines_NNS the_ATI chemokines_NNS possess_VB both_ABX broadly_RB overlapping_JJ and_CC distinct_JJ roles_NNS in_IN the_ATI regulation_NN of_IN phagocyte_NN and_CC lymphocyte_NN motility_NN and_CC activation_NN and_CC thus_RB may_MD play_VB important_JJ roles_NNS in_IN acute_JJ and_CC chronic_JJ inflammation.=20_CD 175_CD in_IN addition_NN , several_AP of_IN the_ATI chemokines_NNS may_MD play_VB a_AT broader_JJR role_NN in_IN cell_NN proliferation_NN the_ATI sequences_NNS for_IN a_AT receptor_JJ dedicated_JJ to_IN IL-8_NP (_( IL-8_NP receptor_NN A_ZZ or_CC IL8RA_NP )_) and_CC for_IN a_AT second_OD receptor_NN (_( IL-8_NP receptor_NN B_ZZ or_CC IL8RB_NP )_) shared_VBD among_IN IL-8_NP and_CC the_ATI closely_RB related_JJ chemokines_NNS called_VBN neutrophil- activating_NN peptide-2_NN (_( NAP-2_NP )_) and_CC the_ATI growth-related_JJ gene_NN product_NN GROalpha_NP have_HV been_BEN deduced_VBN by_IN molecular_JJ cloning_NN by_IN copying_VBG IL8RB_NP , the_ATI more_QL promiscuous_JJ IL-8_NP receptor_NN , HVS_NP may_MD be_BE able_JJ to_TO tap_VB into_IN a_AT richer_JJR variety_NN of_IN potential_JJ signaling_NN pathways_NNS than_IN if_CS it_PP3 had_HVD copied_VBN IL8RA_NP 176_CD when_WRB they_PP3AS are_BER expressed_VBN in_IN frog_NN oocytes_NNS , the_ATI viral_JJ IL-8_NP receptor_NN is_BEZ 200_CD times_NNS more_QL sensitive_JJ than_IN human_JJ IL8RB_NP to_IN GROalpha_NP , a_AT molecule_NN with_IN known_JJ growth-factor_NN activity_NN thus_RB , the_ATI viral_JJ receptor_NN may_MD sensitize_VB cells_NNS infected_VBN with_IN HVS_NP to_IN concentrations_NNS of_IN GROalpha_NP that_CS do_DO not_XNOT activate_VB the_ATI cellular_JJ receptor_NN the_ATI biochemical_JJ changes_NNS that_WPR occur_VB in_IN the_ATI cytoplasm_NN of_IN phagocytes_NNS stimulated_VBN with_IN IL-8_NP , GROalpha_NP , and_CC NAP- 2_NP are_BER similar_JJ to_IN those_DTS that_CS have_HV been_BEN measured_VBN during_IN the_ATI infection_NN of_IN fibroblasts_NNS by_IN HCMV_NP in_IN fact_NN , inhibition_NN of_IN these_DTS biochemical_JJ changes_NNS markedly_RB attenuates_VBZ HCMV_NP replication.=20_CD 177_CD by_IN analogy_NN with_IN HCMV_NP , these_DTS changes_NNS may_MD ensure_VB for_IN HVS_NP a_AT cytoplasmic_JJ milieu_NN that_WPR has_HVZ been_BEN optimally_RB conditioned_VBN for_IN replication_NN or_CC the_ATI establishment_NN of_IN latency_NN in_IN its_PP$ natural_JJ host_NN , the_ATI squirrel_NN monkey_NN , HVS_NP infects_NNS T_ZZ lymphocytes_NNS without_IN causing_VBG disease_NN when_WRB other_AP primates_NNS are_BER infected_VBN , however_RB , HVS_NP causes_NNS fatal_JJ leukemias_NNS and_CC lymphomas_NNS it_PP3 can_MD also_RB transform_VB human_JJ T_ZZ cells_NNS in_IN vitro_NN the_ATI relationship_NN of_IN the_ATI pirated_NN IL-8_NP receptor_NN of_IN HVS_NP to_IN malignant_JJ transformation_NN has_HVZ not_XNOT yet_RB been_BEN tested_VBN in_RB vivo_RB with_IN mutant_NN viruses_NNS 178_CD it_PP3 is_BEZ a_AT fascinating_JJ paradox_NN that_CS although_CS the_ATI HVS_NP homologue_NN of_IN IL8RB_NP is_BEZ only_RB 30%_NP identical_JJ to_IN IL8RB_NP , it_PP3 binds_VBZ the_ATI same_AP three_CD ligands_NNS as_CS IL8RB_NP , whereas_CS mammalian_NN IL8RA_NP is_BEZ 78%_JJ identical_JJ to_IN IL8RB_NP , but_CC it_PP3 has_HVZ a_AT more_QL restricted_JJ ligand_JJ profile_NN another_DT mammalian_NN chemokine_NN receptor_NN that_CS binds_VBZ closely_RB related_JJ molecules_NNS such_IN as_IN macrophage_JJ inflammatory_JJ protein- 1alpha_CD-CD (_( MIP-1alpha_CD-CD )_) and_CC RANTES_NP (_( an_AT acronym_NN for_IN reduced_VBN on_IN activation_JJ normal_JJ T_ZZ expressed_VBN and_CC secreted_VBN )_) has_HVZ also_RB been_BEN pirated_VBN , in_IN this_DT case_NN by_IN HCMV_NP although_CS the_ATI viral_JJ protein_NN binds_VBZ MIP-1alpha_CD-CD and_CC RANTES_NP , its_PP$ capacity_NN for_IN signal_NN transduction_NN has_HVZ not_XNOT yet_RB been_BEN reported_VBN 179_CD in_IN addition_NN to_IN these_DTS functionally_RB characterized_VBN viral_JJ proteins_NNS , several_AP open_JJ reading_NN frames_NNS have_HV been_BEN identified_VBN among_IN the_ATI poxviruses_NNS and_CC herpesviruses_NNS that_CS encode_JJ putative_JJ proteins_NNS with_IN clear-cut_JJ sequence_NN relationships_NNS to_IN families_NNS of_IN cellular_JJ proteins_NNS , but_CC where_WRB the_ATI specific_JJ function_NN of_IN the_ATI viral_JJ protein_NN or_CC its_PP$ closest_JJT cellular_JJ homologue_NN has_HVZ not_XNOT yet_RB been_BEN delineated_VBN several_AP of_IN these_DTS are_BER viral_JJ G_ZZ protein-coupled_JJ receptorlike_NN sequences_NNS the_ATI HVS_NP IL-8_NP receptor_NN and_CC the_ATI HCMV_NP MIP- 1alpha_RANTES_CD-CD binding_JJ protein_NN are_BER the_ATI only_AP functionally_RB characterized_VBN viral_JJ homologues_NNS of_IN mammalian_NN G_ZZ protein-coupled_JJ receptors_NNS there_EX are_BER other_AP examples_NNS of_IN herpesviruses_NNS that_CS have_HV pirated_JJ genes_NNS that_CS may_MD be_BE involved_VBN in_IN cell_NN cycle_NN regulation_NN and_CC programmed_VBN cell_NN death_NN (_( apoptosis_NN )_) 180_CD MOLECULAR_NPT MIMICRY_NPT BY_NPT CONVERGENT_NP EVOLUTION_NP 181_CD two_CD proteins_NNS may_MD have_HV no_ATI sequence_NN similarity_NN but_CC subserve_NN a_AT similar_JJ function_NN this_DT phenomenon_NN is_BEZ termed_VBN convergent_NN evolution_NN interestingly_RB , although_CS the_ATI herpesviruses_NNS have_HV acquired_JJ chemokine_NN receptor_NN genes_NNS to_TO mimic_VB their_PP$ primate_NN hosts_NNS , at_RB least_RB one_CD1 host_NN , Homo_NP sapiens_NNS , has_HVZ inactivated_VBN another_DT chemokine_NN receptor_NN gene_NN under_IN the_ATI pressure_NN of_IN convergent_JJ molecular_JJ mimicry_NN in_IN this_DT case_NN , however_RB , the_ATI pathogen_NN is_BEZ a_AT protozoan_NN the_ATI Duffy_NP blood_NN group_NN antigen_NN has_HVZ been_BEN known_VBN for_IN almost_RB 20_CD years_NNS to_TO be_BE the_ATI receptor_NN for_IN the_ATI malaria_NN parasite_NN Plasmodium_NP vivax_NN it_PP3 is_BEZ also_RB known_VBN that_CS the_ATI majority_NN of_IN inhabitants_NNS of_IN Africa_NP , where_WRB P_ZZ vivax_NN is_BEZ rare_JJ , lack_VB the_ATI Duffy_NP antigen_NN and_CC are_BER thus_RB protected_VBN from_IN vivax_NN malaria_NN it_PP3 has_HVZ recently_RB been_BEN shown_VBN that_CS the_ATI Duffy_NP blood_NN group_NN antigen_NN is_BEZ a_AT red_JJ blood_NN cell_NN chemokine- binding_NN protein_NN that_WPR is_BEZ more_QL promiscuous_JJ in_IN its_PP$ ligand_NN affiliations_NNS than_IN any_DTI of_IN the_ATI white_JJ blood_NN cell_NN chemokine_NN receptors.=20_CD 182_CD in_IN fact_NN , the_ATI Duffy_NP blood_NN group_NN antigen_NN is_BEZ able_JJ to_TO bind_VB all_ABN three_CD sets_NNS of_IN chemokines_NNS (_( IL-8_NP , NAP- 2_NP , GROalpha_NP ; RANTES_NP ; and_CC monocyte_NN chemoattractant_NN protein_NN 1_CD1 )_) that_CS target_NN three_CD distinct_JJ white_JJ blood_NN cell_NN chemokine_NN receptors_NNS recently_RB Chaudhuri_NP et_&FW al_APS succeeded_VBN in_IN cloning_VBG cDNAs_NP encoding_VBG the_ATI Duffy_NP antigen_NN the_ATI deduced_VBN protein_NN sequence_NN is_BEZ clearly_RB related_VBN to_TO that_CS of_IN the_ATI white_JJ cell_NN chemokine_NN receptors_NNS (_( almost_RB 26%_NN amino_NN acid_NN identity_NN )_) the_ATI parasite_NN molecule_NN that_CS binds_VBZ to_IN the_ATI Duffy_NP antigen_NN has_HVZ no_ATI sequence_NN relationship_NN to_IN chemokines_NNS and_CC thus_RB probably_RB targeted_VBN Duffy_NP by_IN a_AT convergent_JJ evolutionary_JJ pathway_NN the_ATI dynamic_JJ coevolution_NN of_IN hosts_NNS and_CC parasites_NNS may_MD be_BE graphically_RB illustrated_VBN by_IN the_ATI loss_NN of_IN the_ATI Duffy_NP antigen_NN in_IN malaria-exposed_JJ Africans_NNPS and_CC their_PP$ American_JNP descendants.=20_CD 183_CD although_CS the_ATI apparent_JJ good_JJ health_NN of_IN persons_NNS not_XNOT possessing_VBG the_ATI Duffy_NP antigen_NN may_MD argue_VB against_IN an_AT important_JJ role_NN in_IN homeostasis_NN for_IN Duffy_NP on_IN red_JJ blood_NN cells_NNS , the_ATI ability_NN of_IN chemokines_NNS to_TO block_VB infection_NN of_IN red_JJ cells_NNS by_IN the_ATI related_JJ parasite_NN Plasmodium_NP knowlesi_NN in_IN vitro_NN raises_VBZ the_ATI possibility_NN of_IN developing_VBG new_JJ chemokine-based_JJ therapeutics_NNS for_IN vivax_NN malaria_NN in_IN patients_NNS with_IN the_ATI Duffy_NP antigen_NN 184_CD several_AP examples_NNS of_IN viral_JJ interference_NN in_IN immunoregulatory_NN pathways_NNS involve_VB proteins_NNS without_IN clear-cut_JJ homology_NN to_IN host_NN proteins_NNS the_ATI p15E_CD protein_NN of_IN murine_NN retroviruses_NNS may_MD contribute_VB to_TO immunosuppression_VB by_IN inhibiting_JJ protein_NN kinase_NN C_ZZ adenoviruses_NNS encode_NN a_AT protein_NN dedicated_JJ to_TO the_ATI subversion_NN of_IN antigen_NN presentation_NN pathways_NNS however_RB , unlike_IN the_ATI UL18_CD gene_JJ product_NN of_IN HCMV_NP , this_DT adenovirus_JJ protein_NN (_( E3-gp19K_CD-CD )_) binds_VBZ to_TO the_ATI variable_JJ chain_NN of_IN the_ATI class_NN I_PP1A molecule_VB , thus_RB preventing_VBG its_PP$ assembly_NN and_CC transport_NN to_IN the_ATI plasma_NN membrane_NN .=20_CD 185_CD at_RB least_RB three_CD genes_NNS from_IN adenoviruses_NNS are_BER known_VBN to_TO disrupt_VB the_ATI TNF_NP cytolytic_JJ signal_NN transduction_NN pathway_NN at_IN the_ATI level_NN of_IN cytosolic_JJ second_OD messengers_NNS and_CC transcription_NN factor_NN activation_NN unlike_IN poxviruses_NNS , which_WDTR cause_NN acute_JJ , cytolytic_JJ infections_NNS in_IN which_WDTR the_ATI virus_NN drives_VBZ the_ATI pathology_NN , adenoviruses_NNS cause_NN persistent_JJ infections_NNS with_IN long- term_JJB viral_JJ shedding_VBG in_IN which_WDTR the_ATI immune_JJ system_NN drives_VBZ the_ATI pathology_NN thus_RB , in_IN contrast_NN to_IN the_ATI decreased_VBD virulence_NN of_IN poxviruses_NNS bearing_VBG inactivating_VBG mutations_NNS in_IN pirated_JJ immunoregulatory_NN genes_NNS , adenoviruses_NNS bearing_VBG inactivating_VBG mutations_NNS in_IN the_ATI genes_NNS that_WPR interfere_VB with_IN TNF_NP signaling_VBG cause_NN dramatically_RB increased_JJ pathology_NN in_IN rodent_NN models_NNS of_IN pneumonia_NN , despite_IN wild-type_JJ levels_NNS of_IN viral_JJ replication_NN 186_CD MOLECULAR_NPT MIMICRY_NPT AND_NPT THE_NPT GENERATION_NPT OF_NPT HOST_NPT DEFENSE_NP PROTEIN_NP DIVERSITY_NP 187_CD the_ATI virus_NN clearly_RB has_HVZ an_AT interest_NN in_IN copying_VBG and_CC improving_VBG what_WDT works_NNS well_RB in_IN the_ATI host_NN the_ATI host_NN , however_RB , has_HVZ an_AT interest_NN in_IN eluding_VBG imitation_NN by_IN the_ATI virus_NN a_AT natural_JJ competition_NN is_BEZ thus_RB established_VBN the_ATI score_NN of_IN this_DT competition_NN may_MD be_BE read_VB in_IN the_ATI sequence_NN differences_NNS between_IN homologous_JJ host_NN and_CC viral_JJ gene_NN products_NNS to_IN the_ATI extent_NN that_CS different_JJ host_NN species_NN may_MD be_BE infected_VBN by_IN different_JJ species-specific_JJ viruses_NNS that_DT may_MD or_CC may_MD not_XNOT target_NN the_ATI same_AP gene_NN for_IN copying_VBG , targeted_VBD genes_NNS might_MD be_BE subjected_VBN to_IN exaggerated_JJ sequence_NN variation_NN relative_JJ to_IN untargeted_JJ genes.=20_CD 188_CD it_PP3 has_HVZ recently_RB been_BEN shown_VBN that_CS human_JJ and_CC rodent_NN versions_NNS of_IN host_NN defense_NN proteins_NNS are_BER far_RB more_QL divergent_JJ in_IN sequence_NN than_IN human_JJ and_CC rodent_NN versions_NNS of_IN proteins_NNS from_IN any_DTI other_AP functional_JJ grouping_NN it_PP3 is_BEZ worth_IN considering_VBG that_CS molecular_JJ mimicry_NN by_IN species-specific_JJ pathogens_NNS may_MD be_BE a_AT potent_JJ selective_JJ force_NN behind_IN the_ATI generation_NN of_IN host_NN defense_NN protein_NN diversity_NN since_IN viruses_NNS can_MD mutate_VB much_AP more_QL quickly_RB than_IN their_PP$ hosts_NNS , the_ATI absolute_JJ dependence_NN of_IN the_ATI virus_NN on_IN the_ATI host_NN may_MD ultimately_RB be_BE the_ATI only_AP thing_NN that_CS constrains_VBZ the_ATI zest_NN with_IN which_WDTR it_PP3 redesigns_VBZ the_ATI cellular_JJ protein_NN to_TO subvert_VB the_ATI immune_JJ system_NN 189_CD CONCLUSION_NP 190_CD finally_RB , it_PP3 is_BEZ likely_JJ that_CS the_ATI pirating_NN of_IN immunoregulatory_NN genes_NNS may_MD not_XNOT be_BE restricted_JJ to_IN viruses_NNS , but_CC may_MD instead_RB be_BE a_AT general_JJ strategy_NN by_IN which_WDTR bacterial_JJ , protozoan_JJB , and_CC perhaps_RB metazoan_JJ parasites_NNS chisel_NN chinks_NNS in_IN the_ATI armor_NN of_IN the_ATI host_NN immune_JJ system_NN several_AP nonviral_JJ examples_NNS have_HV already_RB been_BEN identified_VBN there_EX are_BER probably_RB hundreds_CDS of_IN distinct_JJ cytokines_NNS and_CC dozens_CDS of_IN cytokine-activated_JJ second_OD messenger_NN systems_NNS that_CS regulate_VB immunity_NN and_CC inflammation_NN just_RB as_RB the_ATI retroviral_JJ oncogenes_NNS have_HV been_BEN useful_JJ for_IN identifying_VBG key_NN cellular_JJ proteins_NNS involved_VBN in_IN normal_JJ growth_NN and_CC differentiation_NN , the_ATI greatest_JJT value_NN of_IN the_ATI pirated_NN immunoregulatory_NN genes_NNS may_MD be_BE in_IN quickly_RB directing_VBG the_ATI therapeutic_JJ efforts_NNS of_IN immunologists_NNS , pharmacologists_NNS , and_CC clinicians_NNS to_TO key_NN molecules_NNS , such_ABL as_CS IL-1_CD-CD , TNF_NP , and_CC IL-8_NP , that_DT may_MD be_BE driving_VBG inflammatory_JJ reactions_NNS in_IN people_NNS JGANUE_NP physical_JJ Examination_NN of_IN the_ATI Liver_NP 2_CD the_ATI patient_NN in_IN your_PP$ examining_VBG room_NN is_BEZ new_JJ to_IN the_ATI practice_NN he_PP3A is_BEZ 52_CD years_NNS old_JJ , emigrated_VBD from_IN Southeast_NP Asia_NP about_RB 10_CD years_NNS ago_RB , and_CC has_HVZ no_ATI specific_JJ complaints_NNS except_IN fatigue_NN on_IN examination_NN you_PP2 find_VB little_JJ of_IN note_NN except_IN that_DT his_PP$ liver_NN edge_NN is_BEZ firm_JJ , easily_RB felt_VBD , and_CC extends_VBZ about_IN 6_CD cm_NNU below_IN the_ATI costal_JJ margin_NN across_IN much_AP of_IN the_ATI right_JJ upper_JJB quadrant_NN The_NP span_NN , by_IN light_NN percussion_NN , is_BEZ 17_CD or_CC 18_CD cm._NN should_MD you_PP2 be_BE concerned_VBN ? What_NP does_DOZ the_ATI research_NN literature_NN tell_VB us_PP1OS about_IN the_ATI meaning_NN of_IN these_DTS findings_NNS ? 3_CD ideally_RB , the_ATI clinical_JJ meaning_NN of_IN physical_JJ examination_NN findings_NNS should_MD be_BE established_VBN in_IN research_NN studies_NNS that_CS account_NN for_IN the_ATI overall_JJB context_NN , including_IN other_AP signs_NNS and_CC details_NNS from_IN the_ATI medical_JJ history_NN this_DT approach_NN is_BEZ difficult_JJ in_IN liver_NN disease_NN , because_CS the_ATI physical_JJ manifestations_NNS of_IN hepatic_JJ dysfunction_NN are_BER protean_NN and_CC many_AP multisystem_NN diseases_NNS affect_VB the_ATI liver_NN our_PP$ focus_NN , therefore_RB , is_BEZ on_IN physical_JJ examination_NN of_IN the_ATI liver_NN itself_PPL this_DT means_VBZ , however_RB , that_CS we_PP1AS implicitly_RB depend_VB on_IN the_ATI clinician's_NP$ ability_NN to_TO make_VB a_AT baseline_JJ estimate_NN of_IN the_ATI likelihood_NN of_IN liver_NN disease_NN on_IN the_ATI basis_NN of_IN the_ATI history_NN and_or_CC other_AP physical_JJ findings_NNS 4_CD although_CS many_AP maneuvers_NNS recommended_VBN in_IN liver_NN examination_NN are_BER unproven_JJ , there_EX is_BEZ reasonable_JJ evidence_NN that_CS the_ATI presence_NN or_CC absence_NN of_IN hepatomegaly_RB can_MD be_BE determined_JJ with_IN moderate_JJ accuracy_NN on_IN physical_JJ examination_NN descriptive_JJ studies_NNS suggest_VB that_CS other_AP qualitative_JJ findings_NNS may_MD help_VB in_IN clinical_JJ assessment_NN of_IN patients_NNS with_IN possible_JJ liver_NN disease_NN Liver_NP examination_NN , like_IN most_QL physical_JJ diagnosis_NN maneuvers_NNS , is_BEZ not_XNOT dissimilar_JJ to_IN a_AT screening_NN test_NN ; it_PP3 may_MD support_VB or_CC refute_VB hypotheses_NNS generated_VBN by_IN the_ATI history_NN , and_CC generate_VB further_JJB hypotheses_NNS itself_PPL , allowing_VBG more_QL selective_JJ use_NN of_IN imaging_VBG techniques_NNS and_CC laboratory_NN tests_NNS as_CS tools_NNS to_TO confirm_VB the_ATI suspected_VBD diagnoses_VBZ 5_CD TOPOGRAPHY_NP 6_CD situated_VBN intraperitoneally_RB in_IN the_ATI right_JJ upper_JJB quadrant_NN , the_ATI liver_NN seldom_RB extends_VBZ more_AP than_IN 5_CD to_IN 6_CD cm_NNU across_IN the_ATI midline_NN into_IN the_ATI left_NN upper_JJB quadrant_NN the_ATI upper_JJB surface_NN is_BEZ convex_JJ and_CC nestles_NNS under_IN the_ATI diaphragm_NN typically_RB at_IN the_ATI level_NN of_IN the_ATI fifth_OD or_CC sixth_OD anterior_JJ rib_NN in_IN quiet_JJ respiration_NN the_ATI lower_JJR surface_NN tends_VBZ to_TO be_BE concave_VBN , with_IN the_ATI gallbladder_NN in_IN it_PP3 although_CS the_ATI fundus_NN of_IN the_ATI gallbladder_NN may_MD project_VB below_IN and_CC anteriorly_RB to_IN the_ATI lower_JJR liver_NN edge_NN , it_PP3 is_BEZ not_XNOT felt_VBN in_IN healthy_JJ persons_NNS 7_CD the_ATI bulk_NN of_IN the_ATI liver_NN sits_VBZ posteriorly_RB where_WRB it_PP3 cannot_NN be_BE assessed_VBN from_IN behind_IN because_CS of_IN intervening_JJ retroperitoneal_JJ contents_NNS , ribs_NNS , and_CC lumbar_NN musculature_NN anteriorly_RB , the_ATI liver_NN sits_VBZ partly_RB above_IN the_ATI costal_JJ margin_NN , with_IN ribs_NNS and_CC lung_NN supervening_VBG , and_CC partly_RB below_IN it_PP3 the_ATI portion_NN extending_VBG below_IN or_CC inferior_JJ to_IN the_ATI costal_JJ margin_NN varies_VBZ and_CC typically_RB runs_VBZ parallel_JJ to_IN the_ATI costal_JJ margin_NN however_RB , physicians_NNS working_VBG in_IN modern_JJ imaging_NN departments_NNS , like_IN generations_NNS of_IN surgeons_NNS and_CC anatomists_NNS before_CS them_PP3OS , can_MD attest_VB to_IN the_ATI degree_NN of_IN variability_NN in_IN the_ATI shape_NN of_IN the_ATI organ_NN , including_IN the_ATI extent_NN to_TO which_WDTR the_ATI lower_JJR edge_NN parallels_VBZ the_ATI costal_JJ margin_NN and_CC the_ATI degree_NN of_IN extension_NN beyond_IN the_ATI midline_NN into_IN the_ATI left_NN upper_JJB quadrant_NN (_( Fig_NP 1).=20_CD 8_CD to_IN some_DTI extent_NN , the_ATI vertical_JJ liver_NN span_NN (_( ie_NN , the_ATI linear_JJ distance_NN from_IN the_ATI top_NN of_IN the_ATI liver_NN dome_NN down_RP to_IN the_ATI lower_JJR edge_NN )_) is_BEZ a_AT function_NN of_IN where_WRB in_IN the_ATI right_JJ hypochondrium_VBG the_ATI liver_NN edge_NN is_BEZ palpated_VBN or_CC percussed_VBN (_( Fig_NP 1_CD1 and_CC Fig_NP 2_CD ) _) the_ATI falciform_NN ligament_NN joins_VBZ the_ATI midanterior_JJ surface_NN of_IN the_ATI liver_NN to_IN the_ATI diaphragm_NN and_CC anterior_JJ abdominal_JJ wall_NN with_IN respiration_NN , diaphragmatic_JJ contraction_NN drives_VBZ the_ATI liver_NN downward_JJB , and_CC the_ATI anterior_JJ surface_NN of_IN the_ATI organ_NN rotates_VBZ slightly_RB to_IN the_ATI right_JJ in_IN quiet_JJ inspiration_NN and_CC expiration_NN , the_ATI excursion_NN is_BEZ approximately_RB 2_CD to_IN 3_CD cm._NN 9_CD a_AT SUGGESTED_NPT APPROACH_NPT TO_NPT LIVER_NP EXAMINATION_NP 10_CD we_PP1AS assume_VB that_QL , as_IN part_NN of_IN the_ATI general_JJ abdominal_JJ examination_NN , you_PP2 have_HV already_RB inspected_VBN the_ATI abdomen_NN , including_IN the_ATI right_JJ upper_JJB quadrant_NN , looking_VBG for_IN obvious_JJ irregularities_NNS or_CC deformities_NNS then_RN , in_IN adults_NNS without_IN a_AT history_NN or_CC physical_JJ findings_NNS suggestive_JJ of_IN potential_JJ liver_NN disease_NN , palpate_NN for_IN the_ATI lower_JJR liver_NN edge_NN start_VB with_IN gentle_JJ pressure_NN in_IN the_ATI right_JJ lower_JJR quadrant_NN ; ask_VB the_ATI patient_NN to_TO breathe_VB in_IN gently_RB and_CC slowly_RB to_TO bring_VB the_ATI liver_NN edge_NN down_RP to_IN the_ATI examining_VBG fingertips_NNS at_IN each_DT exhalation_NN , move_VB the_ATI fingers_NNS up_RP about_RB 2_CD cm._NN if_CS the_ATI edge_NN is_BEZ not_XNOT felt_VBN , no_ATI further_JJB examination_NN is_BEZ suggested_VBN 11_CD if_CS the_ATI edge_NN is_BEZ felt_VBN , confirm_VB that_CS you_PP2 are_BER palpating_VBG roughly_RB in_IN the_ATI middle_JJB of_IN the_ATI right_JJ portion_NN of_IN the_ATI abdomen_NN , ie_NN , corresponding_JJ to_IN the_ATI midthoracic_JJ line_NN or_CC so-called_JJB midclavicular_NN line_NN (_( MCL_NP )_) mark_VB the_ATI lower_JJR edge_NN then_RN , in_IN the_ATI same_AP approximate_JJ plane_NN , percuss_NN down_RP from_IN about_IN the_ATI level_NN of_IN the_ATI third_OD rib_NN , with_IN the_ATI pleximeter_NN finger_NN (_( the_ATI finger_NN that_CS you_PP2 strike_NN with_IN the_ATI percussing_NN finger_NN )_) laid_VBN horizontally_RB typical_JJ lung_NN field_NN resonance_NN will_MD be_BE heard_VBN move_VB one_CD1 rib_NN space_NN at_IN a_AT time_NN until_IN the_ATI tone_NN changes_NNS because_CS of_IN the_ATI interposition_NN of_IN the_ATI dome_NN of_IN the_ATI liver_NN behind_IN the_ATI air-filled_JJ lung_NN there_EX will_MD be_BE a_AT gradation_NN with_IN increasing_JJ dullness_NN as_CS you_PP2 move_VB caudally_RB and_CC the_ATI volume_NN of_IN the_ATI air-filled_JJ lung_NN overlying_JJ the_ATI liver_NN is_BEZ diminished_VBN (_( Fig_NP 3_CD )_) 12_CD 12_CD to_TO confirm_VB increased_JJ dullness_NN , spread_NN two_CD or_CC three_CD pleximeter_NN fingers_NNS over_IN adjacent_JJ rib_NN spaces_NNS and_CC percuss_NN quickly_RB a_AT number_NN of_IN times_NNS from_IN greater_JJR to_TO lesser_JJR resonance_NN if_CS doubts_NNS persist_VB , have_HV the_ATI patient_NN take_VB a_AT deeper_JJR breath_NN and_CC hold_VB it_PP3 ; then_RN percuss_NN to_TO confirm_VB an_AT unequivocal_JJ increase_NN in_IN resonance_NN at_IN that_DT rib_NN space_NN determination_NN of_IN a_AT level_NN for_IN the_ATI upper_JJB edge_NN of_IN liver_NN dullness_NN is_BEZ sometimes_RB helped_VBN by_IN placing_VBG the_ATI middle_JJB finger_NN over_IN the_ATI likely_JJ level_NN for_IN initial_JJ tone_NN change_NN and_CC laying_VBG the_ATI second_OD and_CC ring_NN fingers_NNS on_IN adjacent_JJ rib_NN spaces_NNS again_RB , percuss_NN back_RP and_CC forth_RP the_ATI percussion_NN tone_NN over_IN the_ATI fourth_OD or_CC ring_NN (_( ie_NN , top_NN )_) finger_NN should_MD be_BE resonant_JJ ; the_ATI second_OD or_CC index_NN finger_NN , unequivocally_RB dull_JJ ; and_CC the_ATI third_OD finger_NN , in_RP between_RI 13_CD try_VB to_TO ensure_VB that_CS the_ATI lower_JJR and_CC upper_JJB borders_NNS are_BER marked_JJ either_DTX in_IN quiet_JJ respiration_NN or_CC , if_CS deep_JJ breaths_NNS are_BER taken_VBN , in_IN the_ATI same_AP phase_NN of_IN respiration_NN 14_CD in_IN instances_NNS during_IN which_WDTR you_PP2 have_HV other_AP evidence_NN to_TO suggest_VB liver_NN disease_NN , but_CC the_ATI liver_NN edge_NN was_BEDZ not_XNOT palpable_JJ , attempt_NN to_TO locate_VB the_ATI lower_JJR edge_NN by_IN gentle_JJ percussion_NN in_IN the_ATI right_JJ lower_JJR quadrant_NN , following_JJ the_ATI plane_NN of_IN the_ATI MCL_NP and_CC again_RB working_VBG from_IN resonance_NN to_IN dullness_NN Tricks_NNS similar_JJ to_IN these_DTS (_( eg_NN , multiple_JJ pleximeter_NN fingers_NNS and_CC manipulating_JJ level_NN of_IN dullness_NN with_IN changes_NNS in_IN depth_NN of_IN respiration_NN )_) may_MD help_VB confirm_VB the_ATI finding_NN if_CS there_EX is_BEZ no_ATI definite_JJ tone_NN change_NN up_RP to_IN the_ATI costal_JJ margin-a_NN not_XNOT uncommon_JJ finding-end_VBG the_ATI attempt_NN to_TO define_VB liver_NN size_NN 15_CD determination_NN of_IN vertical_JJ liver_NN span_NN in_IN the_ATI MCL_NP can_MD be_BE done_VBN two_CD ways_NNS we_PP1AS recommend_VB gentle_JJ percussion_NN for_IN locating_VBG the_ATI upper_JJB liver_NN border_NN and_CC palpation_NN or_CC gentle_JJ percussion_NN to_TO locate_VB the_ATI lower_JJR border_NN an_AT alternative_NN is_BEZ to_TO use_VB firm_JJ percussion_NN , deliberately_RB ignoring_VBG whether_CS or_CC not_XNOT the_ATI lower_JJR edge_NN is_BEZ palpable_JJ 16_CD liver_NN size_NN correlates_NNS with_IN body_NN size_NN , and_CC liver_NN shape_NN correlates_NNS with_IN habitus_JJ liver_NN span_NN is_BEZ greater_JJR in_IN men_NNS than_IN women_NNS and_CC in_IN tall_JJ vs_IN short_JJ persons_NNS however_RB , as_IN a_AT rough_JJ guide_NN , an_AT MCL_NP span_NN of_IN less_AP than_IN 12_CD to_IN 13_CD cm_NNU with_IN gentle_JJ percussion_NN alone_JJ or_CC gentle_JJ percussion_NN combined_VBN with_IN palpation_NN makes_VBZ hepatomegaly_RB very_QL unlikely_JJ ranges_NNS of_IN normal_JJ have_HV been_BEN established_VBN for_IN firm_JJ percussion_NN (_( Table_NP 1_CD1 )_) but_CC will_MD vary_VB among_IN clinicians_NNS depending_VBG on_IN percussion_NN techniques_NNS enlargement_NN suggested_VBN by_IN percussive_JJ span_JJ alone_JJ is_BEZ weaker_JJR evidence_NN for_IN hepatomegaly_RB than_IN span_NN based_VBN on_IN palpation_NN of_IN the_ATI lower_JJR liver_NN edge_NN 17_CD apart_IN perhaps_RB from_IN the_ATI situation_NN of_IN fulminant_JJ hepatic_JJ failure_NN , observing_VBG reduction_NN in_IN liver_NN span_NN is_BEZ of_IN limited_JJ usefulness_NN since_CS many_AP other_AP features_NNS of_IN chronic_JJ liver_NN failure_NN will_MD be_BE present_NN in_IN situations_NNS in_IN which_WDTR reduction_NN in_IN parenchymal_JJ mass_NN has_HVZ occurred_VBN 18_CD when_WRB the_ATI liver_NN edge_NN is_BEZ palpable_JJ , tracing_JJ the_ATI edge_NN and_CC defining_VBG its_PP$ characteristics_NNS qualitatively_RB is_BEZ recommended_VBN primarily_RB in_IN persons_NNS who_WPR are_BER strongly_RB suspected_VBD of_IN having_HVG liver_NN disease_NN auscultation_NN is_BEZ seldom_RB helpful_JJ once_RB you_PP2 have_HV a_AT high_JJ index_NN of_IN suspicion_NN about_IN liver_NN disease_NN , biochemical_JJ tests_NNS and_CC biopsy_NN are_BER the_ATI main_JJB events_NNS ; the_ATI more_AP esoteric_JJ findings_NNS on_IN physical_JJ examination_NN become_VB a_AT sideshow_NN for_IN impressing_VBG referring_VBG physicians_NNS or_CC trainees_NNS 19_CD EVIDENTIARY_NPT BASIS_NPT FOR_NPT THE_NP APPROACH_NP 20_CD inspection_NN 21_CD visualization_NN of_IN infracostal_JJ extension_NN of_IN the_ATI liver_NN is_BEZ occasionally_RB possible_JJ when_WRB malnutrition_NN and_or_CC cachexia_JJ thin_JJ out_RP the_ATI overlying_JJ tissues_NNS or_CC when_WRB there_EX is_BEZ massive_JJ hepatomegaly_RB no_ATI studies_NNS , to_IN our_PP$ knowledge_NN , describe_VB the_ATI yield_NN from_IN inspection_NN of_IN the_ATI liver_NN outline_NN in_IN the_ATI abdomen_NN , but_CC clear-cut_JJ abnormalities_NNS should_MD at_RB least_RB be_BE specific_JJ thereby_RB ruling_JJ in_IN hepatomegaly_RB and_CC underlying_JJ disease_NN 22_CD auscultation_NN 23_CD friction_NN rubs_NNS may_MD occur_VB with_IN primary_JJ and_CC metastatic_JJ malignancies_NNS , after_IN liver_NN biopsies_NNS , with_IN infective_JJ and_CC inflammatory_JJ conditions_NNS , and_CC with_IN or_CC without_IN concomitant_NN hepatomegaly_RB rubs_NNS , though_CS always_RB abnormal_JJ , are_BER rare_JJ and_CC nonspecific_JJ ; even_RB with_IN careful_JJ examination_NN of_IN patients_NNS with_IN liver_NN tumors_NNS , no_ATI more_AP than_IN 10%_CD of_IN patients_NNS have_HV a_AT rub_NN 24_CD a_AT detailed_JJ review_NN of_IN abdominal_JJ auscultation_NN is_BEZ provided_VBN by_IN Sapira_NP , including_IN bruits_NNS and_CC hums_NNS occurring_VBG in_IN and_CC around_IN the_ATI right_JJ upper_JJB quadrant_NN considerable_JJ time_NN can_MD be_BE spent_VBN on_IN auscultation_NN , but_CC there_EX is_BEZ no_ATI evidence_NN that_CS these_DTS findings_NNS are_BER helpful_JJ in_IN routine_NN examination_NN Features_NNS reputed_VBN to_TO help_VB separate_JJ bruits_NNS of_IN arterial_JJ and_CC venous_JJ sources_NNS are_BER noted_VBN in_IN Table_NP 2_CD venous_JJ hums_NNS occur_VB in_IN portal_NN venous_JJ hypertension_NN of_IN any_DTI cause_NN the_ATI hum_NN , a_AT low-pitched_JJ murmur_NN with_IN systolic_JJ and_CC diastolic_JJ components_NNS , arises_VBZ from_IN communication_NN between_IN the_ATI umbilical_JJ or_CC paraumbilical_JJ veins_NNS and_CC abdominal_JJ wall_NN veins_NNS the_ATI responses_NNS of_IN venous_JJ hums_NNS to_TO Valsalva's_NP$ maneuver_NN , splenic_JJ pressure_NN , or_CC ingestion_NN of_IN meals_NNS are_BER inconsistent_JJ other_AP causes_NNS of_IN true_JJ continuous_JJ murmurs_NNS , such_IN as_IN arteriovenous_JJ fistula_NN in_IN the_ATI splanchnic_JJ circulation_NN or_CC hepatic_JJ hemangioma_NN , are_BER uncommon_JJ , and_CC arterial_JJ bruits_NNS rarely_RB have_HV such_ABL lengthy_JJ diastolic_JJ spillover_NN that_CS they_PP3AS sound_JJ continuous_JJ 25_CD 25_CD arterial_JJ bruits_NNS over_IN the_ATI liver_NN or_CC in_IN the_ATI epigastrium_NN have_HV been_BEN described_VBN with_IN most_QL liver_NN tumors_NNS , as_QL well_RB as_IN alcoholic_JJ hepatitis_NN However_NP , among_IN patients_NNS with_IN liver_NN disease_NN in_IN general_JJ (_( eg_NN , a_AT convenience_NN sample_NN of_IN cirrhosis_NN , alcoholic_JJ hepatitis_NN , and_CC malignancy_NN )_) , the_ATI prevalence_NN of_IN bruits_NNS has_HVZ been_BEN reported_VBN at_IN less_AP than_IN 3%_CD both_ABX clinically_RB and_CC with_IN phonoangiographic_JJ enhancement_NN , the_ATI murmurs_NNS associated_VBN with_IN alcoholic_JJ hepatitis_NN and_CC malignancy_NN cannot_NN be_BE distinguished_JJ from_IN one_CD1 another_DT , although_CS the_ATI former_AP resolve_NN if_CS and_CC when_WRB the_ATI condition_NN improves_VBZ The_NP prevalence_NN of_IN clinically_RB audible_JJ bruits_NNS in_IN patients_NNS with_IN confirmed_VBN liver_NN cancer_NN varies_VBZ from_IN 10%_CD to_TO as_IN much_AP as_IN 56%_NN Kingston_NP et_&FW al_APS reported_VBN a_AT diastolic_JJ component_NN to_IN most_QL bruits_NNS heard_VBN in_IN their_PP$ patients_NNS with_IN hepatoma_NN about_RB 1%_CD to_TO 2%_NN of_IN unselected_JJ patients_NNS on_IN a_AT general_JJ medical_JJ service_NN will_MD have_HV abdominal_JJ bruits_NNS of_IN some_DTI kind_NN , and_CC the_ATI ability_NN of_IN clinicians_NNS to_TO distinguish_VB hepatic_JJ from_IN other_AP arterial_JJ bruits_NNS has_HVZ never_RB been_BEN assessed_VBN 26_CD 26_CD auscultation_NN over_IN the_ATI liver_NN should_MD be_BE considered_VBN only_RB when_WRB history_NN and_CC other_AP physical_JJ findings_NNS are_BER suggestive_JJ of_IN hepatic_JJ disease_NN ; even_RB then_RN , the_ATI findings_NNS should_MD be_BE interpreted_VBN cautiously_RB 27_CD 27_CD a_AT PALPABLE_NPT LIVER_NP EDGE_NP : WHAT_NPT DOES_NPT IT_NP MEAN_NP ? 28_CD 28_CD cirrhosis_NN or_CC infiltrative_JJ disorders_NNS increase_VB the_ATI firmness_NN of_IN the_ATI liver_NN edge_NN and_CC the_ATI likelihood_NN of_IN its_PP$ being_BEG felt_VBD independent_NN of_IN effect_NN on_IN organ_NN size_NN among_IN gastroenterologists_NNS , agreement_NN on_IN the_ATI presence_NN of_IN a_AT palpable_JJ liver_NN edge_NN is_BEZ about_IN 50%_NP greater_JJR than_IN expected_VBN by_IN chance_NN alone_JJ More_NP interobserver_NN disagreement_NN would_MD be_BE expected_VBN in_IN ordinary_JJ practice_NN 29_CD 29_CD there_EX is_BEZ a_AT paucity_NN of_IN data_NNS on_IN the_ATI prevalence_NN of_IN palpable_JJ livers_NNS in_IN the_ATI general_JJ population_NN one_CD1 study_NN has_HVZ reported_VBN data_NNS on_IN palpability_JJ of_IN the_ATI liver_NN among_IN 1000_CD military_JJ personnel_NNS (_( 717_CD men_NNS and_CC 283_CD women_NNS )_) undergoing_VBG routine_NN examination_NN ; 852_NN subjects_NNS were_BED 40_CD years_NNS of_IN age_NN or_CC younger_JJR Palmer_NP , the_ATI author_NN and_CC sole_JJB examiner_NN , excluded_VBD any_DTI persons_NNS in_IN whom_WPOR liver_NN disease_NN was_BEDZ suspected_VBN or_CC who_WPR were_BED difficult_JJ to_TO examine_VB in_IN 57%_NN of_IN subjects_NNS , the_ATI liver_NN either_DTX was_BEDZ not_XNOT palpable_JJ in_IN the_ATI right_JJ upper_JJB quadrant_NN or_CC was_BEDZ felt_VBN just_RB at_RB the_ATI costal_JJ margin_NN an_AT additional_JJ 28%_NN descended_VBD only_RB 1_CD1 to_IN 2_CD cm_NNU below_IN the_ATI costal_JJ margin.=20_CD 30_CD 30_CD findings_NNS were_BED similar_JJ for_IN both_ABX sexes_NNS the_ATI proportion_NN of_IN palpable_JJ livers_NNS was_BEDZ inflated_VBN by_IN two_CD factors_NNS first_OD , all_ABN subjects_NNS were_BED examined_VBN in_IN deep-held_NN inspiration_NN second_OD , as_CS Palmer_NP himself_PPL cautioned_VBD , _** there_EX is_BEZ no_ATI question_NN but_CC that_CS many_AP of_IN the_ATI potentially_RB palpable_JJ livers_NNS would_MD have_HV been_BEN overlooked_VBN if_CS this_DT had_HVD not_XNOT been_BEN a_AT specially_RB directed_JJ study_NN _** 31_CD 31_CD ability_NN to_TO palpate_VB the_ATI liver_NN is_BEZ not_XNOT closely_RB correlated_VBN with_IN liver_NN size_NN in_IN studies_NNS using_VBG reference_NN standards_NNS such_IN as_IN scintigraphy_NN or_CC ultrasonography_NN (_( although_CS many_AP published_JJ studies_NNS use_NN scintigraphy_NN as_IN a_AT reference_NN standard_NN , it_PP3 does_DOZ have_HV the_ATI drawback_NN of_IN motion_NN artifact_NN in_IN conventional_JJ applications_NNS )_) patients_NNS undergoing_VBG liver_NN scintiscan_NN are_BER preselected_VBN , and_CC a_AT high_JJ proportion_NN of_IN palpable_JJ livers_NNS might_MD be_BE expected_VBN However_NP , studies_VBZ from_IN nuclear_JJ medicine_NN departments_NNS show_VB that_CS although_CS the_ATI overwhelming_JJ majority_NN of_IN patients_NNS scanned_VBD have_HV some_DTI infracostal_JJ extension_NN of_IN the_ATI liver_NN , less_AP than_IN half_ABN of_IN these_DTS patients_NNS had_HVD palpable_JJ livers_NNS in_IN one_CD1 study_NN , Rosenfield_NP et_&FW al_APS chose_VBD 100_CD scintiscans_NNS at_IN random_JJ and_CC compared_VBN the_ATI findings_NNS with_IN the_ATI clinical_JJ records.=20_CD 32_CD 32_CD among_IN patients_NNS without_IN definite_JJ evidence_NN for_IN liver_NN disease_NN in_IN the_ATI medical_JJ records_NNS , mean_VB scintigraphic_JJ vertical_JJ span_NN in_IN the_ATI right_JJ MCL_NP was_BEDZ similar_JJ among_IN those_DTS with_IN palpable_JJ (_( 12.9_CD cm_NNU )_) and_CC nonpalpable_JJ organs_NNS (_( 12.5_CD cm_NNU )_) , as_CS were_BED the_ATI proportions_NNS in_IN each_DT category_NN (_( 45%_NN vs_IN 55%_NN )_) Overall_NP , the_ATI chance_NN that_CS a_AT patient_NN with_IN a_AT palpable_JJ liver_NN also_RB had_HVD liver_NN disease_NN were_BED 63%_CD (_( 36_CD of_IN 57_CD patients_NNS ; 95%_NN CI_NP , 49%_NN to_TO 76%_VB )_) , but_CC the_ATI chances_NNS of_IN a_AT palpable_JJ liver_NN meeting_NN scintigraphic_JJ criteria_NNS for_IN enlargement_NN were_BED only_RB 46%_JJ (_( 24_CD of_IN 52_CD patients_NNS ; 95%_NN CI_NP , 32%_CD to_IN 61%_CD )_) Studies_NP on_IN palpability_NN and_CC hepatomegaly_RB are_BER summarized_VBN in_IN Table_NP 3_CD this_DT distinction_NN between_IN abnormal_JJ and_CC enlarged_JJ livers_NNS is_BEZ a_AT recurrent_JJ problem_NN because_CS livers_NNS may_MD be_BE abnormal_JJ yet_RB not_XNOT enlarged_JJ 33_CD 33_CD what_WDT of_IN the_ATI converse_NN proposition_NN , ie_NN , that_CS a_AT nonpalpable_JJ liver_NN is_BEZ not_XNOT enlarged_JJ ? since_CS normal_JJ livers_NNS usually_RB extend_VB below_IN the_ATI costal_JJ margin_NN yet_RB may_MD not_XNOT be_BE palpable_JJ , this_DT proposition_NN rests_VBZ on_IN an_AT assumption_NN that_CS enlarged_JJ livers_NNS will_MD be_BE diseased_JJ , abnormally_RB hard_JJ , and_CC therefore_RB much_AP more_QL easily_RB felt_JJ as_CS summarized_VBN in_IN Table_NP 3_CD , a_AT nonpalpable_JJ liver_NN does_DOZ reduce_VB the_ATI probability_NN of_IN hepatomegaly_RB , even_RB though_IN a_AT palpable_JJ organ_NN has_HVZ less_AP than_IN a_AT 50%_NP chance_NN of_IN being_BEG enlarged_JJ these_DTS figures_NNS are_BER influenced_VBN by_IN the_ATI pooled_VBD prevalence_NN of_IN hepatomegaly_RB , 23%_CD in_IN these_DTS studies_NNS as_IN a_AT prevalence-free_NN parameter_NN , we_PP1AS can_MD report_VB that_CS the_ATI pooled_VBD likelihood_NN ratio_NN (_( LR_NP )_) for_IN hepatomegaly_RB , given_VBN a_AT palpable_JJ liver_NN (_( LR_NP +_IN )_) , is_BEZ 2.5_CD the_ATI LR_NP in_IN the_ATI absence_NN of_IN palpable_JJ hepatomegaly_RB (_( LR- _NP )_) for_IN the_ATI presence_NN of_IN an_AT enlarged_JJ liver_NN detected_VBN by_IN scanning_VBG is_BEZ 0.45.=20_CD 34_CD 34_CD however_RB , there_EX will_MD likely_JJ be_BE a_AT workup_NN bias_NN in_IN these_DTS figures_NNS as_IN a_AT result_NN of_IN preferential_JJ referral_NN of_IN patients_NNS with_IN palpable_JJ livers_NNS for_IN scintigraphy_NN this_DT bias_NN would_MD arguably_RB lead_VB to_IN a_AT slight_JJ overestimate_VB of_IN sensitivity_NN and_CC still_RB larger_JJR underestimate_VB of_IN specificity_NN if_CS specificity_NN were_BED higher_JJR , the_ATI LR_NP +_IN would_MD be_BE stronger_JJR in_IN any_DTI event_NN , an_AT LR_NP approach_NN is_BEZ most_QL useful_JJ if_CS you_PP2 know_VB the_ATI prior_RB odds_NNS of_IN hepatomegaly_RB for_IN representative_JJ cohorts_NNS of_IN patients_NNS with_IN various_JJ diseases-_NN a_AT set_VBN of_IN numbers_NNS that_CS are_BER currently_RB unknown_JJ and_CC should_MD be_BE the_ATI subject_NN of_IN research_NN in_IN the_ATI future_NN 35_CD 35_CD in_IN sum_NN , a_AT palpable_JJ liver_NN is_BEZ not_XNOT necessarily_RB enlarged_JJ or_CC diseased_JJ but_CC does_DOZ increase_VB the_ATI likelihood_NN of_IN hepatomegaly_RB the_ATI vertical_JJ liver_NN span_NN and_CC overall_JJB clinical_JJ context_NN must_MD also_RB be_BE considered_VBN conversely_RB , a_AT nonpalpable_JJ liver_NN edge_NN does_DOZ not_XNOT rule_VB out_RP hepatomegaly_RB but_CC does_DOZ reduce_VB its_PP$ likelihood_NN this_DT is_BEZ particularly_RB relevant_JJ in_IN those_DTS settings_NNS of_IN low_JJ prior_RB probability_NN of_IN liver_NN disease_NN where_WRB further_JJB examination_NN is_BEZ likely_JJ to_TO have_HV little_JJ yield_NN if_CS the_ATI liver_NN cannot_NN be_BE felt_VBN 36_CD 36_CD WHAT_NPT ELSE_NPT CAN_NPT BE_NPT LEARNED_NPT FROM_NP PALPATION_NP ? 37_CD 37_CD da_&FW Costa_NP wrote_VBD 70_CD years_NNS ago_RB , _** Tactile_NP sense_NN decides_VBZ the_ATI questions_NNS of_IN hepatic_JJ tenderness_NN , pulsation_NN , friction_NN , and_CC thrills_NNS and_CC determines_VBZ the_ATI consistence_NN and_CC the_ATI contour_NN of_IN its_PP$ anterior_JJ and_CC lower_JJR surfaces_NNS _** however_RB , there_EX are_BER few_AP data_NNS on_IN the_ATI reliability_NN and_CC accuracy_NN of_IN these_DTS qualitative_JJ judgments_NNS about_IN liver_NN edge_NN characteristics_NNS 38_CD 38_CD a_AT pulsatile_NN liver_NN edge_NN is_BEZ well_RB documented_VBN in_IN tricuspid_NN valvular_NN disease_NN although_CS this_DT sign_NN may_MD be_BE present_JJ clinically_RB in_IN the_ATI majority_NN of_IN cases_NNS , no_ATI modern_JJ studies_NNS adequately_RB document_NN the_ATI frequency_NN of_IN the_ATI association_NN and_CC its_PP$ relationship_NN to_IN differing_JJ degrees_NNS of_IN tricuspid_NN valvular_NN dysfunction_NN unequivocal_JJ pulsatile_NN hepatomegaly_RB is_BEZ also_RB reported_VBN in_IN 35_CD of_IN 55_CD consecutive_JJ patients_NNS (_( 64%_NN ; 95%_NN CI_NP , 50%_NP to_TO 76%_VB )_) with_IN confirmed_VBN constrictive_JJ pericarditis_NN accumulated_VBD in_IN two_CD separate_JJ case_NN series_NN the_ATI low_JJ false-negative_JJ rates_NNS give_VB this_DT sign_NN some_DTI potential_JJ value_NN in_IN a_AT setting_VBG where_WRB constrictive_JJ pericarditis_NN is_BEZ already_RB suspected_VBN 39_CD 39_CD unfortunately_RB , as_CS Osler_NP noted_VBD a_AT century_NN ago_RB , there_EX is_BEZ a_AT need_NN to_TO distinguish_VB between_IN an_AT expansile_NN liver_NN edge_NN and_CC transmitted_VBN aortic_JJ or_CC right_JJ ventricular_JJ impulses_NNS that_CS are_BER commonly_RB present_JJ there_EX are_BER no_ATI data_NNS on_IN examination_NN maneuvers_NNS to_TO make_VB such_ABL a_AT distinction_NN , although_CS inspiratory_NN increase_NN in_IN the_ATI magnitude_NN of_IN the_ATI pulsation_NN has_HVZ been_BEN reported_VBN anecdotally_RB with_IN tricuspid_NN insufficiency_NN detection_NN of_IN differential_JJ timing_NN of_IN hepatic_JJ pulsations_NNS has_HVZ been_BEN described_VBN (_( eg_NN , A_ZZ vs_IN V_ZZ waves_NNS )_) but_CC is_BEZ rare_JJ and_CC doubtless_RB difficult_JJ to_TO pinpoint_VB 40_CD 40_CD palpation_NN for_IN an_AT expansile_NN liver_NN edge_NN should_MD be_BE limited_JJ to_IN cases_NNS of_IN suspected_VBD tricuspid_NN valve_NN disease_NN or_CC constrictive_JJ pericarditis_NN 41_CD 41_CD the_ATI other_AP qualitative_JJ parameters_NNS are_BER consistency_NN , nodularity_NN , and_CC tenderness_NN of_IN a_AT palpable_JJ liver_NN edge_NN among_IN multiple_JJ expert_JJ observers_NNS examining_VBG variously_RB alcoholic_JJ or_CC jaundiced_JJ patients_NNS , kappa_NN statistics_NNS for_IN chance- corrected_JJ agreement_NN were_BED 11%_CD for_IN abnormal_JJ consistency_NN of_IN a_AT palpable_JJ liver_NN edge_NN and_CC 26%_NN or_CC 29%_NN for_IN presence_NN of_IN nodularity_NN only_RB agreement_NN on_IN tenderness_NN of_IN the_ATI liver_NN edge_NN was_BEDZ within_IN a_AT useful_JJ range_NN at_IN 49%_NN 42_CD 42_CD palpation_NN to_TO describe_VB the_ATI liver_NN edge_NN qualitatively_RB or_CC to_TO detect_VB isolated_JJ enlargement_NN of_IN the_ATI left_NN (_( caudate_NN )_) lobe_NN of_IN the_ATI liver_NN should_MD therefore_RB be_BE considered_VBN primarily_RB if_CS there_EX is_BEZ other_AP evidence_NN of_IN organ_NN disease_NN or_CC concern_NN about_IN liver_NN tumor_NN and_CC even_RB then_RN , is_BEZ optional_JJ 43_CD 43_CD ASSESSING_NPT VERTICAL_NPT LIVER_NP SPAN_NP 44_CD 44_CD unequivocal_JJ reduction_NN in_IN liver_NN size_NN should_MD be_BE detectable_JJ in_IN fulminant_JJ hepatic_JJ failure_NN however_RB , no_ATI evidence_NN was_BEDZ located_VBN to_TO support_VB the_ATI common_JJ belief_NN that_CS a_AT substantial_JJ proportion_NN of_IN persons_NNS with_IN chronic_JJ cirrhosis_NN have_HV detectably_RB small_JJ livers_NNS by_IN physical_JJ examination_NN the_ATI focus_NN herein_RB is_BEZ accordingly_RB on_IN hepatomegaly_RB 45_CD 45_CD since_CS half_ABN of_IN all_ABN palpable_JJ livers_NNS are_BER not_XNOT enlarged_JJ , measurement_NN of_IN vertical_JJ liver_NN span_NN in_IN some_DTI plane_NN is_BEZ required_VBN the_ATI usual_JJ reference_NN point_NN is_BEZ the_ATI MCL_NP however_RB , unless_CS care_NN is_BEZ taken_VBN in_IN examination_NN , the_ATI MCL_NP can_MD be_BE _** a_AT wandering_VBG landmark_NN , _** with_IN documented_VBN interobserver_NN variation_NN as_QL much_AP as_IN 10_CD cm_NNU sup_VB 34_CD variation_NN in_IN the_ATI MCL_NP will_MD inevitably_RB lead_VB to_TO imprecision_NN in_IN liver_NN span_NN assessments_NNS (_( Fig_NP 2_CD )_) note_NN also_RB that_CS vertical_JJ span_NN could_MD only_RB be_BE an_AT accurate_JJ predictor_NN of_IN liver_NN mass_NN if_CS the_ATI organ_NN were_BED more_QL or_CC less_QL cuboid_JJ rather_RB than_IN irregular_JJ 46_CD 46_CD palpation_NN should_MD , in_IN theory_NN , be_BE the_ATI most_QL reliable_JJ and_CC accurate_JJ method_NN of_IN locating_VBG the_ATI lower_JJR border_NN of_IN the_ATI liver_NN to_TO measure_VB organ_NN span_NN Two_NP studies_NNS report_NN specialists'_NNS$ ability_NN to_TO agree_VB on_IN distance_NN from_IN the_ATI costal_JJ margin_NN to_IN a_AT palpable_JJ liver_NN edge_NN , an_AT approach_NN that_CS overstates_NNS accuracy_NN by_IN eliminating_VBG the_ATI largest_JJT source_NN of_IN error-location_NN of_IN the_ATI upper_JJB border_NN of_IN the_ATI liver_NN .=20_CD 47_CD 47_CD meyhoff_NN et_&FW al_APS further_JJB controlled_JJ interobserver_NN disagreement_NN by_IN having_HVG all_ABN measurements_NNS made_VBN at_IN a_AT predetermined_JJ MCL_NP mean_VB maximum_JJ interobserver_NN difference_NN about_IN distance_NN from_IN the_ATI costal_JJ margin_NN was_BEDZ 6.1_CD cm_NNU (_( SD_NN , 2.7_CD cm_NNU )_) in_IN the_ATI MCL_NP intraobserver_NN variation_NN was_BEDZ smaller_JJR , with_IN differences_NNS not_XNOT greater_JJR than_IN 2_CD cm_NNU in_IN 60%_NP to_IN 80%_NP of_IN MCL_NP measurements_NNS There_NP was_BEDZ no_ATI clear_JJ relationship_NN to_TO liver_NN size_NN , a_AT finding_VBG that_CS underscores_VBZ the_ATI need_NN to_TO measure_VB span_NN from_IN the_ATI upper_JJB border_NN of_IN the_ATI liver_NN not_XNOT the_ATI costal_JJ margin.=20_CD 48_CD 48_CD theodossi_NN et_&FW al_APS performed_VBN a_AT similar_JJ experiment_NN without_IN marking_VBG the_ATI MCL_NP the_ATI intraclass_NN correlation_NN coefficient_NN was_BEDZ 0.66_CD , analogous_JJ to_IN a_AT weighted_VBN kappa_NN of_IN more_AP than_IN 60%_NP however_RB , agreement_NN beyond_IN chance_NN on_IN whether_CS the_ATI liver_NN was_BEDZ truly_RB enlarged_JJ was_BEDZ only_RB 30%_NP 49_CD 49_CD what_WDT are_BER the_ATI alternatives_NNS to_IN localizing_VBG the_ATI lower_JJR liver_NN edge_NN by_IN palpation_NN ? the_ATI scratch_NN test_NN is_BEZ performed_VBN by_IN placing_VBG the_ATI diaphragm_NN of_IN the_ATI stethoscope_NN at_IN the_ATI xiphisternum_NN or_CC over_IN the_ATI liver_NN just_RB above_IN the_ATI costal_JJ margin_NN in_IN the_ATI MCL_NP starting_VBG low_RB in_IN the_ATI abdomen_NN , a_AT finger_NN is_BEZ moved_VBN up_RP the_ATI abdomen_NN scratching_VBG gently_RB the_ATI intensity_NN becomes_VBZ greatly_RB enhanced_VBN once_RB the_ATI finger_NN is_BEZ over_IN the_ATI lower_JJR border_NN of_IN the_ATI liver_NN the_ATI other_AP major_JJ alternative_NN is_BEZ percussion_NN 50_CD 50_CD comparative_JJ studies_NNS are_BER summarized_VBN in_IN Table_NP 4_CD two_CD caveats_NNS are_BER in_IN order_NN both_ABX studies_NNS involved_VBN limited_JJ numbers_NNS of_IN observers_NNS and_CC patients_NNS as_CS well_RB , the_ATI overall_JJB accuracy_NN in_IN the_ATI report_NN by_IN Fuller_NP et_&FW al_APS is_BEZ greatly_RB exaggerated_JJ on_IN two_CD scores_NNS first_OD , the_ATI ultrasonographic_JJ measurement_NN was_BEDZ made_VBN in_IN a_AT plane_NN defined_VBN by_IN the_ATI observers_NNS in_IN actual_JJ practice_NN , the_ATI MCL_NP of_IN the_ATI clinical_JJ observer_NN varies_VBZ from_IN that_DT of_IN the_ATI scintigrapher_NN or_CC ultrasonographer_NN , a_AT situation_NN that_CS was_BEDZ applicable_JJ for_IN the_ATI patients_NNS examined_VBN by_IN Sullivan_NP et_&FW al_APS second_OD , Fuller_NP et_&FW al_APS took_VBD their_PP$ measurements_NNS from_IN the_ATI costal_JJ margin_NN 51_CD 51_CD the_ATI scratch_NN test_NN may_MD be_BE a_AT useful_JJ adjunct_NN to_TO percussion_NN or_CC palpation_NN in_IN locating_VBG the_ATI lower_JJR edge_NN of_IN the_ATI liver_NN however_RB , further_JJB studies_NNS are_BER needed_VBN before_CS it_PP3 can_MD be_BE recommended_VBN for_IN routine_NN use_NN 52_CD 52_CD also_RB shown_VBN in_IN Table_NP 4_CD are_BER the_ATI results_NNS of_IN other_AP studies_NNS in_IN which_WDTR the_ATI authors_NNS used_JJ percussion_NN and_or_CC palpation_NN to_TO locate_VB the_ATI lower_JJR liver_NN edge_NN excluded_VBN is_BEZ one_CD1 outlying_JJ study_NN in_IN which_WDTR 100%_CD of_IN measurements_NNS were_BED accurate_JJ within_IN 2_CD cm_NNU of_IN scintigraphic_JJ MCL_NP span_NN and_CC exact_JJ agreement_NN at_IN the_ATI 0.1- cm_CD-CD level_NN is_BEZ claimed_VBN for_IN several_AP observations_NNS we_PP1AS also_RB exclude_VB a_AT study_NN using_VBG direct_JJ percussion_NN without_IN a_AT pleximeter_NN finger_NN ; this_DT study_NN related_VBN mean_VB clinical_JJ liver_NN span_NN to_IN ultrasonographic_JJ span_NN , but_CC lacked_VBD measures_NNS of_IN either_DTX case-by-case_JJ absolute_JJ span_NN discrepancies_NNS or_CC categorical_JJ agreement_NN on_IN organ_NN normalcy_NN 53_CD 53_CD once_RB span_JJ has_HVZ been_BEN determined_JJ , clinicians_NNS must_MD still_RB decide_VB whether_CS the_ATI liver_NN is_BEZ enlarged_JJ or_CC not_XNOT blendis_NN et_&FW al_APS reported_VBN that_CS among_IN 28_CD patients_NNS with_IN blood_NN dyscrasias_NNS or_CC liver_NN diseases_NNS examined_VBN by_IN four_CD observers_NNS , three_CD of_IN four_CD observers_NNS agreed_VBD in_IN 93%_CD of_IN cases_NNS about_IN the_ATI presence_NN or_CC absence_NN of_IN hepatic_JJ enlargement_NN , but_CC the_ATI data_NNS do_DO not_XNOT permit_VB a_AT kappa_NN correction_NN theodossi_NN et_&FW al_APS , with_IN five_CD observers_NNS and_CC a_AT structured_VBN history_NN and_CC physical_JJ examination_NN on_IN 20_CD jaundiced_JJ patients_NNS , reported_VBD a_AT kappa_NN for_IN presence_NN or_CC absence_NN of_IN hepatomegaly_RB of_IN 30%.=20_CD 54_CD 54_CD moreover_RB , agreement_NN among_IN the_ATI qualitative_JJ judgments_NNS of_IN clinicians_NNS and_CC an_AT external_JJ reference_NN standard_NN is_BEZ modest_JJ for_IN example_NN , Blendis_NP et_&FW al_APS found_VBN that_CS in_IN the_ATI cases_NNS in_IN which_WDTR at_RB least_RB three_CD clinicians_NNS agreed_VBD on_IN hepatomegaly_RB , concordant_JJ assessments_NNS of_IN radiological_JJ liver_NN surface_NN area_NN were_BED found_VBN in_IN only_RB 48%_JJ of_IN cases_NNS Halpern_NP et_&FW al_APS compared_VBN judgments_NNS recorded_VBN in_IN medical_JJ charts_NNS with_IN a_AT convenience_NN sample_NN of_IN 214_CD scintigraphic_JJ images_NNS with_IN 16_CD cm_NNU as_IN the_ATI cut_JJ point_NN accuracy_NN was_BEDZ 66%_NN , slightly_RB higher_JJR than_CS in_IN the_ATI Blendis_NP study_NN however_RB , when_WRB corrected_VBN for_IN agreement_NN expected_VBN on_IN the_ATI basis_NN of_IN chance_NN alone_JJ , the_ATI resulting_JJ kappa_NN statistic_NN was_BEDZ only_RB 32%.=20_CD 55_CD 55_CD Naylor_NP et_&FW al_APS used_VBN 15_CD cm_NNU as_IN a_AT cut_JJ point_NN for_IN scintigraphic_JJ hepatomegaly_RB and_CC , with_IN two_CD observers_NNS , found_VBD that_CS the_ATI accuracy_NN of_IN clinical_JJ examination_NN ranged_VBD from_IN 67%_NN to_TO 82%_VB , depending_VBG on_IN the_ATI observer_NN and_CC choice_NN of_IN clinical_JJ threshold_NN value_NN for_IN determining_VBG the_ATI presence_NN of_IN hepatomegaly_RB correcting_VBG for_IN chance_NN agreement_NN , the_ATI kappa_NN statistics_NNS ranged_VBD from_IN 28%_NN to_TO 55%_VB overall_JJB , it_PP3 appears_VBZ that_CS combinations_NNS of_IN palpation_NN and_CC percussion_NN yield_NN modest_JJ accuracy_NN greater_JJR than_IN expected_VBN by_IN chance_NN alone_RB in_IN determining_VBG whether_CS the_ATI liver_NN is_BEZ enlarged_JJ or_CC not_XNOT 56_CD 56_CD Castell_NP et_&FW al_APS suggested_VBN measuring_JJ span_NN by_IN percussion_NN alone_JJ They_NP examined_VBD 116_CD healthy_JJ subjects_NNS to_TO establish_VB a_AT range_NN of_IN normal_JJ for_IN percussive_JJ span_NN in_IN the_ATI MCL_NP and_CC midsternal_JJ line_NN since_IN the_ATI goal_NN was_BEDZ to_TO establish_VB a_AT clinical_JJ range_NN of_IN normal_JJ , there_EX was_BEDZ no_ATI reason_NN to_TO validate_VB the_ATI measurements_NNS against_IN a_AT reference_NN standard_NN percussive_JJ span_NN correlated_VBN positively_RB with_IN height_NN and_CC differed_VBD between_IN males_NNS and_CC females_NNS as_CS would_MD be_BE expected_VBN from_IN autopsy_NN studies_NNS (_( Table_NP 1_CD1 )_) formulas_NNS to_TO predict_VB span_NN were_BED derived_VBN that_CS incorporated_VBN height_NN and_CC weight_NN midclavicular_NN line_NN liver_NN dullness_NN for_IN males_NNS (_( cm_NNU )_) =3D_CD {_( (_( 0.032_NP x_IN weight_NN (_( lb_NNU )_) )_) +_IN (_( 0.18_CD x_IN height_NN (_( in_IN )_) )_) }_) -_IN 7.86_NN midclavicular_NN line_NN liver_NN dullness_NN for_IN females_NNS (_( cm_NNU )_) =3D_CD {_( 0.027_NP x_IN weight_NN (_( lb_NNU )_) )_) +_IN (_( 0.22_NP x_IN height_NN (_( in_IN )_) )_) }_) -_IN 10.75_CD 57_CD 57_CD the_ATI advantages_NNS of_IN percussion_NN alone_JJ are_BER that_CS observers_NNS may_MD not_XNOT agree_VB on_IN the_ATI presence_NN of_IN a_AT palpable_JJ liver_NN , and_CC palpable_JJ livers_NNS will_MD often_RB be_BE felt_VBN below_IN the_ATI point_NN where_WRB the_ATI percussion_NN note_NN changes_NNS the_ATI latter_AP occurs_VBZ because_CS the_ATI thin_JJ lower_JJR liver_NN edge_NN may_MD not_XNOT cause_VB dullness.=20_CD 58_CD 58_CD thus_RB , since_CS not_XNOT all_ABN livers_NNS are_BER palpable_JJ , you_PP2 must_MD rely_VB on_IN palpation_NN in_IN a_AT variable_JJ proportion_NN of_IN subjects_NNS , and_CC these_DTS subjects_NNS will_MD tend_VB to_TO have_HV somewhat_RB larger_JJR liver_NN spans_NNS however_RB , clinical_JJ MCL_NP span_NN compared_VBN with_IN technetium_JJ scintigraphic_JJ span_NN is_BEZ less_QL accurate_JJ when_WRB the_ATI lower_JJR border_NN is_BEZ nonpalpable_JJ , and_CC errors_NNS are_BER always_RB greatest_JJT in_IN the_ATI upper_JJB border_NN that_WPR can_MD only_RB be_BE approached_VBN by_IN percussion_NN it_PP3 therefore_RB seems_VBZ counterintuitive_JJ to_TO propose_VB examining_VBG liver_NN span_NN by_IN percussion_NN alone_JJ also_RB , the_ATI forcefulness_NN of_IN percussion_NN greatly_RB modifies_VBZ the_ATI measured_JJ span_NN use_NN of_IN percussive_JJ span_NN therefore_RB demands_VBZ that_CS each_DT observer_NN double-check_NN his_PP$ or_CC her_PP$ own_AP range_NN of_IN normal_JJ against_IN the_ATI established_JJ norms_NNS to_TO ensure_VB that_CS strength_NN of_IN percussion_NN is_BEZ not_XNOT a_AT confounder_NN 59_CD 59_CD another_DT group_NN used_VBN the_ATI percussive_JJ span_NN technique_NN to_TO examine_VB 46_CD patients_NNS with_IN liver_NN disease_NN there_EX was_BEDZ significant_JJ disagreement_NN among_IN six_CD examining_VBG clinicians_NNS , presumably_RB because_CS of_IN strength_NN and_CC plane_NN of_IN percussion_NN interobserver_NN agreement_NN on_IN the_ATI appraisal_NN of_IN the_ATI organ_NN as_CS _** small_JJ , _** _** normal_JJ , _** or_CC _** enlarged_JJ _** was_BEDZ excellent_JJ only_RB for_IN massively_RB enlarged_JJ livers_NNS if_CS moderately_RB enlarged_JJ organs_NNS (_( ultrasound_NN volumes_NNS between_IN 2000_CD and_CC 2700_CD mL_NN )_) are_BER included_VBN , the_ATI probability_NN of_IN any_DTI two_CD randomly_RB chosen_JJ observers_NNS agreeing_VBG on_IN the_ATI presence_NN of_IN hepatomegaly_RB was_BEDZ between_IN 40%_NP and_CC 75%_NN 60_CD 60_CD this_DT limited_JJ performance_NN is_BEZ perhaps_RB understandable_JJ since_IN the_ATI concept_NN of_IN percussive_JJ span_NN rests_VBZ on_IN the_ATI questionable_JJ assumption_NN that_CS it_PP3 consistently_RB underestimates_VBZ liver_NN span_NN allowing_VBG for_IN reliable_JJ demarcation_NN of_IN abnormally_RB sized_JJ livers_NNS nonetheless_RB , Castell_NP et_&FW al_APS are_BER the_ATI only_AP group_NN to_TO establish_VB a_AT range_NN of_IN normal_JJ for_IN clinical_JJ liver_NN span_NN that_CS reflects_VBZ the_ATI known_JJ variability_NN of_IN span_NN with_IN height_NN , weight_NN , and_CC gender_NN 61_CD 61_CD use_NN of_IN percussion_NN alone_JJ to_TO determine_VB span_NN , independent_NN of_IN whether_CS or_CC where_WRB the_ATI lower_JJR liver_NN edge_NN is_BEZ felt_VBN , remains_VBZ feasible_JJ However_NP , clinicians_NP should_MD standardize_VB their_PP$ percussion_NN technique_NN and_CC compare_VB their_PP$ typical_JJ findings_NNS in_IN normal_JJ subjects_NNS to_TO published_VBN normal_JJ ranges_NNS future_NN research_NN should_MD evaluate_VB the_ATI clinical_JJ utility_NN of_IN the_ATI percussive_JJ method_NN as_CS compared_VBN with_IN methods_NNS using_VBG percussion_NN and_CC palpation_NN , with_IN and_CC without_IN the_ATI _** scratch_NN test_NN _** 62_CD 62_CD PHYSICAL_NPT FINDINGS_NPT IN_NP CONTEXT_NP 63_CD 63_CD in_IN the_ATI foregoing_JJ studies_NNS , accuracy_NN is_BEZ generally_RB defined_VBN against_IN a_AT single_JJ reference_NN standard_NN such_IN as_IN ultrasound_NN or_CC scintigraphy_NN this_DT procedure_NN contrasts_NNS with_IN studies_NNS such_IN as_IN the_ATI one_CD1 by_IN Rosenfield_NP et_&FW al_APS in_IN which_WDTR measured_JJ span_NN and_CC palpability_NN were_BED compared_VBN with_IN evidence_NN in_IN the_ATI clinical_JJ record_NN for_IN any_DTI liver_NN disease_NN the_ATI latter_AP study_NN has_HVZ the_ATI advantage_NN of_IN capturing_VBG the_ATI fact_NN that_CS although_CS all_ABN truly_RB enlarged_JJ livers_NNS are_BER diseased_JJ , not_XNOT all_ABN normal_JJ sized_JJ livers_NNS are_BER free_JJ of_IN disease_NN 64_CD 64_CD a_AT further_JJB problem_NN with_IN many_AP studies_NNS is_BEZ the_ATI extent_NN of_IN blinding_JJ Some_NP studies_NNS blind_JJ observers_NNS to_IN all_ABN details_NNS of_IN the_ATI patients'_NNS$ history_NN and_CC other_AP physical_JJ findings_NNS others_APS ask_VB observers_NNS to_TO perform_VB a_AT structured_VBN history_NN and_CC physical_JJ examination_NN or_CC set_JJ inclusion_NN criteria_NNS (_( eg_NN , jaundiced_JJ or_CC alcoholic_JJ patients_NNS )_) that_DT will_MD affect_VB clinicians'_NNS$ judgments_NNS The_NP nature_NN and_CC extent_NN of_IN confounding_VBG from_IN this_DT variable_NN is_BEZ unknown_JJ , but_CC it_PP3 seems_VBZ probable_JJ that_CS the_ATI extent_NN of_IN interobserver_NN agreement_NN , and_CC even_RB the_ATI match_NN between_IN clinical_JJ judgments_NNS and_CC reference_NN standards_NNS , will_MD be_BE affected_VBN by_IN the_ATI amount_NN of_IN information_NN available_JJ to_IN the_ATI examiner_NN 65_CD 65_CD finally_RB , few_AP studies_NNS try_VB to_TO place_VB liver_NN findings_NNS in_IN the_ATI overall_JJB context_NN of_IN clinical_JJ decision_NN making_NN sapira_NN has_HVZ noted_VBN that_CS clinical_JJ liver_NN span_NN assessments_NNS need_MD not_XNOT match_VB closely_RB ultrasonographic_JJ or_CC scintigraphic_JJ measures_NNS , since_IN the_ATI _** clinical_JJ worth_IN _** of_IN a_AT sign_NN is_BEZ its_PP$ potential_JJ contribution_NN to_IN clinical_JJ decision_NN making_NN of_IN interest_NN , Espinoza_NP et_&FW al_APS used_JJ stepwise_NN discriminant_NN analysis_NN to_TO assess_VB the_ATI ability_NN of_IN a_AT variety_NN of_IN physical_JJ findings_NNS to_TO distinguish_VB among_IN 50_CD consecutive_JJ alcoholic_JJ patients_NNS presenting_VBG variously_RB with_IN cirrhosis_NN , noncirrhotic_JJ alcoholic_JJ liver_NN disease_NN , or_CC no_ATI clinical_biochemical_JJ evidence_NN of_IN liver_NN disease_NN three_CD variables-spider_NN nevi_NN , splenomegaly_RB , and_CC abdominal_JJ wall_NN collateral_JJ veins-appeared_JJ useful_JJ ; liver_NN examination_NN findings_NNS were_BED not_XNOT significant_JJ contributors_NNS to_IN the_ATI differential_JJ diagnostic_JJ exercise.=20_CD 66_CD 66_CD similarly_RB , Theodossi_NP et_&FW al_APS examined_VBN the_ATI ability_NN of_IN a_AT large_JJ array_NN of_IN symptoms_NNS and_CC signs_NNS to_TO differentiate_VB between_IN medical_JJ and_CC surgical_JJ causes_NNS of_IN jaundice_NN they_PP3AS found_VBD that_CS descent_NN of_IN the_ATI liver_NN edge_NN more_AP than_IN 2_CD cm_NNU below_IN the_ATI costal_JJ margin_NN was_BEDZ more_QL common_JJ with_IN surgical_JJ causes_NNS of_IN jaundice_NN (_( P{.01_CD )_) , but_CC the_ATI independent_JJ contribution_NN of_IN this_DT sign_NN to_IN the_ATI overall_JJB diagnostic_JJ process_NN was_BEDZ unclear_JJ 67_CD 67_CD both_ABX studies_NNS started_VBD with_IN populations_NNS that_CS had_HVD liver_NN disease_NN and_CC determined_JJ whether_CS physical_JJ diagnosis_NN helped_VBD in_IN categorizing_VBG the_ATI type_NN of_IN disease_NN neither_DTX addresses_NNS whether_CS the_ATI physical_JJ examination_NN was_BEDZ helpful_JJ in_IN deciding_VBG which_WDTR patients_NNS had_HVD liver_NN disease_NN in_IN the_ATI first_OD place_NN little_JJ is_BEZ known_VBN about_IN the_ATI real_JJ contribution_NN of_IN liver_NN examination_NN findings_NNS to_TO the_ATI overall_JJB clinical_JJ diagnostic_JJ and_CC management_NN process_NN this_DT topic_NN should_MD be_BE a_AT research_NN priority_NN 68_CD 68_CD WHAT_NPT CAN_NPT YOU_NPT DO_NPT TO_NPT GET_NPT BETTER_NPT AT_NPT EXAMINING_NPT THE_NP LIVER_NP ? 69_CD 69_CD no_ATI educational_JJ studies_NNS , to_IN our_PP$ knowledge_NN , have_HV tested_VBN methods_NNS to_TO improve_VB your_PP$ accuracy_NN and_CC precision_NN in_IN examining_VBG the_ATI liver_NN , but_CC a_AP few_AP suggestions_NNS can_MD be_BE hazarded_VBD first_OD , once_RB you_PP2 are_BER comfortable_JJ examining_VBG the_ATI liver_NN , pursue_VB the_ATI various_JJ shortcuts_NNS recommended_VBN herein_RB early_JJ on_RP , however_RB , it_PP3 is_BEZ useful_JJ to_TO check_VB the_ATI liver_NN span_NN by_IN percussion_NN even_RB in_IN persons_NNS with_IN a_AT low_JJ probability_NN of_IN liver_NN disease_NN and_CC a_AT nonpalpable_JJ organ_NN This_NN can_MD help_VB you_PP2 begin_VB to_TO understand_VB what_WDT your_PP$ own_AP range_NN of_IN normal_JJ is_BEZ likely_JJ to_TO be_BE second_OD , check_NN your_PP$ reliability_NN by_IN reexamining_VBG stable_JJ patients_NNS and_CC comparing_VBG your_PP$ follow-up_NN assessment_NN with_IN your_PP$ first_OD impressions.=20_CD 70_CD 70_CD third_OD , both_ABX tyros_NNS and_CC experts_NNS should_MD quantitatively_RB and_CC qualitatively_RB benchmark_JJ their_PP$ physical_JJ examinations_NNS of_IN the_ATI liver_NN against_IN findings_NNS on_IN nuclear_JJ examination_NN or_CC ultrasound_NN try_VB to_TO determine_VB how_WRB you_PP2 are_BER doing_VBG in_IN assessing_VBG vertical_JJ liver_NN span_NN or_CC extent_NN of_IN descent_NN of_IN the_ATI edge_NN below_IN the_ATI costal_JJ margin_NN or_CC in_IN _** calling_VBG _** the_ATI presence_NN of_IN hepatomegaly_RB fourth_OD , consider_VB the_ATI potential_JJ errors_NNS in_IN locating_VBG the_ATI MCL_NP If_NP sequential_JJ clinical_JJ span_NN assessments_NNS are_BER being_BEG made_VBN (_( eg_NN , fulminant_NN hepatic_JJ failure_NN or_CC treatment_NN of_IN hepatic_JJ metastases_NNS )_) , it_PP3 may_MD help_VB to_TO record_NN a_AT reference_NN plane_NN such_IN as_IN 10_CD cm_NNU from_IN the_ATI midline_NN or_CC , alternatively_RB , where_WRB the_ATI lateral_JJ edge_NN of_IN the_ATI rectus_JJ abdominus_JJ crosses_NNS the_ATI costal_JJ margin_NN 71_CD 71_CD THE_NPT BOTTOM_NP LINE_NP 72_CD 72_CD once_RB historical_JJ data_NNS and_CC other_AP physical_JJ signs_NNS have_HV been_BEN elicited_VBN , the_ATI additional_JJ value_NN of_IN a_AT detailed_JJ physical_JJ examination_NN of_IN the_ATI liver_NN remains_VBZ uncertain_JJ moreover_RB , just_RB as_CS diagnostic_JJ tests_NNS yield_VB little_JJ at_IN the_ATI extremes_NNS of_IN prior_RB probability_NN , so_QL also_RB would_MD you_PP2 expect_VB less_QL yield_VB from_IN liver_NN examination_NN in_IN persons_NNS who_WPR are_BER not_XNOT suspected_VBD of_IN having_HVG liver_NN disease_NN or_CC who_WPR are_BER obviously_RB suffering_VBG from_IN some_DTI hepatobiliary_NN complaint_NN 73_CD 73_CD a_AT selective_JJ approach_NN to_IN physical_JJ examination_NN of_IN the_ATI liver_NN is_BEZ therefore_RB suggested_VBN palpate_NN to_TO locate_VB the_ATI lower_JJR liver_NN border_NN in_IN the_ATI MCL_NP in_IN situations_NNS of_IN low_JJ probability_NN of_IN liver_NN disease_NN if_CS the_ATI liver_NN is_BEZ not_XNOT palpable_JJ , one_CD1 can_MD defensibly_RB forgo_VB any_DTI further_JJB examination_NN in_IN patients_NNS without_IN reasons_NNS to_TO suspect_VB liver_NN disease_NN since_CS , however_RB , palpation_NN of_IN the_ATI abdomen_NN is_BEZ difficult_JJ in_IN some_DTI subjects_NNS , light_NN percussion_NN remains_VBZ an_AT option_NN to_TO confirm_VB lack_NN of_IN extension_NN of_IN the_ATI liver_NN edge_NN below_IN the_ATI costal_JJ margin_NN and_or_CC guide_NN further_JJB palpation_NN with_IN a_AT palpable_JJ lower_JJR edge_NN , MCL_NP span_NN can_MD be_BE ascertained_VBN by_IN light_NN percussion_NN of_IN the_ATI upper_JJB border.=20_CD 74_CD 74_CD a_AT span_NN of_IN less_AP than_IN 12_CD to_IN 13_CD cm_NNU reduces_VBZ the_ATI probability_NN of_IN hepatomegaly_RB in_IN persons_NNS with_IN an_AT impalpable_JJ liver_NN and_CC a_AT high_JJ probability_NN of_IN liver_NN disease_NN , measuring_JJ span_NN by_IN percussion_NN alone_JJ may_MD also_RB be_BE worthwhile_JJ ; tables_NNS of_IN norms_NNS have_HV been_BEN published_VBN , although_CS these_DTS apply_VB to_TO moderate_JJ or_CC heavy_JJ percussion_NN methods_NNS palpation_NN specifically_RB to_TO assess_VB the_ATI quality_NN of_IN the_ATI liver_NN edge_NN is_BEZ recommended_VBN only_RB if_CS there_EX are_BER signs_NNS of_IN liver_NN disease_NN , including_IN unequivocal_JJ hepatomegaly_RB auscultation_NN over_IN the_ATI liver_NN has_HVZ a_AT limited_JJ role_NN in_IN examination_NN 75_CD Zollinger-Ellison_NP Syndrome_NP : advances_NNS in_IN Treatment_NP of_IN Gastric_NP Hypersecretion_NN and_CC the_ATI Gastrinoma_NP 76_CD case_NN 1_CD1 77_CD a_AT 56-year-old_JJB man_NN had_HVD an_AT 8-year_JJ history_NN of_IN heartburn_NN and_CC diarrhea_NN (_( three_CD to_IN four_CD loose_JJ bowel_NN movements_NNS a_AT day_NN )_) and_CC a_AT 3-year_CD history_NN of_IN epigastric_JJ pain_NN with_IN two_CD episodes_NNS of_IN melena_NN upper_JJB gastrointestinal_JJ endoscopy_NN demonstrated_VBN a_AT duodenal_JJ ulcer_NN ; however_RB , no_ATI Helicobacter_NP pylori_NN was_BEDZ seen_VBN on_IN the_ATI biopsy_NN specimen_NN he_PP3A was_BEDZ treated_VBN with_IN ranitidine_NN pain_NN recurred_VBD when_WRB ranitidine_NN administration_NN was_BEDZ stopped_VBN despite_IN visits_NNS to_IN a_AT number_NN of_IN physicians_NNS , the_ATI diagnosis_NN of_IN Zollinger-Ellison_NP syndrome_NN (_( ZES_NP )_) was_BEDZ not_XNOT made_VBN until_IN 1_CD1 month_NN before_CS he_PP3A was_BEDZ referred_VBN to_IN the_ATI National_NP Institutes_NNS of_IN Health_NP (_( NIH_NP ) _) , when_WRB he_PP3A was_BEDZ found_VBN to_TO have_HV an_AT elevated_VBD fasting_NN gastrin_NN level_NN and_CC a_AT gastric_JJ pH_NN less_AP than_IN 2.5.=20_CD 78_CD fasting_NN gastrin_NN at_IN the_ATI NIH_NP was_BEDZ elevated_VBD at_IN 363_CD ng_L_NN (_( normal_JJ , {_( 100_CD ng_L_NN )_) , and_CC basal_JJ acid_NN output_NN (_( BAO_NP )_) was_BEDZ 46_CD mEq_h_NN (_( normal_JJ , {_( 10_CD mEq_h_NN )_) Results_NNS of_IN the_ATI secretin-provocative_JJ test_NN were_BED positive_JJ , with_IN a_AT baseline_NN value_NN of_IN 352_CD ng_L_JJ increasing_JJ to_IN 708_NP ng_L_NN at_IN 2_CD minutes_NNS after_IN secretin_NN injection_NN (_( normal_JJ increase_NN , {_( 200_CD ng_L_NN )_) ultrasonography_RB , computed_VBN tomographic_JJ (_( CT_NP )_) scan_NN , magnetic_JJ resonance_NN (_( MR_NP )_) imaging_VBG , and_CC angiography_NN failed_VBN to_TO identify_VB a_AT gastrinoma_NN portal_NN venous_JJ gastrin_NN sampling_NN did_DOD not_XNOT demonstrate_VB a_AT selective_JJ gastrin_NN gradient_NN , but_CC hepatic_JJ venous_JJ sampling_NN during_IN selective_JJ intra-arterial_JJ injection_NN of_IN secretin_NN showed_VBD a_AT significant_JJ increase_NN , from_IN 248_CD to_IN 1038_CD ng_L_NN , 30_CD seconds_NNS after_IN gastroduodenal_JJ artery_NN injection_NN (_( normal_JJ increase_NN , {_( 50%).=20_CD 79_CD acid_NN hypersecretion_NN was_BEDZ controlled_VBN with_IN omeprazole_NN (_( 60_CD mg_d_NN )_) there_EX was_BEDZ no_ATI history_NN or_CC laboratory_NN evidence_NN to_TO suggest_VB multiple_JJ endocrine_NN neoplasia_NN type_NN 1_CD1 (_( MEN-I_NP )_) at_IN surgery_NN , palpation_NN , intraoperative_JJ ultrasonography_NN , and_CC duodenal_JJ transillumination_NN were_BED normal_JJ , but_CC a_AT 0.4-cm_NP duodenal_JJ tumor_NN was_BEDZ found_VBN when_WRB a_AT duodenotomy_NN was_BEDZ performed_VBN a_AT peripancreatic_JJ lymph_NN node_NN was_BEDZ also_RB positive_JJ for_IN gastrinoma_NN Postoperatively_NP , the_ATI fasting_NN serum_NN gastrin_NN was_BEDZ normal_JJ , and_CC the_ATI secretin_NN test_NN was_BEDZ negative_JJ both_ABX have_HV remained_VBN normal_JJ for_IN 4_CD years_NNS continued_VBD mild_JJ gastric_JJ hypersecretion_NN (_( BAO_NP , 15_CD mEq_h_NN ) _) is_BEZ controlled_VBN with_IN ranitidine_NN (_( 300_CD mg_d_NN )_) 80_CD case_NN 2_CD 81_CD 7_CD a_AT 57-year-old_JJB woman_NN had_HVD a_AT 7-year_JJ history_NN of_IN abdominal_JJ pain_NN , diarrhea_NN , and_CC heartburn_NN six_CD years_NNS before_CS admission_NN , she_PP3A had_HVD a_AT vagotomy_NN for_IN refractory_JJ duodenal_JJ ulcer_NN disease_NN , and_CC ZES_NP was_BEDZ diagnosed_VBN 4_CD years_NNS later_RBR when_WRB she_PP3A was_BEDZ found_VBN to_TO have_HV hypergastrinemia_NN (_( }1000_CD ng_L_NN )_) , a_AT gastric_JJ pH_NN less_AP than_IN 2.5_CD , and_CC a_AT duodenal_JJ ulcer_NN at_IN admission_NN , her_PP$ fasting_NN gastrin_NN level_NN was_BEDZ elevated_VBD at_IN 4540_CD ng_L_NN (_( normal_JJ , {_( 100_CD ng_L_NN )_) and_CC BAO_NP was_BEDZ 15_CD mEq_h._NN acid_NN secretion_NN was_BEDZ controlled_VBN with_IN omeprazole_NN (_( 20_CD mg_NNU , twice_RB a_AT day).=20_CD 82_CD ultrasonography_RB , CT_NP scan_NN , and_CC angiography_NN demonstrated_VBN a_AT 6-cm_NN mass_NN in_IN the_ATI head_NN of_IN the_ATI pancreas_NNS ; in_IN addition_NN , MR_NP imaging_VBG suggested_VBN a_AP few_AP small_JJ liver_NN metastases_NNS comparison_NN with_IN previous_JJ imaging_NN suggested_VBN that_CS the_ATI pancreatic_JJ mass_NN was_BEDZ increasing_JJ in_IN size_NN the_ATI patient_NN had_HVD a_AT family_NN history_NN of_IN nephrolithiases_NNS and_CC had_HVD a_AT parathyroidectomy_NN 2_CD years_NNS before_CS admission_NN , which_WDTR revealed_VBD hyperplasia_NN of_IN all_ABN glands_NNS and_CC suggested_VBN that_CS ZES_NP was_BEDZ part_NN of_IN the_ATI MEN-I_NP syndrome_NN upper_JJB gastrointestinal_JJ endoscopy_NN demonstrated_VBN gastric_JJ and_CC duodenal_JJ nodules_NNS a_AT biopsy_NN specimen_NN from_IN one_CD1 of_IN the_ATI duodenal_JJ nodules_NNS showed_VBD a_AT neuroendocrine_NN tumor_NN that_CS stained_VBN positive_JJ for_IN gastrin_NN and_CC chromogranin_NN A.=20_NP 83_CD findings_NNS on_IN bone_NN scan_NN were_BED normal_JJ at_IN laparotomy_NN , multiple_JJ small_JJ (_( {_( 0.2_CD cm_NNU )_) nodules_NNS in_IN the_ATI liver_NN and_CC a_AT 5-cm_NN mass_NN in_IN the_ATI head_NN of_IN the_ATI pancreas_NNS were_BED seen_VBN histologically_RB , the_ATI liver_NN nodules_NNS were_BED metastatic_JJ gastrinoma_NN the_ATI metastases_NNS increased_VBN further_JJB in_IN size_NN and_CC the_ATI patient_NN has_HVZ been_BEN treated_VBN with_IN interferon_NN (_( 5_CD million_CD units_NNS per_NNU day_NN )_) for_IN the_ATI past_NN 2_CD years_NNS there_EX has_HVZ been_BEN no_ATI further_JJB growth_NN of_IN the_ATI metastases_NNS or_CC pancreatic_JJ tumor_NN 84_NN case_NN 1_CD1 demonstrates_VBZ that_CS , in_IN addition_NN to_IN abdominal_JJ pain_NN , diarrhea_NN and_CC esophageal_JJ complaints_NNS may_MD be_BE important_JJ early_JJ symptoms_NNS of_IN patients_NNS with_IN ZES_NP the_ATI imaging_NN results_NNS were_BED normal_JJ in_IN this_DT case_NN , as_CS in_IN 50%_NP of_IN patients_NNS the_ATI new_JJ functional_JJ localization_NN method_NN of_IN selective_JJ intra- arterial_JJ secretin_NN injection_NN with_IN hepatic_JJ venous_JJ sampling_NN was_BEDZ positive_JJ , even_RB though_IN the_ATI classical_JJ portal_NN venous_JJ sampling_NN for_IN a_AT gastrin_NN gradient_NN was_BEDZ negative_JJ prospective_JJ studies_NNS have_HV lately_RB demonstrated_VBN that_CS more_AP than_IN 50%_NP of_IN gastrinomas_NNS are_BER in_IN the_ATI duodenum_NN and_CC can_MD be_BE detected_VBN only_RB by_IN duodenotomy_NN , as_IN in_IN this_DT case_NN furthermore_RB , in_IN contrast_NN to_TO older_JJR studies_NNS , it_PP3 is_BEZ now_RN known_VBN that_CS duodenal_JJ gastrinomas_NNS are_BER as_CS frequently_RB malignant_JJ as_CS pancreatic_JJ tumors_NNS (_( this_DT patient_NN is_BEZ typical_JJ , with_IN a_AT metastatic_JJ lymph_NN node_NN found_VBN in_IN addition_NN to_IN the_ATI duodenal_JJ tumor_NN )_) Postoperatively_NP , both_ABX the_ATI secretin_NN test_NN and_CC fasting_NN gastrin_NN level_NN are_BER necessary_JJ to_TO determine_VB cure_NN (_( as_CS was_BEDZ done_VBN for_IN this_DT patient_NN )_) cure_NN is_BEZ reported_VBN in_IN 17%_CD to_TO 82%_NN of_IN patients_NNS immediately_RB after_IN surgery_NN and_CC in_IN 30%_NP up_RP to_IN 5_CD years_NNS later_RBR (_( Table_NP 1_CD1 )_) 85_CD case_NN 2_CD is_BEZ a_AT patient_NN with_IN ZES_NP and_CC MEN-I_NP with_IN metastatic_JJ gastrinoma_NN Studies_NP show_VB that_CS 20%_NP to_TO 25%_NN of_IN patients_NNS with_IN ZES_NP have_HV MEN-I_NP and_CC suggest_VB that_CS gastrinomas_NNS in_IN patients_NNS with_IN MEN-I_NP are_BER found_VBN frequently_RB in_IN the_ATI duodenum_NN this_DT patient_NN also_RB had_HVD a_AT tumor_JJ metastatic_JJ to_IN the_ATI liver_NN , as_CS occurs_VBZ in_IN 30%_NP of_IN patients_NNS with_IN ZES_NP at_IN diagnosis_NN the_ATI metastases_NNS were_BED suggested_VBN only_RB on_IN the_ATI MR_NP imaging_NN , a_AT finding_VBG consistent_JJ with_IN a_AT report_NN demonstrating_VBG that_CS the_ATI best_JJT noninvasive_JJ method_NN of_IN detecting_JJ liver_NN metastases_NNS in_IN patients_NNS with_IN ZES_NP is_BEZ MR_NP imaging_VBG .=20_CD 86_CD recent_JJ studies_NNS show_VB patients_NNS with_IN liver_NN metastases_NNS with_IN ZES_NP have_HV a_AT worse_JJR prognosis_NN than_IN previously_RB thought_VBD ; because_CS the_ATI metastases_NNS increased_VBN in_IN size_NN , the_ATI patient_NN was_BEDZ treated_VBN with_IN interferon_NN however_RB , there_EX was_BEDZ no_ATI decrease_NN in_IN tumor_NN size_NN or_CC progression_NN over_IN 2_CD years_NNS this_DT result_NN is_BEZ consistent_JJ with_IN a_AT study_NN demonstrating_VBG that_CS interferon_NN did_DOD not_XNOT decrease_NN tumor_NN size_NN in_IN any_DTI patients_NNS with_IN gastrinoma_JJ metastatic_JJ to_IN the_ATI liver_NN , although_CS in_IN 25%_NN of_IN patients_NNS the_ATI tumor_NN did_DOD not_XNOT increase_VB in_IN size_NN 87_CD newer_JJR data_NNS suggest_VB that_CS the_ATI differentiation_NN of_IN patients_NNS with_IN ZES_NP with_IN MEN-I_NP (_( familial_JJ form_NN )_) (_( case_NN 2_CD )_) from_IN those_DTS with_IN ZES_NP without_IN MEN-I_NP (_( sporadic_JJ form_NN )_) (_( case_NN 1_CD1 )_) is_BEZ more_QL difficult_JJ and_CC more_QL clinically_RB important_JJ than_IN previously_RB thought_NN patients_NNS with_IN MEN-I_NP develop_VB multiple_JJ endocrine_NN tumors_NNS with_IN hyperparathyroidism_NN occurring_VBG in_IN 88%_NN to_TO 97%_VB , pancreatic_JJ endocrine_NN tumors_NNS in_IN 81%_CD to_IN 100%_CD (_( of_IN which_WDTR nonfunctional_JJ or_CC pancreatic_JJ polypeptide-producing_NN tumors_NNS occur_VB in_IN 80%_NP to_IN 100%_CD )_) , gastrinomas_VBZ in_IN 54%_NN , insulinomas_NNS in_IN 21%_CD , pituitary_NN tumors_NNS in_IN 21%_CD to_TO 65%_VB , and_CC adrenal_JJ tumors_NNS in_IN 27%_NN to_IN 36%_CD previously_RB , it_PP3 was_BEDZ generally_RB felt_VBN that_CS the_ATI differentiation_NN between_IN the_ATI sporadic_JJ and_CC familial_JJ forms_NNS of_IN ZES_NP was_BEDZ not_XNOT difficult_JJ because_CS patients_NNS were_BED thought_VBN to_TO almost_RB always_RB develop_VB hyperparathyroidism_NN or_CC pituitary_NN disease_NN prior_RB to_IN developing_VBG a_AT functional_JJ pancreatic_JJ endocrine_NN tumor_NN .=20_CD 88_CD recent_JJ studies_NNS in_IN some_DTI patients_NNS with_IN MEN-I_NP demonstrate_VB that_CS either_DTX a_AT gastrinoma_NN (_( up_RP to_TO one_CD1 third_OD of_IN all_ABN familial_JJ ZES_NP cases_NNS in_IN one_CD1 study_NN )_) or_CC insulinoma_NN may_MD be_BE an_AT initial_JJ manifestation_NN of_IN the_ATI MEN- I_NP the_ATI differentiation_NN between_IN these_DTS two_CD forms_NNS of_IN ZES_NP is_BEZ important_JJ because_CS they_PP3AS may_MD differ_VB in_IN natural_JJ history_NN , need_NN for_IN family_NN screening_NN , difficulty_NN in_IN controlling_VBG the_ATI gastric_JJ acid_NN hypersecretory_NN state_NN , need_NN for_IN routine_NN exploratory_JJ laparotomy_NN for_IN cure_NN , and_CC the_ATI potential_JJ risk_NN of_IN developing_VBG a_AT gastric_JJ carcinoid_NN tumor_NN .=20_CD 89_CD because_CS of_IN the_ATI importance_NN of_IN identifying_VBG patients_NNS with_IN ZES_NP with_IN MEN-I_NP , all_ABN patients_NNS with_IN ZES_NP should_MD have_HV a_AT careful_JJ family_NN and_CC personal_JJ history_NN taken_VBN for_IN nephrolithiasis_NN , hyperparathyroidism_NN , or_CC disorders_NNS attributable_JJ to_TO pituitary_VB or_CC pancreatic_JJ endocrine_NN tumors_NNS ; however_RB , the_ATI history_NN is_BEZ usually_RB contributory_JJ in_IN only_RB 50%_NP of_IN patients_NNS therefore_RB , all_ABN patients_NNS with_IN ZES_NP also_RB need_NN assessment_NN of_IN parathyroid_NN function_NN (_( serum_NN calcium_NN and_CC plasma_NN parathormone_NN levels_NNS )_) , pituitary_NN function_NN (_( prolactin_NN measurements_NNS and_CC MR_NP imaging_VBG of_IN sella_NN turcica_NN )_) , and_CC adrenal_JJ status_NN (_( 24-hour_NN urinary_NN cortisol_NN )_) in_IN family_NN members_NNS , the_ATI minimum_NN screening_NN tests_NNS should_MD be_BE serum_NN calcium_NN levels_NNS and_CC , if_CS symptoms_NNS of_IN acromegaly_RB , peptic_JJ disease_NN , or_CC hypoglycemia_NN occur_VB , appropriate_JJ hormonal_JJ assays_NNS 90_CD case_NN 1_CD1 and_CC case_NN 2_CD demonstrate_VB the_ATI current_JJ long_JJ delay_NN (_( mean_VB , 6_CD years_NNS )_) in_IN establishing_VBG the_ATI diagnosis_NN of_IN ZES_NP in_IN the_ATI past_NN , the_ATI disease_NN was_BEDZ suspected_VBN in_IN any_DTI patients_NNS with_IN nonhealing_VBG peptic_JJ ulcers_NNS , ulcers_NNS in_IN unusual_JJ locations_NNS , gastric_JJ acid_NN hypersecretion_NN with_IN hypergastrinemia_NN , the_ATI presence_NN of_IN prominent_JJ gastric_JJ folds_NNS , recurrent_JJ ulcer_NN after_IN surgery_NN , a_AT familial_JJ history_NN of_IN peptic_JJ ulcer_NN , or_CC peptic_JJ ulcers_NNS with_IN other_AP endocrine_NN disorders_NNS it_PP3 still_RB should_MD be_BE strongly_RB suspected_VBN in_IN these_DTS situations_NNS , but_CC ZES_NP also_RB should_MD be_BE suspected_VBN in_IN patients_NNS with_IN duodenal_JJ ulcer_NN without_IN H_ZZ pylori_NN , as_IN in_IN case_NN 1_CD1 , because_CS only_RB 50%_NP of_IN patients_NNS with_IN ZES_NP with_IN duodenal_JJ ulcer_NN have_HV H_ZZ pylori_NN , whereas_CS more_AP than_IN 90%_NP of_IN patients_NNS with_IN idiopathic_JJ ulcer_NN disease_NN have_HV H_ZZ pylori_NN infection_NN .=20_CD 91_CD once_RB ZES_NP is_BEZ suspected_VBN clinically_RB , fasting_NN gastrin_NN levels_NNS should_MD be_BE determined_JJ as_QL well_RB as_IN gastric_JJ pH_NN it_PP3 is_BEZ important_JJ to_TO measure_VB both_ABX , not_XNOT only_RB to_TO exclude_VB achlorhydria_NN , but_CC also_RB because_CS in_IN individual_JJ patients_NNS there_EX may_MD be_BE a_AT poor_JJ correlation_NN between_IN these_DTS two_CD parameters_NNS if_CS fasting_NN gastrin_NN is_BEZ greater_JJR than_IN 1000_CD ng_L_NN and_CC the_ATI pH_NN is_BEZ less_AP than_IN 2.5_CD , the_ATI patient_NN almost_RB certainly_RB has_HVZ ZES_NP , as_IN in_IN case_NN 2_CD if_CS the_ATI fasting_NN gastrin_NN is_BEZ elevated_VBD but_CC less_AP than_IN 1000_CD ng_L_NN , as_IN in_IN case_NN 1_CD1 (_( which_WDTR occurs_VBZ in_IN 60%_NP of_IN patients_NNS with_IN ZES_NP )_) , acid_NN secretory_NN rate_NN and_CC a_AT secretin-provocative_JJ test_NN should_MD be_BE done_VBN eighty-seven_CD percent_NNU of_IN patients_NNS with_IN ZES_NP will_MD have_HV a_AT positive_JJ secretin_NN test_NN and_CC more_AP than_IN 90%_NP will_MD have_HV a_AT BAO_NP greater_JJR than_IN 15_CD mEq_h_NN if_CS no_ATI previous_JJ gastric_JJ surgery_NN was_BEDZ done_VBN (_( as_IN in_IN case_NN 1_CD1 )_) or_CC greater_JJR than_IN 5_CD mEq_h_NN if_CS a_AT previous_JJ gastric_JJ resection_NN or_CC vagotomy_NN was_BEDZ done_VBN (_( as_IN in_IN case_NN 2_CD )_) 92_CD IMPORTANCE_NPT OF_NPT RECENT_NPT ADVANCES_NPT IN_NPT PATIENTS_NPT WITH_NP ZES_NP 93_CD in_IN 1955_CD , Zollinger_NP and_CC Ellison_NP described_VBD two_CD patients_NNS with_IN extreme_JJ gastric_JJ acid_NN hypersecretion_NN , refractory_JJ peptic_JJ ulcer_NN disease_NN and_CC a_AT non-beta_NN islet_NN cell_NN tumor_NN of_IN the_ATI pancreas_NNS subsequently_RB , this_DT syndrome_NN was_BEDZ shown_VBN to_TO be_BE attributable_JJ to_IN autonomous_JJ release_NN of_IN gastrin_NN by_IN the_ATI tumor_NN this_DT syndrome_NN , subsequently_RB called_VBN the_ATI Zollinger-Ellison_NP syndrome_NN , was_BEDZ the_ATI second_OD pancreatic_JJ endocrine_NN tumor_NN syndrome_NN described_VBN after_IN insulinomas_NNS in_IN 1927_CD studies_NNS demonstrate_VB that_CS pancreatic_JJ endocrine_NN tumors_NNS are_BER uncommon_JJ (_( only_RB four_CD new_JJ cases_NNS per_NNU 1_CD1 million_CD population_NN per_NNU year_NN )_) gastrinomas_NNS , pancreatic_JJ polypeptide-producing_NN islet_NN cell_NN tumors_NNS (_( PPomas_NP )_) , and_CC insulinomas_NNS are_BER equally_RB common_JJ and_CC are_BER eight_CD times_NNS more_QL common_JJ than_IN pancreatic_JJ islet_NN G-cell_NP tumors_NNS (_( VIPomas_NP )_) , 17_CD times_NNS more_QL common_JJ than_IN glucagonomas_NNS , and_CC more_AP than_IN 100_CD times_NNS more_QL common_JJ than_IN somatostatinomas_NNS .=20_CD 94_CD Zollinger-Ellison_NP syndrome_NN was_BEDZ the_ATI first_OD pancreatic_JJ endocrine_NN tumor_NN syndrome_NN described_VBN in_IN which_WDTR the_ATI majority_NN of_IN the_ATI patients_NNS had_HVD a_AT malignant_JJ tumor_NN subsequent_JJ studies_NNS have_HV demonstrated_VBN that_CS almost_RB all_ABN of_IN the_ATI clinical_JJ symptoms_NNS patients_NNS with_IN ZES_NP develop_VB , except_CS for_IN those_DTS due_JJ to_TO advanced_JJ metastatic_JJ tumors_NNS late_RB in_IN the_ATI course_NN of_IN the_ATI disease_NN , are_BER attributable_JJ to_IN the_ATI profound_JJ gastric_JJ acid_NN hypersecretion_NN patients_NNS with_IN ZES_NP have_HV two_CD treatment_NN issues_NNS that_DT must_MD be_BE addressed_VBN first_OD , therapy_NN must_MD be_BE directed_VBN initially_RB and_CC over_IN the_ATI long_JJ term_NN at_IN controlling_VBG the_ATI symptoms_NNS caused_VBN by_IN the_ATI autonomous_JJ release_NN of_IN the_ATI hormone_NN by_IN the_ATI tumor_NN Second_NP , therapy_NN must_MD be_BE directed_VBN against_IN the_ATI tumor_NN itself.=20_CD 95_CD in_IN patients_NNS with_IN ZES_NP , gastric_JJ acid_NN hypersecretion_NN was_BEDZ initially_RB treated_VBN satisfactorily_RB only_RB by_IN total_JJ gastrectomy_NN however_RB , almost_RB all_ABN patients_NNS can_MD now_RN be_BE treated_VBN medically_RB studies_NNS have_HV provided_VBN information_NN on_IN subsets_NNS of_IN patients_NNS who_WPR require_VB higher_JJR drug_NN doses_NNS , on_IN effective_JJ drug_NN regimens_NNS when_WRB parenteral_JJ dosing_NN is_BEZ required_VBN , on_IN drug_NN dosing_NN after_IN tumor_NN resection_NN , and_CC on_IN identifying_VBG subsets_NNS of_IN patients_NNS who_WPR require_VB lower_JJR doses_NNS of_IN antisecretory_NN drugs_NNS than_IN generally_RB recommended_VBN With_NP the_ATI increased_JJ ability_NN to_TO control_VB gastric_JJ acid_NN hypersecretion_NN , the_ATI progression_NN of_IN the_ATI tumor_NN is_BEZ becoming_VBG the_ATI primary_JJ determinant_NN of_IN long-term_JJB survival_NN 96_CD increased_JJ understanding_NN of_IN the_ATI natural_JJ history_NN of_IN ZES_NP and_CC the_ATI development_NN of_IN improved_JJ treatment_NN methods_NNS have_HV broad_JJ implications_NNS beyond_IN the_ATI disease_NN there_EX is_BEZ increasing_JJ concern_NN over_IN the_ATI possible_JJ long-term_JJB effects_NNS of_IN hypergastrinemia_NN , and_CC ZES_NP is_BEZ an_AT excellent_JJ model_NN for_IN studying_VBG this_DT question_NN for_IN example_NN , patients_NNS with_IN advanced_JJ idiopathic_JJ reflux_NN disease_NN require_VB continuous_JJ treatment_NN with_IN omeprazole_NN , and_CC most_QL will_MD develop_VB mild_JJ hypergastrinemia_NN in_IN some_DTI cases_NNS , however_RB , gastrin_NN levels_NNS will_MD be_BE in_IN the_ATI range_NN seen_VBN in_IN patients_NNS with_IN ZES_NP whereas_CS duodenal_JJ ulcer_NN disease_NN now_RN may_MD be_BE curable_VBN by_IN eradication_NN of_IN H_ZZ pylori_NN , advanced_JJ reflux_NN disease_NN is_BEZ a_AT common_JJ disorder_NN and_CC is_BEZ not_XNOT curable_JJ ; therefore_RB , a_AT significant_JJ number_NN of_IN patients_NNS will_MD require_VB long-term_JJB omeprazole_NN treatment_NN long-term_JJB treatment_NN with_IN omeprazole_NN or_CC other_AP means_NNS of_IN inducing_VBG prolonged_JJ hypergastrinemia_NN results_NNS in_IN gastric_JJ carcinoid_NN tumors_NNS in_IN rats_NNS , and_CC some_DTI of_IN these_DTS tumors_NNS are_BER malignant_JJ .=20_CD 97_CD in_IN addition_NN , some_DTI experimental_JJ studies_NNS in_IN isolated_JJ cells_NNS and_CC in_IN animals_NNS , but_CC not_XNOT epidemiologic_JJ studies_NNS in_IN humans_NNS , suggest_VB that_CS hypergastrinemia_NN may_MD affect_VB the_ATI growth_NN of_IN some_DTI cancers_NNS of_IN the_ATI colon_NN and_CC stomach_NN some_DTI studies_NNS have_HV reported_VBN higher_JJR fasting_NN and_or_CC postprandial_JJ serum_NN gastrin_NN levels_NNS in_IN patients_NNS with_IN colon_NN polyps_NNS or_CC cancers_NNS ; others_APS have_HV not_XNOT furthermore_RB , an_AT increase_NN in_IN in_RB vivo_RB colonic_JJ cell_NN proliferation_NN has_HVZ recently_RB been_BEN reported_VBN in_IN patients_NNS with_IN ZES_NP because_CS of_IN the_ATI delay_NN in_IN diagnosis_NN , almost_RB all_ABN patients_NNS with_IN ZES_NP have_HV evidence_NN of_IN chronic_JJ hypergastrinemic_JJ changes_NNS in_IN the_ATI stomach_NN when_WRB first_OD seen_VBN also_RB , only_RB 30%_NP of_IN patients_NNS are_BER cured_VBN long_JJ term_NN (_( discussed_VBN hereinafter_RB )_) , hence_RB most_QL patients_NNS will_MD have_HV life-long_JJ profound_JJ hypergastrinemia_NN therefore_RB , ZES_NP provides_VBZ an_AT excellent_JJ natural_JJ model_NN to_TO study_VB the_ATI possible_JJ long-term_JJB risks_NNS of_IN prolonged_JJ hypergastrinemia_NN 98_NN studying_VBG patients_NNS with_IN gastrinomas_NNS may_MD lead_VB to_IN insights_NNS that_DT will_MD apply_VB to_IN the_ATI treatment_NN of_IN the_ATI other_AP , less_QL common_JJ malignant_JJ pancreatic_JJ endocrine_NN tumors_NNS gastrinoma_RB , in_IN contrast_NN to_TO insulinoma_VB , resembles_VBZ the_ATI other_AP less_QL common_JJ tumors_NNS in_IN frequently_RB being_BEG malignant_JJ in_IN older_JJR studies_NNS , 60%_NP to_IN 90%_NP of_IN patients_NNS with_IN gastrinomas_NNS had_HVD metastatic_JJ disease_NN similar_JJ to_IN the_ATI other_AP less-common_NN tumors_NNS ; at_IN present_NN , 34%_CD of_IN patients_NNS have_HV metastatic_JJ disease_NN at_IN diagnosis_NN , and_CC the_ATI percentage_NN developing_VBG metastases_NNS with_IN time_NN is_BEZ unclear_JJ gastrinoma_NN resembles_VBZ the_ATI other_AP tumors_NNS in_IN its_PP$ histology_NN , ability_NN to_TO secrete_VB multiple_JJ peptides_NNS , and_CC patterns_NNS of_IN metastatic_JJ spread_NN .=20_CD 99_CD further_JJB , gastrinoma_NN is_BEZ being_BEG increasingly_RB diagnosed_VBN earlier_RBR Therefore_NP , patients_NNS are_BER seen_VBN before_CS metastatic_JJ spread_NN occurs_VBZ , thereby_RB allowing_VBG the_ATI assessment_NN of_IN methods_NNS to_TO localize_VB smaller_JJR gastrinomas_NNS These_NP results_NNS will_MD likely_JJ be_BE applicable_JJ to_IN the_ATI less- common_NN tumors_NNS if_CS they_PP3AS can_MD be_BE diagnosed_VBN earlier_RBR 100_CD 26_CD also_RB , medical_JJ therapies_NNS such_IN as_IN octreotide_NN are_BER less_QL successful_JJ for_IN the_ATI other_AP less-common_JJ pancreatic_JJ endocrine_NN tumors_NNS and_CC , therefore_RB , long-term_JJB follow-up_NN and_CC information_NN on_IN the_ATI natural_JJ history_NN of_IN these_DTS tumors_NNS is_BEZ limited_JJ in_IN contrast_NN , there_EX is_BEZ effective_JJ long-term_JJB treatment_NN for_IN gastric_JJ hypersecretion_NN in_IN ZES_NP (_( described_VBN hereinafter_RB )_) therefore_RB , it_PP3 is_BEZ likely_JJ that_CS studying_VBG gastrinoma_NN will_MD lead_VB to_IN the_ATI collection_NN of_IN excellent_JJ data_NNS that_DT will_MD likely_JJ be_BE applicable_JJ to_TO other_AP less-common_NN malignant_JJ pancreatic_JJ endocrine_NN tumors_NNS conclusions_NNS from_IN recent_JJ prospective_JJ studies_NNS (_( reviewed_VBN hereinafter_RB )_) are_BER already_RB changing_VBG a_AT number_NN of_IN the_ATI widely_RB held_JJ conclusions_NNS about_IN ZES_NP that_CS have_HV been_BEN used_VBN for_IN clinical_JJ decisions_NNS , but_CC were_BED based_VBN on_IN small_JJ numbers_NNS of_IN cases_NNS these_DTS include_VB the_ATI prognosis_NN of_IN patients_NNS with_IN advanced_JJ metastatic_JJ disease_NN , location_NN of_IN primary_JJ tumors_NNS , ability_NN to_TO cure_VB , and_CC effectiveness_NN of_IN medical_JJ therapies_NNS 101_CD 27_CD TREATMENT_NPT OF_NPT THE_NPT GASTRIC_NPT HYPERSECRETORY_NP STATE_NP 102_CD 28_CD older_JJR studies_NNS reported_VBN variable_NN results_NNS for_IN histamine_NN H_ZZ sub_NN 2_CD -blockers_NNS in_IN controlling_VBG gastric_JJ hypersecretion_NN in_IN patients_NNS with_IN ZES_NP More_NP recent_JJ studies_NNS demonstrate_VB that_CS it_PP3 is_BEZ possible_JJ to_TO control_VB acid_NN secretion_NN in_IN most_QL patients_NNS only_RB if_CS enough_QLP antisecretory_NN drug_NN is_BEZ used_VBN to_TO inhibit_VB acid_NN secretion_NN to_IN less_AP than_IN 10_CD mEq_h_NN for_IN the_ATI hour_NN before_IN the_ATI next_AP dose_NN this_DT level_NN of_IN control_NN required_VBN high_JJ dosages_NNS (_( mean_VB dosage_NN , 3_CD g_ZZ of_IN ranitidine_CD per_NNU day_NN )_) , frequent_JJ dosing_NN (_( every_AT 4_CD to_IN 6_CD hours_NNS )_) , and_CC yearly_JJ increases_NNS in_IN dosage_NN in_IN patients_NNS with_IN complicated_JJ ZES_NP (_( ZES_NP with_IN previous_JJ gastric_JJ surgery_NN , with_IN esophageal_JJ reflux_NN disease_NN , or_CC with_IN MEN-I_NP )_) , it_PP3 was_BEDZ often_RB difficult_JJ to_TO eliminate_VB all_ABN mucosal_JJ disease_NN with_IN the_ATI availability_NN of_IN the_ATI hydrogen_potassium_NN adenosine_NN triphosphatase_NN inhibitors_NNS omeprazole_NN and_CC lansoprazole_NN , acid_NN secretion_NN can_MD be_BE controlled_VBN in_IN all_ABN patients_NNS (_( Table_NP 2).=20_CD 103_CD 29_CD omeprazole_NN and_CC lansoprazole_NN have_HV a_AT prolonged_JJ duration_NN of_IN action_NN in_IN patients_NNS with_IN ZES_NP (_( half-life_NN , 35_CD to_IN 37_CD hours_NNS )_) ; hence_RB , dosing_NN once_RB a_AT day_NN is_BEZ possible_JJ for_IN most_QL patients_NNS (_( 70%_NP )_) , and_CC twice_RB a_AT day_NN is_BEZ sufficient_JJ for_IN the_ATI remainder_NN the_ATI median_JJ dosages_NNS were_BED 60_CD to_IN 100_CD mg_NNU of_IN omeprazole_NN per_NNU day_NN and_CC 60_CD to_IN 90_CD mg_NNU of_IN lansoprazole_CD per_NNU day_NN patients_NNS with_IN complicated_JJ ZES_NP more_QL frequently_RB require_VB dosing_NN twice_RB a_AT day_NN with_IN omeprazole_NN , it_PP3 has_HVZ been_BEN possible_JJ to_IN heal_JJ anastomotic_JJ ulcers_NNS in_IN patients_NNS with_IN previous_JJ gastric_JJ surgery_NN and_CC to_TO eliminate_VB all_ABN esophageal_JJ disease_NN However_NP , in_IN some_DTI patients_NNS , sufficient_JJ omeprazole_NN may_MD have_HV to_TO be_BE given_VBN to_TO reduce_VB gastric_JJ hypersecretion_NN to_TO less_AP than_IN 1_CD1 mEq_h_NN patients_NNS with_IN ZES_NP have_HV now_RN been_BEN treated_VBN continuously_RB with_IN omeprazole_NN for_IN up_RP to_IN 9_CD years_NNS without_IN evidence_NN of_IN tachyphylaxis_NN or_CC drug-related_JJ toxicity_NN 104_CD 30_CD research_NN has_HVZ demonstrated_VBN that_CS the_ATI currently_RB recommended_VBN maintenance_NN dosages_NNS of_IN omeprazole_NN and_CC lansoprazole_NN (_( 60_CD to_IN 100_CD mg_d_NN )_) are_BER too_QL high_JJ for_IN many_AP patients_NNS with_IN ZES_NP in_IN a_AT recent_JJ study_NN involving_VBG 37_CD patients_NNS with_IN ZES_NP , the_ATI omeprazole_NN maintenance_NN doses_NNS were_BED successfully_RB reduced_VBN to_IN 20_CD to_IN 40_CD mg_NNU per_IN day_NN in_IN 20_CD (_( 95%_JJ )_) of_IN the_ATI 21_CD patients_NNS without_IN complicated_JJ disease_NN (_( such_IN as_IN MEN-I_NP , moderate-to-severe_JJ esophageal_JJ disease_NN , or_CC gastric_JJ surgery_NN )_) taking_VBG the_ATI drug_NN once_RB or_CC twice_RB a_AT day_NN this_DT reduction_NN was_BEDZ possible_JJ in_IN only_RB 25%_JJ of_IN patients_NNS with_IN complicated_JJ disease_NN (_( P{.01).=20_CD 105_CD 31_CD currently_RB , it_PP3 is_BEZ recommended_VBN that_CS patients_NNS be_BE started_VBN on_IN higher_JJR doses_NNS (_( ie_NN , at_RB least_RB 60_CD mg_d_NN )_) , with_IN the_ATI initial_JJ dosing_NN established_VBN by_IN titration_NN studies_NNS and_CC then_RN the_ATI daily_JJ dose_NN reduced_VBN in_IN patients_NNS with_IN uncomplicated_JJ disease_NN for_IN a_AT number_NN of_IN reasons_NNS omeprazole_NN is_BEZ acid_JJ labile_NN , and_CC high_JJ levels_NNS of_IN acid_NN secretion_NN may_MD alter_VB the_ATI effectiveness_NN of_IN low_JJ doses_NNS patients_NNS are_BER frequently_RB severely_RB ill_JJ when_WRB the_ATI diagnosis_NN of_IN ZES_NP is_BEZ made_VBN , and_CC it_PP3 is_BEZ important_JJ that_CS the_ATI high_JJ acid_NN secretion_NN be_BE rapidly_RB controlled_VBN no_ATI data_NNS show_NN that_CS low-dose_NN omeprazole_NN is_BEZ equally_RB effective_JJ as_IN the_ATI currently_RB used_VBN high_JJ doses_NNS in_IN the_ATI initial_JJ setting_NN 106_CD 32_CD patients_NNS with_IN ZES_NP frequently_RB require_VB parenteral_JJ gastric_JJ antisecretory_NN therapy_NN at_IN some_DTI time_NN during_IN the_ATI course_NN of_IN their_PP$ disease_NN Although_NP intermittent_JJ bolus_JJ injection_NN of_IN omeprazole_NN is_BEZ highly_RB effective_JJ , it_PP3 is_BEZ not_XNOT available_JJ in_IN the_ATI United_NP States_NP studies_NNS show_VB that_CS continuous_JJ infusions_NNS of_IN either_DTX ranitidine_NN or_CC cimetidine_NN are_BER highly_RB effective_JJ in_IN controlling_VBG gastric_JJ hypersecretion_NN the_ATI median_JJ dosage_NN found_VBN effective_JJ was_BEDZ 3_CD mg_NNU of_IN cimetidine_CD per_NNU kilogram_NN of_IN body_NN weight_NN per_NNU hour_NN (_( range_NN , 1_CD1 to_IN 6_CD mg_NNU )_) or_CC 1_CD1 mg_NNU of_IN ranitidine_CD per_NNU kilogram_NN per_NNU hour_NN (_( range_NN , 0.5_CD to_IN 3_CD mg_NNU )_) Patients_NP have_HV been_BEN treated_VBN for_IN up_RP to_IN 81_CD days_NNS without_IN any_DTI dose-related_JJ side_NN effects_NNS 107_CD 33_CD LONG-TERM_NPT EFFECTS_NPT AND_NPT RISKS_NPT OF_NPT HYPERGASTRINEMIA_NPT ON_NPT THE_NP GASTRIC_NP MUCOSA_NP 108_CD 34_CD studies_NNS of_IN patients_NNS with_IN ZES_NP are_BER providing_VBG information_NN on_IN the_ATI course_NN and_CC magnitude_NN of_IN changes_NNS in_IN the_ATI gastric_JJ mucosa_NN caused_VBN by_IN chronic_JJ hypergastrinemia_NN patients_NNS with_IN ZES_NP have_HV thickened_VBN gastric_JJ mucosa_NN , increased_JJ numbers_NNS of_IN parietal_JJ cells_NNS and_CC a_AT twofold_JJ to_IN threefold_JJ increase_NN in_IN enterochromaffinlike_NN cells_NNS (_( ECL_NP cells_NNS )_) the_ATI mean_NN delay_NN in_IN diagnosing_VBG ZES_NP is_BEZ 6_CD years_NNS ; thus_RB , it_PP3 is_BEZ often_RB unclear_JJ when_WRB the_ATI disease_NN first_OD started_VBD in_IN a_AT given_JJ patient_NN , and_CC the_ATI onset_NN of_IN changes_NNS is_BEZ difficult_JJ to_TO determine_VB However_NP , the_ATI time_NN course_NN of_IN the_ATI reversal_NN of_IN these_DTS changes_NNS in_IN patients_NNS cured_VBN of_IN their_PP$ gastrinoma_NN was_BEDZ recently_RB assessed_VBN by_IN examining_VBG BAO_NP and_CC maximal_JJ acid_NN output_NN (_( MAO_NP )_) at_IN different_JJ postoperative_JJ times.=20_CD 109_CD 35_CD changes_NNS in_IN the_ATI MAO_NP have_HV been_BEN shown_VBN to_TO correlate_VB with_IN changes_NNS in_IN parietal_JJ cell_NN mass_NN basal_JJ acid_NN output_NN and_CC MAO_NP decreased_VBD 75%_NN and_CC 40%_NP , respectively_RB , by_IN 3_CD to_IN 6_CD months_NNS after_IN surgery_NN and_CC then_RN remained_VBD unchanged_JJ for_IN up_RP to_IN 4_CD years_NNS these_DTS results_NNS demonstrate_VB that_CS the_ATI trophic_JJ changes_NNS are_BER rapidly_RB reversible_JJ about_IN 60%_NP of_IN the_ATI patients_NNS continued_VBD mild_JJ gastric_JJ acid_NN hypersecretion_NN for_IN up_RP to_IN 4_CD years_NNS after_IN curative_JJ resection_NN , and_CC 60%_NP require_VB continued_VBD low_JJ doses_NNS of_IN gastric_JJ antisecretory_NN drugs_NNS 110_CD 36_CD at_IN present_NN , it_PP3 is_BEZ not_XNOT established_VBN that_CS the_ATI long- term_JJB changes_NNS in_IN the_ATI gastric_JJ mucosa_NN and_CC long-term_JJB risks_NNS of_IN chronic_JJ hypergastrinemia_NN in_IN the_ATI achlorhydric_JJ stomach_NN are_BER the_ATI same_AP as_CS those_DTS in_IN the_ATI hyperacidic_JJ stomach_NN of_IN patients_NNS with_IN ZES_NP however_RB , similar_JJ to_IN patients_NNS with_IN pernicious_JJ anemia_NN , patients_NNS with_IN ZES_NP have_HV increased_JJ numbers_NNS of_IN ECL_NP cells_NNS and_CC both_ABX types_NNS of_IN patients_NNS have_HV an_AT increased_JJ risk_NN of_IN developing_VBG gastric_JJ carcinoid_NN tumors_NNS numerous_JJ studies_NNS now_RN demonstrate_VB that_CS the_ATI risk_NN of_IN chronic_JJ hypergastrinemia_NN causing_VBG a_AT gastric_JJ carcinoid_NN tumor_NN (_( ECLoma_NP )_) is_BEZ related_VBN to_TO whether_CS the_ATI patient_NN also_RB has_HVZ MEN-I_NP .=20_CD 111_CD 37_CD in_IN patients_NNS with_IN ZES_NP without_IN MEN-I_NP , fundic_JJ argyrophilic_JJ cells_NNS showed_VBD a_AT normal_JJ pattern_NN in_IN 16%_CD , diffuse_NN pattern_NN in_IN 71%_CD , and_CC linear_JJ hyperplasia_NN in_IN 13%_CD in_IN patients_NNS with_IN ZES_NP with_IN MEN-I_NP , diffuse_NN hyperplasia_NN occurred_VBD in_IN 53%_CD and_CC linear_JJ hyperplasia_NN in_IN 47%_NN 112_CD 38_CD the_ATI availability_NN of_IN potent_JJ gastric_JJ acid_NN antisecretory_NN agents_NNS has_HVZ changed_VBN this_DT situation_NN studies_NNS of_IN 200_CD patients_NNS with_IN intact_JJ stomachs_NNS followed_VBN up_RP at_IN NIH_NP for_IN up_RP to_IN 18_CD years_NNS have_HV reported_VBN that_CS 0.6%_NP of_IN patients_NNS without_IN MEN-I_NP had_HVD a_AT gastric_JJ carcinoid_NN tumor_NN and_CC 13%_CD of_IN patients_NNS who_WPR had_HVD ZES_NP with_IN MEN-I_NP developed_VBD such_ABL a_AT tumor_NN these_DTS data_NNS are_BER similar_JJ to_TO research_NN reported_VBN by_IN Lehy_NP et_&FW al_APS involving_VBG 48_CD patients_NNS with_IN ZES_NP in_IN which_WDTR 30%_NP of_IN patients_NNS who_WPR had_HVD ZES_NP and_CC MEN- I_NP and_CC 0%_NP who_WPR did_DOD not_XNOT have_HV MEN-I_NP developed_VBN gastric_JJ carcinoid_NN tumors_NNS these_DTS data_NNS demonstrate_VB that_CS genetic_JJ factors_NNS are_BER important_JJ in_IN determining_VBG the_ATI risk_NN of_IN developing_VBG a_AT gastric_JJ ECLoma.=20_CD 113_CD 39_CD in_IN a_AT patient_NN with_IN ZES_NP without_IN MEN-I_NP , the_ATI risk_NN appears_VBZ to_TO be_BE low_JJ , whereas_CS in_IN patients_NNS who_WPR have_HV ZES_NP with_IN MEN-I_NP , it_PP3 increases_NNS more_AP than_IN 20-_NP to_IN 30- fold_NP recent_JJ genetic_JJ studies_NNS show_VB allelic_JJ losses_NNS on_IN chromosome_NN 11q13_CD in_IN parathyroid_NN and_CC pancreatic_JJ tumors_NNS of_IN patients_NNS with_IN MEN-I_NP , suggesting_VBG that_CS the_ATI MEN-I_NP gene_NN functions_NNS as_IN a_AT tumor-suppressor_NN gene_NN Loss_NN of_IN heterozygosity_NN in_IN an_AT ECLoma_NP from_IN a_AT patient_NN who_WPR had_HVD ZES_NP and_CC MEN-I_NP has_HVZ recently_RB been_BEN reported_VBN this_DT finding_VBG suggests_VBZ that_CS , in_IN patients_NNS with_IN ZES_NP with_IN MEN-I_NP , gastric_JJ ECLomas_NP also_RB result_NN from_IN the_ATI inactivation_JJ of_IN two_CD copies_NNS of_IN the_ATI MEN-I_NP gene_NN and_CC provides_VBZ direct_JJ evidence_NN of_IN the_ATI genetic_JJ contribution_NN to_IN gastric_JJ ECLomas_NP 114_CD 40_CD ADVANCES_NPT IN_NPT TREATMENT_NPT OF_NPT THE_NP GASTRINOMA_NP 115_CD 41_CD in_IN older_JJR studies_NNS , 60%_NP to_IN 70%_NP of_IN patients_NNS treated_VBN with_IN total_JJ gastrectomy_NN to_TO control_VB acid_NN secretion_NN eventually_RB died_VBD from_IN the_ATI tumor_NN Further_NP , the_ATI prognosis_NN is_BEZ directly_RB related_VBN to_IN the_ATI spread_NN of_IN the_ATI tumor_NN Patients_NP with_IN liver_NN metastases_NNS have_HV only_RB a_AT 20%_NP to_IN 30%_NP chance_NN of_IN surviving_JJ for_IN 5_CD years_NNS , whereas_CS patients_NNS without_IN liver_NN metastases_NNS have_HV an_AT excellent_JJ long- term_JJB prognosis_NN (_( }90%_NP 5-year_NN survival_NN rate_NN )_) at_IN present_NN , approximately_RB 30%_NP of_IN patients_NNS with_IN ZES_NP present_JJ with_IN liver_NN metastases_NNS The_NP percentage_NN of_IN patients_NNS who_WPR do_DO not_XNOT initially_RB have_HV liver_NN metastases_NNS who_WPR will_MD develop_VB liver_NN metastases_NNS over_IN a_AT 5-_NN or_CC 10-year_CD-CD period_NN is_BEZ currently_RB unknown.=20_CD 116_CD 42_CD gastrinomas_NNS release_NN increased_JJ amounts_NNS of_IN gastrin_NN precursors_NNS including_IN progastrin_NN , NH_NP sub_NN 2_CD terminal_JJ and_CC COOH_NP terminal_JJ gastrin_NN fragments_NNS , chromogranin_NN , numerous_JJ other_AP gastrointestinal_JJ hormones_NNS , and_CC alpha-_NN and_CC beta- subunits_NNS of_IN human_JJ chorionic_JJ gonadotropin_NN , and_CC none_PN have_HV proved_VBN to_TO adequately_RB predict_VB which_WDTR gastrinomas_VBZ will_MD metastasize_VB about_IN 20%_NP to_IN 30%_NP of_IN patients_NNS with_IN ZES_NP also_RB have_HV MEN-I_NP , and_CC research_NN suggests_VBZ that_CS , contrary_NN to_IN earlier_RBR reports_NNS , these_DTS patients_NNS may_MD not_XNOT have_HV a_AT lower_JJR rate_NN of_IN metastatic_JJ disease_NN 117_CD 43_CD patients_NNS who_WPR have_HV ZES_NP with_IN MEN-I_NP have_HV multiple_JJ microadenomas_NNS throughout_IN the_ATI pancreas_NNS in_IN addition_NN to_IN some_DTI larger_JJR tumors_NNS ; thus_RB , until_CS recently_RB it_PP3 was_BEDZ thought_VBN that_CS they_PP3AS could_MD not_XNOT be_BE cured_VBN by_IN simple_JJ gastrinoma_NN enucleation_NN Pipeleers-Marichal_NP et_&FW al_APS found_VBN all_ABN of_IN the_ATI gastrinomas_NNS in_IN their_PP$ patients_NNS were_BED in_IN the_ATI duodenum_NN and_CC raised_VBD the_ATI possibility_NN , therefore_RB , that_CS the_ATI disease_NN could_MD be_BE surgically_RB cured_VBN These_NP results_NNS suggest_VB the_ATI importance_NN of_IN developing_VBG effective_JJ treatment_NN directed_VBN against_IN the_ATI gastrinoma_NN in_IN patients_NNS who_WPR have_HV ZES_NP with_IN and_CC without_RI MEN-I._NP in_IN contrast_NN to_IN 10_CD years_NNS ago_RB , most_QL authorities_NNS currently_RB recommend_VB that_CS all_ABN patients_NNS with_IN ZES_NP without_IN MEN-I_NP (_( and_CC without_IN other_AP diseases_NNS that_DT would_MD contraindicate_VB surgery_NN )_) should_MD undergo_VB tumor_VB localization_NN studies_NNS and_CC be_BE considered_VBN for_IN exploratory_JJ laparotomy_NN it_PP3 is_BEZ currently_RB unproven_JJ that_CS surgical_JJ resection_NN decreases_VBZ the_ATI rate_NN of_IN development_NN of_IN metastatic_JJ disease_NN or_CC improves_VBZ survival.=20_CD 118_CD 44_CD however_RB , because_CS the_ATI risk_NN of_IN developing_VBG metastatic_JJ disease_NN is_BEZ unknown_JJ and_CC the_ATI risk_NN of_IN surgery_NN by_IN experienced_JJ surgeons_NNS is_BEZ low_JJ (_( mortality_NN , 0%_NP in_IN 100_CD cases_NNS at_IN the_ATI NIH_NP )_) , it_PP3 is_BEZ recommended_VBN that_CS routine_NN laparotomy_NN be_BE performed_VBN it_PP3 is_BEZ also_RB recommended_VBN that_CS surgery_NN be_BE done_VBN only_RB in_IN centers_NNS with_IN considerable_JJ experience_NN with_IN pancreatic_JJ endocrine_NN tumors_NNS in_IN patients_NNS who_WPR have_HV ZES_NP with_IN MEN-I_NP , the_ATI usefulness_NN of_IN surgery_NN is_BEZ still_RB not_XNOT established_VBN , and_CC most_QL authorities_NNS do_DO not_XNOT recommend_VB routine_NN laparotomy_NN 119_CD 45_CD tumor_NN localization_NN studies_NNS demonstrate_VB that_CS ultrasonography_NN , CT_NP scanning_VBG , and_CC angiography_NN are_BER helpful_JJ and_CC will_MD localize_VB 20%_NP , 30%_NP , and_CC 50%_NP of_IN the_ATI primary_JJ tumors_NNS , respectively_RB pisegna_NN et_&FW al_APS report_NN that_CS MR_NP imaging_VBG , particularly_RB the_ATI short_JJ T_ZZ sub_NN 1_CD1 inversion-recovery_NN sequence_NN , does_DOZ not_XNOT localize_VB primary_JJ tumors_NNS any_DTI better_JJR than_IN CT_NP scanning_VBG even_RB with_IN the_ATI addition_NN of_IN gadolinium_NN however_RB , MR_NP imaging_VBG was_BEDZ better_JJR at_IN localizing_VBG gastrinoma_JJ metastatic_JJ to_IN the_ATI liver_NN (_( Fig_NP 1_CD1 )_) and_CC is_BEZ now_RN the_ATI noninvasive_JJ method_NN of_IN choice_NN for_IN localizing_VBG metastatic_JJ disease_NN endoscopic_JJ ultrasonography_NN and_CC radionuclide_NN scanning_VBG using_VBG radiolabeled_JJ octreotide_NN , which_WDTR identifies_VBZ somatostatin_NN receptors_NNS that_CS are_BER frequently_RB present_JJ in_IN large_JJ numbers_NNS on_IN gastrinomas_NNS and_CC other_AP pancreatic_JJ endocrine_NN tumors_NNS , are_BER two_CD new_JJ techniques_NNS that_DT may_MD prove_VB useful_JJ , but_CC it_PP3 is_BEZ not_XNOT clear_JJ whether_CS they_PP3AS will_MD localize_VB small_JJ duodenal_JJ gastrinomas_NNS .=20_CD 120_CD 46_CD functional_JJ localization_NN using_VBG a_AT transhepatic_JJ approach_NN to_TO measure_NN selective_JJ venous_JJ gastrin_NN gradients_NNS has_HVZ been_BEN shown_VBN to_TO be_BE less_QL sensitive_JJ and_CC to_TO have_HV a_AT higher_JJR morbidity_NN than_IN hepatic_JJ venous_JJ gastrin_NN sampling_NN after_IN intra- arterial_JJ injection_NN of_IN small_JJ amounts_NNS of_IN secretin_NN This_NN approach_NN is_BEZ particularly_RB good_JJ at_IN localizing_VBG duodenal_JJ gastrinomas_NNS and_CC can_MD be_BE done_VBN during_IN angiography_NN a_AT typical_JJ diagnostic_JJ result_NN is_BEZ shown_VBN in_IN Fig_NP 2_CD a_AT similar_JJ approach_NN has_HVZ been_BEN used_VBN in_IN insulinomas_NNS after_IN intra-arterial_JJ injection_NN of_IN calcium_NN imaging_VBG studies_NNS can_MD detect_VB more_QL than_IN 95%_NN of_IN patients_NNS with_IN liver_NN metastases_NNS and_CC , thus_RB , avoid_VB unnecessary_JJ surgery_NN however_RB , the_ATI reverse_NN is_BEZ not_XNOT true_JJ an_AT experienced_JJ surgeon_NN will_MD find_VB gastrinoma_NN in_IN more_AP than_IN 90%_NP of_IN all_ABN patients_NNS , so_QL even_CS if_CS imaging_VBG is_BEZ normal_JJ , surgical_JJ exploration_NN should_MD still_RB be_BE done_VBN 121_CD 47_CD Sugg_NP et_&FW al_APS demonstrate_VB that_CS palpation_NN , even_RB after_IN extensive_JJ mobilization_NN of_IN the_ATI duodenum_NN , will_MD find_VB only_RB 65%_JJ of_IN duodenal_JJ tumors_NNS Intraoperative_NP ultrasonography_NN localizes_VBZ no_ATI additional_JJ duodenal_JJ tumors_NNS , endoscopic_JJ transillumination_NN an_AT additional_JJ 20%_NP , and_CC duodenotomy_NN an_AT additional_JJ 15%_CD not_XNOT localized_VBN by_IN any_DTI other_AP modality_NN (_( Fig_NP 3_CD )_) for_IN duodenal_JJ tumors_NNS , 71%_CD are_BER located_VBN in_IN the_ATI first_OD part_NN , 21%_CD in_IN the_ATI second_OD , and_CC 8%_NN in_IN the_ATI third_OD therefore_RB , it_PP3 is_BEZ recommended_VBN that_CS all_ABN patients_NNS have_HV a_AT 3-cm_CD duodenotomy_NN along_IN the_ATI lateral_JJ aspect_NN of_IN the_ATI duodenum_NN beginning_NN in_IN the_ATI first_OD part_NN using_VBG this_DT approach_NN on_IN the_ATI last_AP 42_CD patients_NNS at_IN NIH_NP , surgeons_NNS found_JJ gastrinomas_NNS in_IN 95%_NN and_CC duodenal_JJ tumors_NNS in_IN 71%_CD (_( Fig_NP 3_CD )_) 122_CD 48_CD newer_JJR studies_NNS from_IN centers_NNS with_IN extensive_JJ experience_NN in_IN the_ATI surgical_JJ treatment_NN of_IN patients_NNS with_IN ZES_NP report_NN that_CS 58%_NN to_TO 82%_NN of_IN patients_NNS have_HV a_AT normal_JJ fasting_NN gastrin_NN level_NN and_CC negative_JJ secretin_NN test_NN when_WRB a_AT routine_NN duodenotomy_NN is_BEZ done_VBN , and_CC 30%_NP will_MD remain_VB cured_VBN at_IN 5_CD years_NNS (_( Table_NP 1_CD1 )_) this_DT cure_NN rate_NN is_BEZ higher_JJR than_IN that_DT reported_VBN in_IN older_JJR studies_NNS fishbeyn_NN et_&FW al_APS have_HV shown_VBN that_CS both_ABX a_AT fasting_NN gastrin_NN determination_NN and_CC secretin_NN test_NN are_BER required_VBN to_TO diagnose_VB all_ABN recurrent_JJ disease_NN Furthermore_NP , all_ABN patients_NNS will_MD demonstrate_VB recurrent_JJ disease_NN by_IN an_AT alteration_NN in_IN either_DTX the_ATI fasting_NN gastrin_NN level_NN or_CC secretin_NN test_NN before_CS imaging_VBG studies_NNS become_VB positive_JJ therefore_RB , repeat_VB imaging_VBG for_IN functionally_RB cured_VBN postoperative_JJ patients_NNS who_WPR had_HVD a_AT negative_JJ secretin_NN test_NN , and_CC normal_JJ fasting_NN gastrin_NN level_NN was_BEDZ not_XNOT needed_VBN this_DT latter_AP study_NN also_RB demonstrates_VBZ that_CS if_CS patients_NNS have_HV both_ABX a_AT normal_JJ fasting_NN gastrin_NN level_NN and_CC secretin_NN test_NN immediately_RB after_IN surgery_NN , there_EX is_BEZ a_AT 70%_NP likelihood_NN they_PP3AS will_MD remain_VB cured_VBN 3_CD years_NNS later_RBR 123_CD 49_CD it_PP3 has_HVZ been_BEN proposed_VBN that_CS some_DTI patients_NNS with_IN gastrinoma_NN be_BE considered_VBN for_IN a_AT proximal_JJ pancreatoduodenectomy_NN (_( Whipple's_NP$ operation_NN )_) Such_NP patients_NNS include_VB those_DTS with_IN a_AT high_JJ likelihood_NN of_IN multiple_JJ tumors_NNS , those_DTS with_IN large_JJ nonenucleatable_JJ tumors_NNS in_IN the_ATI head_NN area_NN of_IN the_ATI pancreas_NNS , those_DTS with_IN no_ATI tumor_NN found_VBN at_IN surgery_NN but_CC with_IN preoperative_JJ functional_JJ localization_NN to_IN the_ATI pancreatic_JJ head_NN area_NN , or_CC those_DTS found_VBN at_IN surgery_NN to_TO have_HV multiple_JJ positive_JJ lymph_NN nodes_NNS in_IN the_ATI pancreatic_JJ head_NN area_NN most_AP of_IN these_DTS patients_NNS have_HV an_AT excellent_JJ long-term_JJB prognosis_NN without_IN a_AT Whipple_NP operation_NN , and_CC it_PP3 is_BEZ not_XNOT possible_JJ to_TO predict_VB the_ATI few_AP patients_NNS who_WPR will_MD have_HV an_AT aggressive_JJ course_RB .=20_CD 124_CD 50_CD flow_NN cytometry_JJ results_NNS of_IN tumor_NN DNA_NP have_HV recently_RB been_BEN shown_VBN to_TO be_BE an_AT independent_JJ predictor_NN of_IN tumor_NN extent_NN , but_CC whether_CS these_DTS will_MD be_BE useful_JJ in_IN identifying_VBG subsets_NNS of_IN patients_NNS where_WRB such_ABL extensive_JJ surgery_NN should_MD be_BE done_VBN remains_VBZ to_TO be_BE established_VBN at_IN present_NN , this_DT operation_NN is_BEZ not_XNOT recommended_VBN until_CS it_PP3 is_BEZ established_VBN that_CS the_ATI benefits_NNS outweigh_VB the_ATI risks_NNS in_IN a_AT defined_JJ group_NN of_IN patients_NNS 125_CD 51_CD in_IN patients_NNS with_IN metastases_NNS to_IN the_ATI liver_NN , approximately_RB 15%_CD were_BED found_VBN to_TO have_HV disease_NN localized_VBN to_TO one_CD1 lobe_NN and_CC , thus_RB , potentially_RB resectable_JJ data_NNS from_IN a_AT number_NN of_IN studies_NNS involving_VBG patients_NNS with_IN gastrinomas_NNS and_CC other_AP pancreatic_JJ endocrine_NN tumors_NNS suggest_VB that_CS surgery_NN is_BEZ beneficial_JJ for_IN patients_NNS with_IN resectable_JJ metastatic_JJ disease_NN in_IN the_ATI 85%_NN of_IN patients_NNS with_IN diffuse_NN liver_NN metastases_NNS , recent_JJ studies_NNS at_IN the_ATI NIH_NP show_VB that_CS 12%_CD to_IN 20%_NP have_HV bone_NN metastases_NNS and_CC , thus_RB , treatment_NN cannot_NN be_BE directed_VBN only_RB at_IN the_ATI liver_NN patients_NNS with_IN diffuse_JJ metastatic_JJ disease_NN to_TO the_ATI liver_NN have_HV a_AT 5-year_NN survival_NN rate_NN of_IN only_RB 20%_NP to_IN 30%_NP , which_WDTR is_BEZ less_QL than_IN previously_RB thought_NN 126_CD 52_CD according_IN to_IN older_JJR studies_NNS , streptozocin_NN and_CC fluorouracil_NN were_BED the_ATI chemotherapeutic_JJ agents_NNS of_IN choice_NN and_CC resulted_VBD in_IN a_AT response_NN rate_NN of_IN 20%_NP to_IN 80%_NP however_RB , these_DTS studies_NNS frequently_RB involved_VBN several_AP different_JJ pancreatic_JJ endocrine_NN tumors_NNS , and_CC it_PP3 is_BEZ not_XNOT clear_JJ that_CS all_ABN are_BER equally_RB sensitive_JJ to_TO chemotherapy_VB studies_NNS in_IN patients_NNS with_IN metastatic_JJ gastrinoma_NN reported_VBN chemotherapy_NN response_NN rates_NNS of_IN 5%_NN and_CC 40%_NP with_IN streptozocin_NN and_CC fluorouracil_NN treatment_NN , and_CC in_IN one_CD1 study_NN chemotherapy_NN did_DOD not_XNOT prolong_VB life_NN recently_RB , the_ATI combination_NN of_IN streptozocin_NN and_CC doxorubicin_NN was_BEDZ observed_VBN to_TO be_BE superior_JJ to_TO streptozocin_VB and_CC fluorouracil_NN , with_IN a_AT response_NN rate_NN of_IN 65%_NN and_CC improved_JJ survival_NN However_NP , this_DT study_NN involved_VBN a_AT number_NN of_IN different_JJ pancreatic_JJ endocrine_NN tumors_NNS , and_CC research_NN needs_NNS to_TO be_BE done_VBN on_IN patients_NNS with_IN metastatic_JJ gastrinoma_NN only_RB streptozocin_NN has_HVZ important_JJ side_NN effects_NNS , especially_RB nephrotoxicity_NN 127_CD 53_CD interferon_NN is_BEZ reported_VBN effective_JJ in_IN metastatic_JJ carcinoid_NN and_CC pancreatic_JJ endocrine_NN tumors_NNS however_RB , in_IN a_AT recent_JJ prospective_JJ study_NN of_IN 13_CD patients_NNS with_IN metastatic_JJ gastrinoma_NN , none_PN of_IN the_ATI tumors_NNS decreased_VBD in_IN size_NN and_CC 25%_NN of_IN them_PP3OS stabilized_VBD without_IN further_JJB growth_NN similarly_RB , preliminary_JJ data_NNS on_IN octreotide_NN demonstrate_VB that_CS only_RB a_JJ few_AP patients_NNS with_IN metastatic_JJ pancreatic_JJ endocrine_NN tumors_NNS show_VB a_AT decrease_NN in_IN tumor_NN size_NN , while_CS a_AT significant_JJ percentage_NN demonstrate_VB no_ATI further_JJB growth_NN neither_DTX octreotide_NN nor_CC interferon_NN has_HVZ been_BEN shown_VBN to_TO prolong_VB survival_NN 128_CD 54_CD last_AP , after_IN resection_NN of_IN a_AT primary_JJ endocrine_NN tumor_NN , liver_NN transplantation_NN is_BEZ being_BEG performed_VBN on_IN some_DTI patients_NNS with_IN metastases_NNS confined_VBN to_IN the_ATI liver_NN , but_CC whether_CS this_DT treatment_NN will_MD result_VB in_IN improved_JJ survival_NN remains_VBZ to_TO be_BE proven_VBN at_IN present_NN , the_ATI treatment_NN of_IN choice_NN for_IN gastrinoma_JJ metastatic_JJ to_IN the_ATI liver_NN is_BEZ chemotherapy_JJ with_IN streptozocin_NN and_CC doxorubicin_NN it_PP3 is_BEZ , however_RB , of_IN limited_JJ benefit_NN , and_CC better_JJR regimens_NNS and_CC newer_JJR agents_NNS or_CC methods_NNS will_MD need_VB to_TO be_BE developed_VBN to_TO further_JJB extend_VB the_ATI survival_NN of_IN this_DT group_NN of_IN patients_NNS , which_WDTR is_BEZ increasing_JJ in_IN number_NN because_IN effective_JJ treatment_NN of_IN gastric_JJ hypersecretion_NN leads_VBZ to_TO longer_RBR survival_NN 129_CD is_BEZ This_JJ Patient_NP Malnourished_NP ? 130_CD case_NN 1_CD1 : ten_CD days_NNS prior_RB to_TO being_BEG seen_VBN a_AT 65- year-old_JJB man_NN suffered_VBD a_AT Wallenberg_NP stroke_NN involving_VBG the_ATI lateral_JJ medulla_NN this_DT left_VBD him_PP3O with_IN difficulty_NN swallowing_NN since_IN that_DT time_NN he_PP3A had_HVD been_BEN treated_VBN with_IN intravenous_JJ fluids_NNS , and_CC attempts_NNS at_IN eating_VBG led_VBD to_IN mild_JJ aspiration_NN with_IN pneumonia_NN in_IN that_DT period_NN he_PP3A lost_JJ 6%_NN of_IN his_PP$ usual_JJ body_NN weight_NN and_CC was_BEDZ continuing_VBG to_TO lose_VB weight_NN he_PP3A felt_VBD weak_JJ and_CC was_BEDZ able_JJ to_TO ambulate_VB only_RB with_IN difficulty_NN , both_ABX because_CS of_IN his_PP$ stroke-related_JJ ataxia_NN and_CC generalized_JJ weakness_NN on_IN physical_JJ examination_NN there_EX was_BEDZ an_AT obvious_JJ squared- off_NN appearance_NN to_IN his_PP$ shoulders_NNS from_IN subcutaneous_JJ tissue_NN and_CC muscle_NN wasting_VBG there_EX was_BEDZ no_ATI edema_NN 131_CD case_NN 2_CD : a_AT 63-year-old_JJB man_NN was_BEDZ admitted_VBN to_IN the_ATI hospital_NN for_IN gastric_JJ resection_NN of_IN an_AT obstructing_VBG gastric_JJ carcinoma_NN he_PP3A was_BEDZ well_RB until_IN 6_CD weeks_NNS prior_RB to_TO admission_NN when_WRB he_PP3A began_VBD to_TO notice_VB the_ATI rapid_JJ onset_NN of_IN early_JJ satiety_NN this_DT progressed_VBN to_IN the_ATI point_NN where_WRB he_PP3A began_VBD to_TO vomit_VB virtually_RB all_ABN food_NN and_CC fluids_NNS he_PP3A had_HVD lost_VBN 15%_CD of_IN his_PP$ body_NN weight_NN and_CC was_BEDZ continuing_VBG to_TO lose_VB weight_NN he_PP3A was_BEDZ ambulatory_NN but_CC felt_VBD weak_JJ and_CC was_BEDZ no_ATI longer_RBR able_JJ to_TO carry_VB on_IN his_PP$ usual_JJ daily_JJ activities_NNS because_CS of_IN this_DT weakness_NN on_IN physical_JJ examination_NN the_ATI man_NN looked_VBD wasted_VBN there_EX was_BEDZ obvious_JJ subcutaneous_JJ tissue_NN loss_NN in_IN the_ATI triceps_NNS and_CC thoracic_JJ regions_NNS as_CS well_RB as_IN muscle_NN loss_NN in_IN the_ATI deltoids_NNS there_EX was_BEDZ edema_NN in_IN his_PP$ ankles_NNS but_CC no_ATI ascites_NNS 132_CD case_NN 3_CD : a_AT 70-year-old_JJB man_NN was_BEDZ admitted_VBN to_IN the_ATI hospital_NN for_IN resection_NN of_IN his_PP$ descending_JJ colon_NN because_CS of_IN an_AT adenocarcinoma_NN detected_VBN on_IN investigation_NN for_IN bright-red_JJ blood_NN in_IN his_PP$ bowel_NN movements_NNS between_IN 6_CD and_CC 3_CD months_NNS prior_RB to_TO admission_NN he_PP3A had_HVD lost_VBN 10%_CD of_IN his_PP$ body_NN weight_NN for_IN reasons_NNS that_CS he_PP3A could_MD not_XNOT explain_VB however_RB , his_PP$ weight_NN had_HVD stabilized_VBN in_IN the_ATI 2_CD months_NNS prior_RB to_TO admission_NN , and_CC in_IN fact_NN he_PP3A had_HVD gained_VBN back_RP 4%_NN of_IN his_PP$ weight_NN his_PP$ dietary_JJ intake_NN had_HVD been_BEN slightly_RB below_IN normal_JJ but_CC had_HVD recently_RB improved_JJ he_PP3A reported_VBD no_ATI significant_JJ gastrointestinal_JJ symptoms_NNS other_AP than_IN the_ATI bleeding_NN and_CC a_AT mild_JJ change_NN in_IN his_PP$ bowel_NN habits_NNS he_PP3A had_HVD his_PP$ usual_JJ level_NN of_IN energy_NN on_IN physical_JJ examination_NN there_EX was_BEDZ no_ATI evidence_NN of_IN subcutaneous_JJ tissue_NN loss_NN , muscle_NN wasting_VBG , edema_NN , or_CC ascites_NNS 133_CD WHY_NPT PERFORM_NPT NUTRITIONAL_NPT STATUS_NP ASSESSMENT_NP ? 134_CD malnutrition_NN occurs_VBZ among_IN patients_NNS either_DTX because_CS of_IN their_PP$ primary_JJ diseases_NNS (_( eg_NN , malignancy_NN )_) or_CC because_CS the_ATI procedures_NNS they_PP3AS undergo_VB in_IN order_NN to_TO treat_VB the_ATI primary_JJ disease_NN prevent_VB them_PP3OS from_IN receiving_VBG adequate_JJ nutritional_JJ intake_NN for_IN prolonged_JJ periods_NNS of_IN time_NN (_( eg_NN , surgery_NN )_) 135_CD there_EX are_BER two_CD components_NNS of_IN nutritional_JJ status_NN assessment_NN the_ATI first_OD is_BEZ body_NN composition_NN analysis_NN , the_ATI determination_NN of_IN the_ATI mass_NN of_IN body_NN components_NNS , such_IN as_IN total_JJ body_NN protein_NN and_CC total_JJ body_NN fat_NN these_DTS components_NNS are_BER measured_VBN by_IN in_RB vivo_RB neutron_NN activation_NN analysis_NN and_CC tritiated_JJ water_NN dilution_NN technique_NN , which_WDTR represents_VBZ the_ATI criterion_NN standard_NN (_( also_RB known_VBN as_IN the_ATI gold_NN standard_NN )_) for_IN measures_NNS of_IN body_NN composition_NN the_ATI second_OD component_NN is_BEZ physiological_JJ function_NN defined_VBN by_IN some_DTI as_CS changes_NNS in_IN cellular_JJ and_CC organ_NN function_NN , measured_VBD in_IN a_AT variety_NN of_IN ways_NNS , such_IN as_IN skeletal_JJ muscle_NN strength_NN , respiratory_JJ function_NN , protein_NN synthesis_NN , and_CC tissue_NN repair_NN 136_CD during_IN the_ATI past_JJB three_CD decades_NNS , clinicians_NNS have_HV become_VBN increasingly_RB aware_JJ of_IN the_ATI prevalence_NN of_IN malnutrition_NN among_IN hospitalized_JJ patients_NNS (_( 1-4_CD-CD )_) clinicians_NNS have_HV recognized_VBN that_CS malnourished_JJ patients_NNS are_BER at_IN a_AT higher_JJR risk_NN of_IN developing_VBG complications_NNS while_CS undergoing_VBG treatment_NN These_NP complications_NNS include_VB death_NN , sepsis_NN , abscess_NN formation_NN , other_AP infections_NNS , such_IN as_IN pneumonia_NN , wound_NN healing_NN difficulties_NNS postoperatively_RB , and_CC respirator_NN failure_NN some_DTI have_HV used_VBN the_ATI term_NN _** nutrition-associated_JJ complications_NNS _** (_( 5,6_NN )_) to_TO highlight_NN the_ATI relationship_NN between_IN malnutrition_NN and_CC these_DTS adverse_JJ events_NNS the_ATI increased_JJ risk_NN for_IN malnourished_JJ patients_NNS is_BEZ thought_VBN to_TO be_BE caused_VBN more_AP by_IN functional_JJ impairment_NN than_IN changes_NNS in_IN body_NN composition_NN (_( 7_CD )_) , although_CS in_IN studied_VBN subjects_NNS there_EX is_BEZ clearly_RB a_AT correlation_NN between_IN the_ATI two_CD components_NNS of_IN nutritional_JJ status_NN 137_CD investigations_NNS in_IN the_ATI 1970s_CD (_( 1,2_CD )_) estimated_VBN that_CS the_ATI prevalence_NN of_IN malnutrition_NN among_IN hospitalized_JJ patients_NNS was_BEDZ as_QL high_JJ as_IN 40%_NP more_AP recent_JJ studies_NNS (_( 4,8_NN )_) on_IN patients_NNS undergoing_VBG general_JJ gastrointestinal_JJ surgery_NN showed_VBD the_ATI prevalence_NN of_IN either_DTX mild_JJ or_CC severe_JJ malnutrition_NN was_BEDZ 48%_NN (_( 3_CD )_) and_CC 31%_CD , respectively_RB detsky_NN et_&FW al_APS (_( 4_CD )_) confirmed_VBN the_ATI relationship_NN between_IN malnutrition_NN and_CC the_ATI risk_NN of_IN nutrition-associated_JJ complications_NNS In_NP their_PP$ series_NN of_IN 202_CD patients_NNS undergoing_VBG general_JJ gastrointestinal_JJ surgery_NN at_IN two_CD Toronto_NP (_( Ontario_NP )_) teaching_NN hospitals_NNS , 10%_CD of_IN the_ATI total_JJ series_NN of_IN patients_NNS suffered_VBD from_IN major_JJ nutrition-associated_JJ complications_NNS , including_IN six_CD deaths_NNS related_VBN to_TO sepsis_VB , two_CD nonfatal_JJ episodes_NNS of_IN sepsis_NN , three_CD subphrenic_JJ or_CC intra-abdominal_JJ abscesses_NNS , two_CD anastomotic_JJ breakdowns_NNS , two_CD wound_NN dehiscences_NNS , and_CC five_CD major_JJ wound_NN abscesses_NNS however_RB , among_IN those_DTS who_WPR were_BED assessed_VBN to_TO be_BE severely_RB malnourished_VBN preoperatively_RB , this_DT major_JJ complication_NN rate_NN was_BEDZ 67%_NN Windsor_NP and_CC Hill_NPL (_( 7_CD )_) , using_VBG a_AT slightly_RB different_JJ system_NN of_IN nutritional_JJ status_NN assessment_NN in_IN 102_CD patients_NNS undergoing_VBG major_JJ gastrointestinal_JJ surgery_NN , also_RB showed_VBD that_CS severely_RB malnourished_JJ patients_NNS had_HVD a_AT higher_JJR risk_NN of_IN major_JJ complications_NNS than_IN patients_NNS designated_VBN as_CS having_HVG normal_JJ nutritional_JJ status_NN these_DTS results_NNS confirm_VB the_ATI usefulness_NN of_IN nutritional_JJ status_NN assessment_NN as_IN a_AT predictor_NN of_IN high_JJ risk_NN for_IN postoperative_JJ complications_NNS thus_RB , it_PP3 becomes_VBZ both_ABX a_AT method_NN of_IN assessing_VBG prognosis_NN as_CS well_RB as_IN a_AT method_NN of_IN diagnosing_VBG a_AT particular_JJ health_NN state_NN 138_CD furthermore_RB , assessing_VBG nutritional_JJ status_NN identifies_VBZ patients_NNS who_WPR may_MD benefit_VB from_IN enteral_JJ or_CC parenteral_JJ nutritional_JJ repletion_NN to_TO reduce_VB the_ATI risk_NN of_IN these_DTS complications_NNS (_( 9-11_CD-CD )_) although_CS patients_NNS with_IN chronic_JJ medical_JJ conditions_NNS also_RB are_BER thought_VBN to_TO be_BE at_IN higher_JJR risk_NN of_IN developing_VBG complications_NNS , such_IN as_IN respiratory_JJ failure_NN or_CC infection_NN , most_AP of_IN what_WDT we_PP1AS know_VB comes_VBZ from_IN patients_NNS undergoing_VBG surgical_JJ procedures_NNS 139_CD THE_NPT ANATOMIC_PHYSIOLOGICAL_NPT ORIGIN_NPT OF_NPT FINDINGS_NPT IN_NPT THIS_NP AREA_NP 140_CD syndromes_NNS of_IN undernutrition_NN of_IN calories_NNS and_CC protein_NN have_HV been_BEN studied_VBN most_QL extensively_RB in_IN children_NNS of_IN developing_VBG nations_NNS and_CC are_BER not_XNOT frequently_RB observed_VBN in_IN North_NP America_NP two_CD polar_JJ extremes_NNS of_IN protein-energy_NN malnutrition_NN have_HV been_BEN defined_VBN : (_( 1_CD1 )_) marasmus_JJ , caused_VBD primarily_RB by_IN deficiency_NN of_IN calories_NNS resulting_JJ in_IN stunted_JJ growth_NN in_IN children_NNS , loss_NN of_IN adipose_NN tissue_NN , and_CC generalized_JJ wasting_VBG of_IN lean_JJ body_NN mass_NN without_IN edema_NN ; and_CC (_( 2_CD )_) kwashiorkor_NN , a_AT primary_JJ deficiency_NN of_IN protein_NN manifested_VBN by_IN edema_NN , but_CC adipose_NN tissue_NN is_BEZ preserved_VBN 141_CD many_AP individuals_NNS who_WPR are_BER malnourished_VBN will_MD have_HV elements_NNS of_IN both_ABX protein_NN and_CC calorie_NN deficiencies_NNS the_ATI complex_JJ metabolic_JJ processes_NNS that_CS result_NN from_IN protein- energy_NN malnutrition_NN are_BER beyond_IN the_ATI scope_NN of_IN this_DT overview_NN however_RB , it_PP3 is_BEZ important_JJ to_TO note_VB that_CS in_IN North_NP America_NP , nutritional_JJ assessment_NN is_BEZ used_VBN as_IN a_AT predictor_NN of_IN future_NN complications_NNS in_IN patients_NNS and_CC therefore_RB may_MD go_VB beyond_IN the_ATI traditional_JJ measurement_NN of_IN pure_JJ malnutrition_NN resulting_JJ from_IN inadequate_JJ intake_NN of_IN protein_NN , calories_NNS , or_CC micronutrients_NNS nutritional_JJ assessment_NN , particularly_RB if_CS it_PP3 encompasses_VBZ or_CC focuses_VBZ on_IN physiological_JJ function_NN , may_MD be_BE an_AT overall_JJB marker_NN of_IN illness_NN that_WPR is_BEZ not_XNOT caused_VBN solely_RB by_IN inadequate_JJ intake_NN or_CC reversed_VBD by_IN nutritional_JJ supplementation_NN this_DT may_MD explain_VB why_WRB the_ATI clinical_JJ trials_NNS of_IN total_JJ parenteral_JJ nutrition_NN in_IN a_AT variety_NN of_IN clinical_JJ circumstances_NNS have_HV in_IN some_DTI cases_NNS produced_VBN disappointing_JJ results_NNS in_IN improving_VBG outcomes_NNS (_( 12_CD )_) 142_CD nutritional_JJ deficiency_NN syndromes_NNS involving_VBG vitamins_NNS and_CC micronutrients_NNS evolve_VB through_IN three_CD stages_NNS because_CS most_QL micronutrients_NNS are_BER stored_VBN in_IN tissues_NNS , and_CC a_AT temporary_JJ reduction_NN in_IN intake_NN is_BEZ buffered_VBN by_IN a_AT reduction_NN in_IN body_NN stores_NNS the_ATI second_OD stage_NN involves_VBZ metabolic_JJ changes_NNS without_IN symptoms_NNS , while_CS severe_JJ depletion_NN will_MD result_VB in_IN the_ATI final_JJ stage_NN of_IN clinical_JJ signs_NNS and_CC symptoms_NNS they_PP3AS will_MD not_XNOT be_BE discussed_VBN in_IN this_DT article_NN 143_CD HOW_NPT TO_NPT PERFORM_NPT NUTRITIONAL_NP ASSESSMENT_NP 144_CD this_DT article_NN primarily_RB describes_VBZ features_NNS of_IN the_ATI history_NN and_CC physical_JJ examination_NN , as_CS do_DO all_ABN articles_NNS in_IN this_DT series_NN on_IN The_NP Rational_NP Clinical_NP Examination_NN , in_IN assessing_VBG overall_JJB nutritional_JJ status_NN 145_CD the_ATI relevant_JJ features_NNS of_IN a_AT patient's_NN$ history_NN and_CC physical_JJ examination_NN can_MD be_BE elicited_VBN by_IN a_AT technique_NN known_VBN as_IN the_ATI Subjective_NP Global_NP Assessment_NP (_( SGA_NP )_) of_IN nutritional_JJ status_NN (_( 8_CD )_) the_ATI application_NN of_IN this_DT technique_NN divides_VBZ patients_NNS into_IN three_CD classes_NNS : class_NN A_ZZ , well_RB nourished_VBN ; class_NN B_ZZ , moderately_RB (_( or_CC suspected_VBD of_IN being_BEG )_) malnourished_VBN ; and_CC class_NN C_ZZ , severely_RB malnourished_VBN the_ATI components_NNS of_IN this_DT technique_NN are_BER described_VBN in_IN Table_NP 1_CD1 there_EX are_BER four_CD elements_NNS of_IN the_ATI history_NN 146_CD weight_NN Loss_NN in_IN the_ATI 6_CD Months_NP Prior_NP to_IN the_ATI Examination_NN , Expressed_NP as_CS a_AT Proportionate_NP Loss_NN From_NP Previous_JJ Weight_NP 147_CD a_AT weight_NN loss_NN of_IN less_AP than_IN 5%_NN is_BEZ considered_VBN small_JJ a_AT weight_NN loss_NN between_IN 5%_NN and_CC 10%_CD is_BEZ considered_VBN potentially_RB significant_JJ , and_CC a_AT weight_NN loss_NN of_IN more_AP than_IN 10%_CD is_BEZ considered_VBN definitely_RB significant_JJ in_IN addition_NN to_IN considering_VBG the_ATI amount_NN of_IN weight_NN loss_NN it_PP3 is_BEZ important_JJ to_TO note_VB the_ATI pattern_NN of_IN the_ATI weight_NN loss_NN for_IN example_NN , if_CS a_AT patient_NN lost_VBN 12%_CD of_IN his_PP$ or_CC her_PP$ weight_NN in_IN the_ATI period_NN 6_CD months_NNS to_TO 1_CD1 month_NN prior_RB to_IN the_ATI examination_NN but_CC regained_VBD half_ABN of_IN that_DT weight_NN in_IN the_ATI subsequent_JJ month_NN , resulting_JJ in_IN a_AT net_JJB loss_NN of_IN 6%_NN for_IN the_ATI entire_JJB period_NN , the_ATI patient_NN is_BEZ considered_VBN better_JJR nourished_VBN than_IN a_AT patient_NN who_WPR had_HVD lost_JJ 6%_NN progressively_RB in_IN the_ATI 6_CD months_NNS prior_RB to_IN the_ATI examination_NN and_CC who_WPR is_BEZ continuing_VBG to_TO lose_VB weight.=20_CD 148_CD we_PP1AS still_RB consider_VB patients_NNS to_TO be_BE well_RB nourished_VBN despite_IN significant_JJ proportions_NNS of_IN weight_NN loss_NN if_CS there_EX has_HVZ been_BEN a_AT recent_JJ stabilization_NN or_CC increase_NN in_IN weight_NN in_IN eliciting_VBG the_ATI history_NN of_IN weight_NN pattern_NN from_IN patients_NNS , we_PP1AS recommend_VB asking_VBG the_ATI patient_NN what_WDT his_PP$ or_CC her_PP$ maximum_JJ weight_NN was_BEDZ , what_WDT it_PP3 was_BEDZ 1_CD1 year_NN ago_RB , 6_CD months_NNS ago_RB , 1_CD1 month_NN ago_RB , and_CC at_IN the_ATI present_JJ time_NN (_( of_RB course_RB , current_JJ weight_NN can_MD be_BE measured_VBN )_) if_CS the_ATI patient_NN reports_NNS substantial_JJ weight_NN loss_NN , we_PP1AS ask_VB for_IN confirming_VBG history_NN of_IN a_AT change_NN in_IN clothing_NN size_NN or_CC whether_CS their_PP$ clothes_NNS fit_VB very_QL loosely_RB now_RN finally_RB , we_PP1AS ask_VB for_IN the_ATI pattern_NN of_IN the_ATI weight_NN loss_NN during_IN the_ATI past_NN few_AP weeks_NNS (_( continued_VBD loss_NN , stabilization_NN , or_CC gain_VB )_) 149_CD dietary_JJ Intake_NP in_IN Relation_NN to_IN the_ATI Patient's_NP$ Usual_NP Pattern_NP 150_CD patients_NNS are_BER classified_VBN as_CS having_HVG either_DTX normal_JJ or_CC abnormal_JJ (_( decreased_VBD )_) intake_NN in_IN the_ATI weeks_NNS to_IN months_NNS prior_RB to_IN the_ATI examination_NN the_ATI duration_NN and_CC degree_NN of_IN abnormality_NN is_BEZ also_RB noted_VBN (_( eg_NN , starvation_NN , hypocaloric_JJ liquids_NNS , full_JJ liquid_JJ diet_NN , or_CC suboptimal_JJ solid_JJ diet_NN )_) for_IN example_NN , patients_NNS with_IN strokes_NNS resulting_JJ in_IN swallowing_NN difficulties_NNS may_MD have_HV been_BEN starved_VBN , simply_RB receiving_VBG intravenous_JJ or_CC hypocaloric_JJ fluids_NNS for_IN several_AP weeks_NNS prior_RB to_IN the_ATI examination_NN patients_NNS with_IN lesions_NNS that_CS obstruct_VB the_ATI outflow_NN from_IN the_ATI stomach_NN , such_IN as_IN cancer_NN or_CC severe_JJ ulcers_NNS , may_MD have_HV been_BEN on_IN pure_JJ liquid_JJ diets_NNS in_IN eliciting_VBG this_DT history_NN , we_PP1AS recommend_VB asking_VBG patients_NNS whether_CS their_PP$ eating_VBG patterns_NNS have_HV changed_VBN during_IN the_ATI past_JJB few_AP weeks_NNS , then_RN during_IN the_ATI past_JJB few_AP months_NNS has_HVZ the_ATI amount_NN of_IN food_NN eaten_VBN decreased_VBD ? if_CS so_PN , by_IN how_WRB much_AP ? are_BER there_EX certain_JJ kinds_NNS of_IN foods_NNS that_CS they_PP3AS used_VBD to_TO eat_VB that_CS they_PP3AS can_MD no_RB longer_RBR eat_VB ? why_WRB are_BER they_PP3AS eating_VBG less_QL (_( intentional_JJ reduction_NN , unintentional_JJ reduction_NN , ordered_VBN by_IN clinician_NN )_) ? what_WDT happens_VBZ if_CS they_PP3AS try_VB to_TO eat_VB more_QL ? ask_VB for_IN an_AT example_NN of_IN a_AT typical_JJ breakfast_NN , lunch_NN , and_CC dinner_NN and_CC a_AT comparison_NN with_IN typical_JJ meals_NNS 6_CD to_IN 12_CD months_NNS ago_RB 151_CD presence_NN of_IN Significant_NPT Gastrointestinal_NP Symptoms_NP : anorexia_RB , Nausea_NP , Vomiting_NP , and_CC Diarrhea_NP 152_CD by_IN significant_JJ we_PP1AS mean_VB that_CS these_DTS symptoms_NNS must_MD have_HV persisted_VBN on_IN virtually_RB a_AT daily_JJ basis_NN for_IN a_AT period_NN longer_RBR than_IN 2_CD weeks_NNS short-term_JJB diarrhea_NN or_CC intermittent_JJ vomiting_NN is_BEZ not_XNOT considered_VBN significant_JJ daily_JJ or_CC twice-daily_RB vomiting_NN secondary_JJ to_TO obstruction_NN is_BEZ considered_VBN significant_JJ 153_CD the_ATI Patient's_NP$ Functional_NP Capacity_NP or_CC Energy_NP , Ranging_NPT From_NP Full_NP Capacity_NP to_IN Bedridden_NP 154_CD patients_NNS who_WPR are_BER unable_JJ to_TO eat_VB will_MD often_RB complain_VB of_IN fatigue_NN and_CC weakness_NN to_IN the_ATI point_NN where_WRB they_PP3AS are_BER bedridden_NN 155_CD there_EX are_BER three_CD features_NNS of_IN the_ATI physical_JJ examination_NN that_CS are_BER recorded_VBN as_CS normal_JJ (_( 0_CD )_) , mild_JJ (_( 1_CD1 +_IN ) _) , moderate_JJ (_( 2_CD +_IN )_) , or_CC severe_JJ (_( 3_CD +_IN )_) 156_CD loss_NN of_IN Subcutaneous_JJ Fat_NP 157_CD there_EX are_BER several_AP locations_NNS where_WRB one_CD1 can_MD look_VB for_IN loss_NN of_IN subcutaneous_JJ fat_NN , and_CC the_ATI best_JJT are_BER the_ATI triceps_NNS region_NN of_IN the_ATI arms_NNS , the_ATI midaxillary_NN line_NN at_IN the_ATI costal_JJ margin_NN , the_ATI interosseous_JJ and_CC palmar_JJ areas_NNS of_IN the_ATI hand_NN , and_CC the_ATI deltoid_JJ regions_NNS of_IN the_ATI shoulder_NN (_( 1_CD1 and_CC 2_CD )_) positive_JJ findings_NNS are_BER loss_NN of_IN fullness_NN or_CC one_CD1 or_CC more_QL areas_NNS where_WRB the_ATI skin_NN fits_VBZ too_QL loosely_RB over_IN the_ATI deeper_JJR tissues_NNS ; this_DT latter_AP sign_NN may_MD be_BE falsely_RB positive_NN in_IN elderly_JJ individuals_NNS who_WPR may_MD appear_VB to_TO have_HV lost_VBN subcutaneous_JJ tissue_NN without_IN being_BEG clinically_RB malnourished_VBN 158_CD muscle_NN Wasting-_NP 159_CD the_ATI best_JJT muscles_NNS to_TO examine_VB are_BER the_ATI quadriceps_NNS femoris_NN and_CC deltoids_NNS in_IN the_ATI deltoid_NN region_NN , malnourished_JJ patients_NNS have_HV a_AT squared-off_NN appearance_NN to_IN their_PP$ shoulders_NNS from_IN the_ATI combination_NN of_IN muscle_NN and_CC subcutaneous_JJ tissue_NN loss_NN (_( 3_CD )_) in_IN severe_JJ malnutrition_NN , the_ATI quadriceps_NNS will_MD have_HV loss_NN of_IN bulk_NN and_CC tone_NN obviously_RB , neurological_JJ lesions_NNS (_( that_CS may_MD present_JJ with_IN unilateral_JJ wasting_VBG )_) may_MD produce_VB false-positive_JJ findings_NNS here_RN 160_CD loss_NN of_IN Fluid_NP From_NP the_ATI Intravascular_NP to_IN Extravascular_NP Space_NP , Namely_NP , Ankle_NP or_CC Sacral_NP Edema_NP and_CC Ascites-_NP 161_CD the_ATI first_OD two_CD signs_NNS are_BER best_JJT assessed_VBN by_IN inspection_NN and_CC then_RN by_IN palpation_NN , remembering_VBG that_CS some_DTI features_NNS are_BER best_JJT inspected_VBN from_IN a_AT distance_NN , eg_NN , squared-off_NN shoulders_NNS edema_NN is_BEZ assessed_VBN by_IN pressing_VBG the_ATI ankle_NN (_( leg_NN )_) or_CC sacrum_NN , feeling_VBG the_ATI fluid_NN move_NN out_RP of_IN the_ATI subcutaneous_JJ tissue_NN , and_CC then_RN observing_VBG _** pitting_NN , _** persistent_JJ depression_NN of_IN the_ATI area_NN pressed_VBD (_( more_AP than_IN 5_CD seconds_NNS )_) 162_CD there_EX is_BEZ no_ATI explicit_JJ numerical_JJ weighting_NN scheme_NN described_VBN for_IN combining_VBG these_DTS features_NNS of_IN the_ATI history_NN and_CC physical_JJ examination_NN into_IN an_AT SGA_NP rather_RB , they_PP3AS are_BER combined_VBN subjectively_RB into_IN an_AT overall_JJB or_CC global_JJ assessment_NN in_IN the_ATI study_NN that_CS established_VBN the_ATI precision_NN and_CC accuracy_NN of_IN SGA_NP (_( 4,8_NN )_) , clinicians_NNS placed_VBN greatest_JJT importance_NN on_IN the_ATI following_JJ variables_NNS : weight_NN loss_NN of_IN more_AP than_IN 10%_CD , poor_JJ dietary_JJ intake_NN , loss_NN of_IN subcutaneous_JJ tissue_NN , and_CC muscle_NN wasting_VBG patients_NNS suspected_VBD of_IN being_BEG malnourished_VBN or_CC judged_VBN to_TO have_HV moderate_JJ malnourishment_NN (_( class_NN B_ZZ )_) had_HVD lost_VBN at_RB least_RB 5%_NN of_IN their_PP$ body_NN weight_NN in_IN the_ATI weeks_NNS prior_RB to_TO examination_NN without_IN stabilization_NN or_CC weight_NN gain_NN , had_HVD a_AT definite_JJ history_NN of_IN reduction_NN in_IN dietary_JJ intake_NN , and_CC exhibited_VBN mild_JJ (_( 1_CD1 +_IN )_) loss_NN of_IN subcutaneous_JJ tissue_NN when_WRB patients_NNS had_HVD considerable_JJ edema_NN , ascites_NNS , or_CC tumor_NN mass_NN , less_QL attention_NN was_BEDZ paid_VBN to_IN the_ATI amount_NN of_IN weight_NN loss_NN the_ATI other_AP historical_JJ features_NNS helped_VBD the_ATI clinicians_NNS confirm_VB the_ATI patient's_NN$ self-report_NN of_IN weight_NN loss_NN or_CC dietary_JJ change_NN but_CC received_VBD less_QL weight_NN in_IN the_ATI ranking_NN system_NN 163_CD if_CS , on_IN the_ATI other_AP hand_NN , a_AT patient_NN had_HVD a_AT recent_JJ weight_NN gain_NN that_CS did_DOD not_XNOT appear_VB to_TO be_BE merely_RB fluid_JJ retention_NN , clinicians_NNS designated_VBN that_CS patient_NN well_RB nourished_VBN (_( class_NN A_ZZ )_) , even_CS if_CS the_ATI net_JJB weight_NN loss_NN was_BEDZ between_IN 5%_NN and_CC 10%_CD , and_CC there_EX was_BEDZ mild_JJ loss_NN of_IN subcutaneous_JJ tissue_NN the_ATI assignment_NN of_IN a_AT class_NN A_ZZ rank_NN also_RB should_MD occur_VB in_IN settings_NNS where_WRB the_ATI patient_NN has_HVZ had_HVN an_AT improvement_NN in_IN the_ATI other_AP historical_JJ features_NNS of_IN SGA_NP , such_IN as_IN appetite_NN 164_CD in_IN order_NN to_TO be_BE classified_VBN as_CS severely_RB malnourished_VBN (_( class_NN C_ZZ )_) , patients_NNS should_MD demonstrate_VB obvious_JJ physical_JJ signs_NNS of_IN malnutrition_NN , such_ABL as_CS severe_JJ (_( 3_CD +_IN )_) subcutaneous_JJ tissue_NN loss_NN and_CC muscle_NN wasting_VBG , often_RB with_IN edema_NN , in_IN the_ATI presence_NN of_IN a_AT clear_JJ and_CC convincing_JJ pattern_NN of_IN ongoing_VBG weight_NN loss_NN of_IN at_RB least_RB 10%_CD 165_CD by_IN design_NN , this_DT system_NN is_BEZ less_QL sensitive_JJ and_CC more_QL specific_JJ that_DT is,very_NN few_AP well-nourished_JJ patients_NNS will_MD receive_VB a_AT false-positive_JJ diagnosis_NN of_IN malnourishment_NN , but_CC some_DTI patients_NNS with_IN mild_JJ degrees_NNS of_IN malnutrition_NN may_MD be_BE missed_VBN 166_CD Windsor_NP and_CC Hill_NPL (_( 7_CD )_) describe_VB a_AT slightly_RB different_JJ system_NN of_IN nutritional_JJ status_NN that_CS focuses_VBZ more_AP on_IN physiological_JJ function_NN their_PP$ system_NN has_HVZ two_CD components_NNS : weight_NN loss_NN and_CC functional_JJ status_NN Preoperative_NP percentage_NN of_IN weight_NN loss_NN is_BEZ defined_VBN as_CS recalled_VBD well_RB weight_NN minus_IN current_JJ measured_JJ weight_NN divided_VBN by_IN well_RB weight_NN a_AT weight_NN loss_NN of_IN more_AP than_IN 10%_CD during_IN the_ATI preceding_JJ 3_CD months_NNS was_BEDZ considered_VBN significant_JJ confirmation_NN of_IN weight_NN loss_NN is_BEZ sought_VBN in_IN the_ATI physical_JJ examination_NN by_IN palpating_VBG skin_NN folds_NNS for_IN loss_NN of_IN fat_NN and_CC muscles_NNS in_IN a_AT manner_NN similar_JJ to_TO that_CS just_RB described_VBN functional_JJ impairment_NN of_IN overall_JJB activity_NN levels_NNS (_( by_IN observing_VBG the_ATI patient_NN on_IN the_ATI ward_NN )_) , overall_JJB mood_NN (_( alertness_NN , ability_NN to_TO concentrate_VB , and_CC irritability_NN )_) , skeletal_JJ muscle_NN function_NN (_( having_HVG the_ATI patient_NN squeeze_VB the_ATI examiner's_NN$ hand_NN )_) , respiratory_JJ function_NN (_( effort_NN and_CC sound_NN of_IN coughing_NN and_CC shortness_NN of_IN breath_NN )_) , wound_NN healing_NN (_( unhealed_JJ wounds_NNS and_CC sores_NNS or_CC scratches_NNS and_or_CC skin_NN sepsis_NN )_) , and_CC serum_NN albumin_NN level_NN of_IN less_AP than_IN 32_CD g_L_NN if_CS patients_NNS have_HV weight_NN loss_NN of_IN less_AP than_IN 10%_CD , with_IN no_ATI evidence_NN of_IN abnormal_JJ physiological_JJ function_NN , they_PP3AS are_BER placed_VBN in_IN group_NN 1_CD1 with_IN weight_NN loss_NN of_IN more_AP than_IN 10%_CD but_CC no_ATI abnormal_JJ physiological_JJ function_NN , patients_NNS are_BER placed_VBN in_IN group_NN 2_CD , and_CC with_IN both_ABX features_NNS , they_PP3AS are_BER placed_VBN in_IN group_NN 3_CD 167_CD READER_NP PARTICIPATION_NP 168_CD before_CS reading_NN further_JJB , we_PP1AS suggest_VB that_CS you_PP2 return_VB to_IN the_ATI patient_NN scenarios_NNS that_WPR opened_VBD this_DT overview_NN and_CC decide_VB whether_CS you_PP2 judge_VB them_PP3OS to_TO be_BE well_RB nourished_VBN , moderately_RB malnourished_VBN , or_CC severely_RB malnourished_VBN using_VBG SGA_NP after_IN doing_VBG so_PN , read_VB on_RP 169_CD case_NN 1_CD1 was_BEDZ moderately_RB malnourished_VBN (_( class_NN B_ZZ )_) this_DT ranking_VBG was_BEDZ determined_VBN by_IN his_PP$ continuing_JJ loss_NN of_IN weight_NN , the_ATI limitation_NN of_IN nutritional_JJ intake_NN to_IN hypocaloric_JJ fluids_NNS for_IN 2_CD weeks_NNS , and_CC the_ATI mild_JJ loss_NN of_IN subcutaneous_JJ tissue_NN and_CC muscle_NN 170_CD case_NN 2_CD was_BEDZ severely_RB malnourished_VBN (_( class_NN C_ZZ )_) this_DT judgment_NN was_BEDZ most_QL influenced_VBN by_IN his_PP$ continuing_VBG large_JJ weight_NN loss_NN , change_NN in_IN dietary_JJ intake_NN , and_CC positive_JJ physical_JJ findings_NNS 171_CD case_NN 3_CD was_BEDZ well_RB nourished_VBN (_( class_NN A_ZZ )_) although_CS he_PP3A had_HVD suffered_VBN considerable_JJ weight_NN loss_NN at_IN some_DTI time_NN prior_RB to_TO admission_NN , his_PP$ weight_NN had_HVD stabilized_VBN and_CC increased_VBN in_IN the_ATI period_NN just_RB prior_RB to_IN admission_NN 172_CD PRECISION_NPT OF_NPT THE_NPT ASSESSMENT_NPT OF_NPT NUTRITIONAL_NP STATUS_NP 173_CD investigators_NNS at_IN the_ATI University_NPL of_IN Toronto_NP studied_VBD 202_CD patients_NNS at_IN two_CD teaching_NN hospitals_NNS who_WPR were_BED undergoing_VBG major_JJ gastrointestinal_JJ surgery_NN (_( 8_CD )_) a_AT nurse_NN and_CC three_CD residents_NNS learned_VBD the_ATI technique_NN of_IN nutritional_JJ status_NN described_VBN herein_RB by_IN examining_VBG a_AT series_NN of_IN patients_NNS and_CC reviewing_VBG their_PP$ assessments_NNS with_IN those_DTS of_IN a_AT senior_JJ clinician_NN the_ATI emphasis_NN was_BEDZ on_IN combining_VBG the_ATI symptoms_NNS and_CC signs_NNS of_IN malnutrition_NN in_IN such_ABL a_AT way_NN as_IN to_TO minimize_VB the_ATI false-positive_JJ diagnosis_NN of_IN malnutrition_NN (_( high_JJ specificity_NN )_) at_IN the_ATI expense_NN of_IN increasing_JJ false_JJ negatives_NNS (_( lower_JJR sensitivity_NN )_) after_IN reviewing_VBG several_AP patients_NNS together_RB , the_ATI nurse_NN and_CC one_CD1 of_IN the_ATI three_CD residents_NNS performed_VBN duplicate_NN , independent_JJ assessments_NNS of_IN 109_CD patients_NNS there_EX was_BEDZ perfect_JJ agreement_NN in_IN 100_CD (_( 91%_CD )_) of_IN 109_CD patients_NNS on_IN the_ATI SGA_NP rankings_NNS this_DT was_BEDZ 78%_NN above_IN the_ATI agreement_NN that_CS could_MD be_BE expected_VBN by_IN chance_NN alone_JJ (_( the_ATI kappa_NN statistic_NN was_BEDZ 0_CD 784_NN with_IN an_AT SE_NN of_IN 0_CD 08_NP and_CC 95%_NN confidence_NN interval_NN ranging_VBG from_IN 0_CD 62_CD to_IN 0_CD 94_CD )_) The_NP kappa_NN statistics_NNS for_IN the_ATI three_CD pairings_NNS of_IN the_ATI nurse_NN with_IN the_ATI individual_JJ residents_NNS were_BED 0_CD 60_CD , 0_CD 81_CD , and_CC 1_CD1 0_CD , respectively_RB , revealing_VBG some_DTI variation_NN in_IN agreement_NN between_IN different_JJ clinicians_NNS Hirsch_NP et_&FW al_APS (_( 13_CD )_) also_RB document_NN 79%_NN concordance_NN between_IN SGA_NP rankings_NNS of_IN residents_NNS and_CC specialists_NNS in_IN clinical_JJ nutrition_NN 174_CD ACCURACY_NPT OF_NPT NUTRITIONAL_NP ASSESSMENT_NP 175_CD since_CS there_EX is_BEZ no_ATI criterion_NN standard_NN for_IN the_ATI diagnosis_NN of_IN malnutrition_NN that_CS incorporates_VBZ body_NN composition_NN and_CC physiological_JJ function_NN (_( the_ATI in_RB vivo_RB neutron_NN activation_NN analysis_NN and_CC tritiated_JJ water_NN technique_NN are_BER the_ATI criterion_NN standards_NNS of_IN body_NN composition_NN alone_JJ ) _) , studies_NNS of_IN the_ATI accuracy_NN of_IN techniques_NNS of_IN nutritional_JJ status_NN assessment_NN have_HV related_VBN it_PP3 to_IN the_ATI development_NN of_IN complications_NNS judged_VBN to_TO result_VB from_IN malnutrition_NN therefore_RB , the_ATI criterion_NN standard_NN conditions_NNS that_CS constitute_VB the_ATI columns_NNS of_IN the_ATI usual_JJ 2x2_NN accuracy_NN table_NN constitute_VB patients_NNS who_WPR do_DO and_CC do_DO not_XNOT develop_VB nutrition-associated_JJ complications_NNS 176_CD the_ATI study_NN of_IN Detsky_NP et_&FW al_APS (_( 4_CD )_) once_RB again_RB provides_VBZ useful_JJ data_NNS on_IN the_ATI accuracy_NN of_IN SGA_NP the_ATI major_JJ results_NNS of_IN this_DT study_NN are_BER summarized_VBN in_IN Table_NP 2_CD nineteen_CD patients_NNS (_( 10%_CD of_IN the_ATI total_JJ studied_VBN )_) were_BED classified_VBN as_CS severely_RB malnourished_VBN (_( class_NN C_ZZ ) _) , 44_CD (_( 21%_CD )_) were_BED classified_VBN as_CS moderately_RB (_( or_CC suspected_VBD of_IN being_BEG )_) malnourished_VBN (_( class_NN B_ZZ )_) , and_CC 139_CD (_( 69%_NN )_) were_BED classified_VBN as_CS well_RB nourished_VBN (_( class_NN A_ZZ )_) the_ATI likelihood_NN ratios_NNS in_IN this_DT table_NN show_NN that_CS the_ATI SGA_NP is_BEZ a_AT powerful_JJ predictor_NN of_IN postoperative_JJ complications_NNS the_ATI likelihood_NN ratio_NN greater_JJR than_IN 4_CD for_IN severely_RB malnourished_JJ patients_NNS means_NNS that_CS this_DT designation_NN (_( class_NN C_ZZ )_) was_BEDZ more_QL than_IN four_CD times_NNS as_CS likely_JJ to_TO be_BE found_VBN in_IN patients_NNS with_IN , as_CS opposed_VBN to_IN patients_NNS without_IN , postoperative_JJ complications_NNS patients_NNS designated_VBN moderately_RB (_( or_CC suspected_VBD of_IN being_BEG )_) malnourished_VBN (_( class_NN B_ZZ )_) generated_VBN a_AT likelihood_NN ratio_NN of_IN close_RB to_TO unity_NN , indicating_VBG no_ATI clinically_RB important_JJ change_NN between_IN the_ATI preexamination_NN and_CC postexamination_JJ probability_NN of_IN postoperative_JJ complications_NNS (_( 20_202_NP , or_CC 10%_CD )_) finally_RB , well-nourished_JJ patients_NNS (_( class_NN A_ZZ )_) generated_VBN likelihood_NN ratios_NNS of_IN 0_CD 66_CD for_IN their_PP$ admission_NN SGA_NP and_CC only_RB 0_CD 38_CD for_IN their_PP$ minimum_NN SGA_NP , indicating_VBG a_AT lower_JJR than_IN average_JJ risk_NN of_IN postoperative_JJ complications_NNS 177_CD it_PP3 is_BEZ important_JJ to_TO note_VB that_CS SGA_NP performed_VBD better_JJR than_IN objective_JJ measurements_NNS of_IN the_ATI physical_JJ examination_NN , such_IN as_IN percentage_NN of_IN ideal_JJ weight_NN on_IN admission_NN and_CC percentage_NN of_IN body_NN fat_NN calculated_VBN from_IN anthropometric_JJ measurements_NNS the_ATI range_NN of_IN likelihood_NN ratios_NNS for_IN these_DTS variables_NNS displayed_VBN considerably_RB less_QL accuracy_NN than_IN those_DTS associated_VBN with_IN SGA_NP and_CC the_ATI combination_NN of_IN SGA_NP (_( Table_NP 3_CD )_) 178_CD laboratory_NN determination_NN of_IN serum_NN albumin_NN level_NN was_BEDZ also_RB shown_VBN to_TO be_BE an_AT accurate_JJ predictor_NN of_IN complications_NNS , associated_VBN with_IN a_AT progression_NN of_IN likelihood_NN ratios_NNS that_DT is_BEZ similar_JJ to_TO that_CS of_IN SGA_NP moreover_RB , the_ATI combination_NN of_IN SGA_NP and_CC albumin_NN provided_VBN slightly_RB improved_JJ accuracy_NN compared_VBN with_IN either_DTX method_NN alone_JJ however_RB , other_AP objective_JJ methods_NNS that_CS are_BER frequently_RB said_VBD to_TO be_BE useful_JJ techniques_NNS of_IN assessing_VBG nutritional_JJ status_NN (_( serum_NN transferrin_NN level_NN , creatinine-height_NN index_NN , and_CC total_JJ lymphocyte_NN count_NN )_) were_BED not_XNOT shown_VBN to_TO be_BE accurate_JJ predictors_NNS of_IN complications_NNS (_( 4_CD )_) 179_CD the_ATI study_NN by_IN Windsor_NP and_CC Hill_NPL (_( 7_CD )_) provides_VBZ similar_JJ data_NNS demonstrating_VBG the_ATI predictive_JJ validity_NN of_IN their_PP$ system_NN of_IN the_ATI 102_CD patients_NNS , 43_CD (_( 42%_NN )_) were_BED in_IN group_NN 1_CD1 (_( analogous_JJ to_IN SGA_NP class_NN A_ZZ )_) , 17_CD (_( 17%_CD )_) were_BED in_IN group_NN 2_CD (_( analogous_JJ to_IN SGA_NP class_NN B_ZZ )_) , and_CC 42_CD (_( 41%_CD )_) were_BED in_IN group_NN 3_CD (_( analogous_JJ to_IN SGA_NP class_NN C_ZZ )_) the_ATI rate_NN of_IN major_JJ complications_NNS , septic_JJ complications_NNS , and_CC pneumonia_NN in_IN the_ATI three_CD groups_NNS was_BEDZ significantly_RB different_JJ , and_CC the_ATI likelihood_NN ratios_NNS for_IN predicting_VBG major_JJ complications_NNS showed_VBD a_AT similar_JJ progression_NN to_IN SGA_NP of_IN 0_CD 53_CD , 0_CD 69_CD , and_CC 1_CD1 8_CD for_IN groups_NNS 1_CD1 , 2_CD , and_CC 3_CD , respectively_RB 180_CD finally_RB , the_ATI predictive_JJ validity_NN of_IN SGA_NP was_BEDZ also_RB reported_VBN by_IN the_ATI Veterans_NNS Affairs_NNS perioperative_JJ total_JJ parenteral_JJ nutrition_NN randomized_VBN trial_NN (_( 11_CD )_) that_CS enrolled_VBN only_RB malnourished_JJ patients_NNS of_IN varying_JJ degrees_NNS Among_NP the_ATI control_NN patients_NNS , those_DTS in_IN SGA_NP class_NN C_ZZ had_HVD higher_JJR rates_NNS of_IN major_JJ infectious_JJ complications_NNS and_CC noninfectious_JJ complications_NNS 181_CD some_DTI have_HV also_RB reported_VBN the_ATI high_JJ correlation_NN between_IN SGA_NP and_CC other_AP measures_NNS of_IN nutritional_JJ status_NN assessments_NNS that_CS are_BER felt_VBN to_TO be_BE perhaps_RB more_QL objective_JJ , such_IN as_IN anthropometry_NN (_( 3,13_CD )_) , albumin_NN (_( 3,13_CD )_) , total_JJ serum_NN protein_NN (_( 3,13_CD )_) , and_CC criterion_NN standard_JJ measures_NNS of_IN body_NN composition_NN Windsor_NP and_CC Hill_NPL (_( 7_CD )_) also_RB show_VB good_JJ correlations_NNS between_IN their_PP$ system_NN and_CC anthropometry_NN , body_NN composition_NN , and_CC objective_JJ measures_NNS of_IN the_ATI physiological_JJ functions_NNS in_IN their_PP$ method_NN (_( eg_NN , grip_NN strength_NN and_CC respiratory_JJ muscle_NN index_NN )_) 182_CD ARE_NPT THESE_NPT SYMPTOMS_NPT OR_NPT SIGNS_NPT EVER_NP NORMAL_NP ? 183_CD many_AP individuals_NNS are_BER thin_JJ , and_CC this_DT in_IN itself_PPL does_DOZ not_XNOT constitute_VB malnutrition_NN however_RB , we_PP1AS should_MD note_VB that_CS overnutrition_NN or_CC obesity_NN , defined_VBN as_IN an_AT excess_NN of_IN adipose_NN tissue_NN or_CC by_IN the_ATI degree_NN to_TO which_WDTR a_AT patient's_NN$ weight_NN exceeds_VBZ that_CS which_WDTR is_BEZ judged_VBN ideal_JJ by_IN some_DTI anthropometric_JJ formula_NN , is_BEZ also_RB a_AT common_JJ problem_NN in_IN hospitalized_VBN patients_NNS epidemiologic_JJ studies_NNS have_HV shown_VBN that_CS a_AT 20%_NP excess_JJ over_IN ideal_JJ weight_NN imparts_VBZ a_AT health_NN risk_NN similarly_RB , obesity_NN has_HVZ been_BEN shown_VBN to_TO place_VB patients_NNS at_IN a_AT high_JJ risk_NN of_IN suffering_VBG from_IN surgical_JJ complications_NNS , such_ABL as_IN poor_JJ wound_NN healing_NN and_CC venous_JJ thrombosis_NN 184_CD SPECIAL_NPT WAYS_NPT TO_NP LEARN_NP , TEST_NP YOURSELF_NP , AND_NPT CORRECT_NPT DEFICIENCIES_NP IN_NP THE_NPT ELICITATION_NPT OF_NPT THESE_NPT SYMPTOMS_NPT AND_NP SIGNS_NP 185_CD clinicians_NNS who_WPR wish_VB to_TO become_VB competent_JJ at_IN nutritional_JJ assessment_NN can_MD do_DO so_QL by_IN applying_VBG the_ATI following_JJ strategies_NNS : first_OD , they_PP3AS should_MD undergo_VB a_AT training_NN period_NN with_IN other_AP learners_NNS in_IN which_WDTR they_PP3AS discuss_VB each_DT of_IN the_ATI features_NNS of_IN the_ATI technique_NN together_RB and_CC review_NN a_AT series_NN of_IN patients_NNS for_IN each_DT of_IN the_ATI findings_NNS in_IN particular_JJ , the_ATI group_NN should_MD review_VB methods_NNS of_IN eliciting_VBG the_ATI history_NN , performing_VBG the_ATI inspection_NN , and_CC standardizing_VBG terms_NNS such_ABL as_CS normal_JJ , mild_JJ , moderate_JJ , and_CC severe_JJ next_AP , they_PP3AS should_MD rank_VB several_AP patients_NNS together_RB and_CC reach_VB consensus_NN about_IN what_WDT constitutes_VBZ an_AT A_ZZ , B_ZZ , or_CC C_ZZ ranking_NN finally_RB , they_PP3AS should_MD perform_VB their_PP$ own_AP tests_NNS of_IN clinical_JJ reproducibility_NN by_IN seeing_VBG a_AT series_NN of_IN (_( perhaps_RB 10_CD )_) patients_NNS independently_RB and_CC comparing_VBG their_PP$ rankings_NNS in_IN order_NN to_TO improve_VB the_ATI precision_NN and_CC validity_NN of_IN their_PP$ elicitation_NN of_IN the_ATI individual_JJ features_NNS of_IN the_ATI SGA_NP , they_PP3AS should_MD consider_VB verification_VB strategies_NNS , such_ABL as_CS asking_VBG the_ATI patient's_NN$ spouse_NN about_IN the_ATI features_NNS of_IN the_ATI history_NN , examining_VBG physician_NN records_NNS for_IN previous_JJ weights_NNS , asking_VBG whether_CS the_ATI patient's_NN$ clothes_NNS now_RN fit_VB loosely_RB , and_CC examining_VBG recent_JJ and_CC remote_JJ pictures_NNS of_IN the_ATI patient_NN 186_CD clinicians_NNS can_MD learn_VB to_TO perform_VB SGA_NP of_IN nutritional_JJ status_NN in_IN a_AT precise_JJ fashion_NN the_ATI features_NNS of_IN the_ATI history_NN and_CC physical_JJ examination_NN are_BER shown_VBN in_IN Table_NP 1_CD1 we_PP1AS recommend_VB the_ATI group_NN approach_NN to_TO standardize_VB the_ATI definitions_NNS of_IN the_ATI features_NNS of_IN the_ATI history_NN and_CC physical_JJ examination_NN contained_VBD in_IN SGA_NP and_CC to_TO gain_VB competency_NN in_IN their_PP$ application_NN in_IN doing_VBG so_PN , we_PP1AS recommend_VB that_CS clinicians_NNS train_NN themselves_PPLS to_TO be_BE less_QL sensitive_JJ and_CC more_QL specific_JJ in_IN labeling_VBG patients_NNS as_IN malnourished_VBN since_CS there_EX is_BEZ no_ATI criterion_NN standard_NN for_IN malnutrition_NN that_CS incorporates_VBZ body_NN composition_NN and_CC physiological_JJ function_NN , this_DT clinical_JJ skill_NN should_MD be_BE used_VBN as_IN a_AT prognostic_JJ instrument_NN to_TO identify_VB patients_NNS who_WPR are_BER at_IN high_JJ risk_NN of_IN developing_VBG complications_NNS and_CC who_WPR may_MD benefit_VB from_IN nutritional_JJ repletion_NN and_CC support_NN the_ATI technique_NN is_BEZ an_AT accurate_JJ predictor_NN of_IN patients_NNS who_WPR are_BER at_IN higher_JJR risk_NN of_IN developing_VBG complications_NNS such_IN as_IN infection_NN or_CC poor_JJ wound_NN healing_NN 187_CD the_ATI Emerging_NP Role_NP of_IN Vitamins_NNS as_CS Antioxidants_NNS >_&FO 188_CD the_ATI recommended_VBN dietary_JJ allowances_NNS for_IN vitamins_NNS are_BER designed_VBN to_TO estimate_VB the_ATI levels_NNS of_IN intake_NN needed_VBN to_TO prevent_VB known_JJ deficiency_NN states_NNS in_IN most_QL healthy_JJ people_NNS evidence_NN is_BEZ now_RN accumulating_JJ that_CS some_DTI vitamins_NNS may_MD have_HV health-promoting_VBN benefits_NNS in_IN amounts_NNS higher_JJR than_IN the_ATI current_JJ recommendations.=20_CD 189_CD the_ATI antioxidant_JJ properties_NNS of_IN vitamins_NNS may_MD play_VB a_AT role_NN in_IN treating_VBG or_CC preventing_VBG a_AT variety_NN of_IN disorders_NNS , including_IN atherosclerosis_NN , age-related_JJ cataracts_NNS and_CC macular_NN degeneration_NN , and_CC some_DTI cancers_NNS this_DT article_NN reviews_NNS the_ATI possible_JJ risks_NNS and_CC benefits_NNS of_IN high_JJ intakes_NNS of_IN antioxidant_NN vitamins_NNS , including_IN the_ATI controversy_NN about_IN supplementation_NN 190_CD it_PP3 has_HVZ now_RN been_BEN about_RB 100_CD years_NNS since_IN the_ATI discovery_NN that_CS vitamin_NN deficiencies_NNS were_BED responsible_JJ for_IN many_AP common_JJ diseases_NNS for_IN example_NN , niacin_NN deficiency_NN is_BEZ responsible_JJ for_IN pellagra_NN ; vitamin_NN C_ZZ (_( ascorbic_JJ acid_NN )_) deficiency_NN , scurvy_NN ; vitamin_NN D_ZZ deficiency_NN , rickets_NNS (_( in_IN children_NNS )_) and_CC osteomalacia_NN (_( in_IN adults_NNS )_) ; and_CC thiamine_NN deficiency_NN , beriberi_NN relatively_RB small_JJ amounts_NNS of_IN these_DTS vitamins_NNS (_( termed_VBD micronutrients_NNS )_) are_BER necessary_JJ to_TO prevent_VB these_DTS deficiency_NN states_NNS ; for_IN example_NN , 10_CD mg_d_NN of_IN vitamin_NN C_ZZ will_MD prevent_VB scurvy_NN the_ATI recommended_VBN dietary_JJ allowances_NNS (_( RDAs_NP )_) are_BER the_ATI result_NN of_IN a_AT rigorous_JJ attempt_NN to_TO scientifically_RB determine_VB how_WRB much_AP of_IN each_DT vitamin_NN most_QL healthy_JJ people_NNS need_NN to_TO consume_VB to_TO prevent_VB the_ATI known_VBN and_CC agreed_VBD on_IN classic_JJ deficiency_NN states_NNS there_EX is_BEZ now_RN a_AT growing_JJ recognition_NN , however_RB , that_CS some_DTI vitamins_NNS may_MD have_HV important_JJ disease-preventing_NN and_CC health-promoting_NN effects_NNS at_IN intakes_NNS higher_JJR than_IN the_ATI RDAs_NP (_( Table_NP 1_CD1 )_) that_DT is_BEZ , the_ATI amount_NN of_IN a_AT vitamin_NN necessary_JJ for_IN optimum_JJ health_NN may_MD be_BE higher_JJR than_IN that_DT needed_VBN to_TO prevent_VB deficiency_NN states_NNS the_ATI RDAs_NP are_BER not_XNOT minimal_JJ requirements_NNS , and_CC they_PP3AS do_DO not_XNOT claim_VB to_TO represent_VB optimal_JJ intakes_NNS this_DT makes_VBZ their_PP$ utility_NN confusing_JJ for_IN the_ATI practicing_VBG clinician_NN the_ATI RDAs_NP were_BED designed_VBN for_IN population_NN groups_NNS ; there_EX are_BER many_AP conditions_NNS that_WPR require_VB adjustments_NNS for_IN any_DTI specific_JJ individual_JJ in_IN addition_NN , the_ATI RDAs_NP continue_VB to_TO include_VB elderly_JJ persons_NNS within_IN the_ATI category_NN of_IN all_ABN persons_NNS above_IN 51_CD years_NNS of_IN age_NN , which_WDTR may_MD not_XNOT be_BE appropriate_JJ for_IN certain_JJ vitamins_NNS and_CC minerals_NNS 191_CD it_PP3 is_BEZ difficult_JJ to_TO find_VB a_AT balanced_JJ assessment_NN of_IN the_ATI potential_JJ antioxidant_NN role_NN for_IN vitamins_NNS definitive_JJ and_CC incontrovertible_JJ experimental_JJ conclusions_NNS are_BER still_RB lacking_JJ and_CC may_MD be_BE years_NNS away_RP this_DT article_NN is_BEZ designed_VBN to_TO clarify_VB what_WDT is_BEZ currently_RB known_VBN about_IN the_ATI emerging_VBG role_NN of_IN antioxidants_NNS in_IN health_NN and_CC disease_NN in_IN adults_NNS , particularly_RB the_ATI role_NN of_IN vitamins_NNS as_CS antioxidants_NNS , and_CC to_TO allow_VB physicians_NNS to_TO intelligently_RB counsel_NN adult_JJ patients_NNS who_WPR have_HV questions_NNS about_IN high-dose_NN vitamin_NN intake_NN or_CC may_MD already_RB be_BE consuming_VBG vitamins_NNS for_IN their_PP$ antioxidant_NN properties_NNS this_DT article_NN concerns_VBZ antioxidative_JJ effects_NNS and_CC does_DOZ not_XNOT cover_VB all_ABN potential_JJ positive_JJ effects_NNS of_IN high-dose_NN vitamin_NN intake_NN 192_CD THE_NPT DAMAGING_NPT EFFECTS_NPT OF_NP OXIDATION_NP 193_CD oxygen_NN is_BEZ essential_JJ for_IN human_JJ life_NN , and_CC oxygen_NN therapy_NN has_HVZ many_AP benefits_NNS however_RB , like_IN most_QL other_AP chemicals_NNS , it_PP3 can_MD also_RB be_BE toxic_JJ Environments_NNS with_IN high_JJ levels_NNS of_IN oxygen_NN are_BER known_VBN to_TO injure_VB the_ATI eyes_NNS (_( retinopathy_NN of_IN prematurity_NN )_) , lungs_NNS (_( adult_JJ respiratory_JJ distress_NN syndrome_NN , atelectasis_NN , and_CC bronchopulmonary_NN dysplasia_NN )_) , and_CC central_JJ nervous_JJ system_NN (_( seizures_NNS )_) in_IN addition_NN , potentially_RB toxic_JJ intermediate_JJ compounds_NNS are_BER generated_VBN as_IN oxygen_NN is_BEZ metabolized_VBN normally_RB within_IN the_ATI body_NN as_CS electrons_NNS are_BER added_VBN to_TO oxygen_NN (_( oxygen_NN reduction_NN )_) , free_JJ radicals_NNS (_( possessing_VBG one_CD1 or_CC more_QL unpaired_JJ electrons_NNS that_WPR make_VB them_PP3OS very_QL reactive_JJ to_IN other_AP molecules_NNS )_) and_CC other_AP unstable_JJ compounds_NNS are_BER generated_VBN (_( Figure_NP 1_CD1 )_) subcellular_NN organelles_NNS , membranes_NNS , and_CC various_JJ enzymes_NNS in_IN all_ABN tissues_NNS , including_IN the_ATI cytochrome_NN P-450_NP system_NN in_IN the_ATI liver_NN , can_MD reduce_VB oxygen_NN and_CC make_VB free_JJ radicals_NNS highly_RB reactive_JJ oxygen_NN metabolites_NNS are_BER also_RB generated_VBN by_IN the_ATI mitochondrial_JJ respiratory_JJ chain_NN , by_IN detoxification_NN of_IN xenobiotics_NNS by_IN cytochromes_NNS , and_CC during_IN metabolism_NN of_IN arachidonic_JJ acid_NN that_CS generates_NNS prostaglandins_NNS and_CC leukotrienes_NNS Cigarette_NP smoke_NN , ozone_NN , carbon_NN tetrachloride_NN , and_CC ionizing_VBG radiation_NN appear_VB to_TO be_BE toxic_JJ in_IN part_NN because_IN of_IN free_JJ radical_JJ generation_NN 194_CD the_ATI controlled_JJ production_NN and_CC release_NN of_IN free_JJ radicals_NNS allow_VB phagocytes_NNS to_TO kill_VB invading_JJ organisms_NNS and_CC may_MD be_BE successfully_RB exploited_VBN in_IN some_DTI forms_NNS of_IN cancer_NN chemotherapy_NN however_RB , free_JJ radicals_NNS from_IN the_ATI environment_NN or_CC generated_VBN within_IN the_ATI body_NN can_MD also_RB cause_VB damage_NN when_WRB reactive_JJ electrons_NNS are_BER passed_VBN from_IN molecule_NN to_TO molecule_VB , a_AT cascade_NN of_IN injury_NN can_MD result_VB the_ATI body_NN has_HVZ many_AP natural_JJ defenses_NNS ; but_CC , over_IN time_NN or_CC under_IN stressful_JJ conditions_NNS , these_DTS defenses_NNS may_MD wane_VB or_CC be_BE overwhelmed_VBN The_NP accumulation_NN of_IN free_JJ radical_JJ damage_NN can_MD lead_VB to_TO injury_NN , disease_NN , or_CC aging_VBG phenomena_NNS for_IN example_NN , strenuous_JJ physical_JJ exercise_NN can_MD cause_VB free_JJ radical-mediated_JJ muscle_NN cell_NN injury_NN that_WPR may_MD be_BE prevented_VBN by_IN antioxidant_NN administration_NN free_JJ radicals_NNS can_MD react_VB with_IN fatty_JJ acids_NNS in_IN cell_NN membranes_NNS to_TO produce_VB lipid_NN peroxides_NNS , which_WDTR in_IN turn_NN inhibit_VB cellular_JJ enzymes_NNS or_CC decompose_VB into_IN other_AP reactive_JJ metabolites_NNS lipid_NN peroxidation_NN can_MD lead_VB to_IN accumulation_NN of_IN lipofuscin_NN in_IN amounts_NNS found_VBN inversely_RB related_VBN to_IN longevity_NN free_JJ radicals_NNS also_RB impair_VB generation_NN of_IN adenosine_NN triphosphate_NN , damage_NN DNA_NP , depolymerize_NN mucopolysaccharides_NNS , and_CC inactivate_NN enzymes_NNS by_IN protein_NN sulfhydryl_NN oxidation_NN free_JJ radicals_NNS may_MD play_VB a_AT role_NN in_IN cancer_NN or_CC immune_JJ disorders_NNS and_CC have_HV been_BEN implicated_VBN in_RP over_IN 50_CD diseases_NNS 195_CD both_ABX intracellular_NN and_CC extracellular_JJ protective_JJ antioxidant_NN systems_NNS exist_VB enzymes_NNS such_IN as_IN superoxide_NN dismutase_NN , catalase_NN , and_CC glutathione_NN peroxidase_NN are_BER important_JJ intracellularly_RB antioxidants_NNS can_MD also_RB be_BE divided_VBN into_IN those_DTS that_CS are_BER water_NN soluble_JJ (_( nonenzymatic_JJ )_) (_( vitamin_NN C_ZZ , uric_JJ acid_NN , bilirubin_NN , glutathione_NN , albumin_NN , ferritin_NN , transferrin_NN , and_CC ceruloplasmin_NN )_) or_CC lipid_JJ soluble_JJ (_( vitamin_NN E_ZZ (_( tocopherol_NN )_) , carotenoids_NNS (_( including_IN beta-carotene_NN )_) , and_CC ubiquinone_NN (_( coenzyme_NN Q_ZZ )_) )_) this_DT dichotomy_NN helps_VBZ predict_VB or_CC explain_VB their_PP$ different_JJ modes_NNS of_IN action_NN estrogens_NNS like_IN estriol_NN and_CC estradiol-17beta_CD-CD are_BER naturally_RB occurring_VBG antioxidants_NNS that_DT may_MD have_HV the_ATI capacity_NN to_TO protect_VB lipids_NNS from_IN oxidation_NN , while_CS corticosterone_NN and_CC cortisone_NN have_HV mild_JJ prooxidant_NN properties_NNS various_JJ foods_NNS (_( eg_NN , soybeans_NNS , garlic_NN , and_CC tea_NN )_) also_RB have_HV antioxidant_NN properties_NNS 196_CD OXIDATION_NPT AND_NP ATHEROGENESIS_NP 197_CD 11_CD oxidative_JJ damage_NN appears_VBZ to_TO play_VB a_AT significant_JJ role_NN in_IN atherogenesis_NN (_( Figure_NP 2_CD )_) oxidized_JJ low-density_NN lipoprotein_NN (_( LDL_NP )_) cholesterol_NN and_CC probably_RB other_AP oxidized_JJ lipoproteins_NNS such_ABL as_CS small_JJ , dense_JJ , LDL_NP particles_NNS and_CC lipoprotein_NN (_( a_AT )_) , unlike_IN unmodified_JJ LDL_NP , can_MD bypass_VB a_AT down-regulation_JJ protective_JJ system_NN and_CC become_VB actively_RB taken_VBN up_RP by_IN special_JJ scavenger_NN receptors_NNS on_IN monocytes_NNS and_CC macrophages_NNS in_IN the_ATI subendothelial_JJ space_NN of_IN blood_NN vessel_NN walls_NNS oxidized_JJ LDL_NP within_IN the_ATI vessel_NN wall_NN eventually_RB leads_VBZ to_TO foam_VB cell_NN formation_NN , attracting_VBG monocytes_NNS and_CC inhibiting_JJ macrophage_NN movement_NN out_RP of_IN the_ATI vessel_NN wall_NN , which_WDTR further_JJB induces_VBZ endothelial_JJ cell_NN damage_NN and_CC begins_VBZ atherogenesis_NN Glycation_NN (_( or_CC glycosylation_JJ )_) of_IN proteins_NNS , as_IN occurs_VBZ in_IN diabetes_NN mellitus_JJ , can_MD accelerate_VB vascular_VB injury_NN caused_VBN by_IN oxidized_JJ LDL_NP Intervention_NN directed_VBN at_IN reducing_VBG the_ATI oxidation_NN of_IN LDL_NP may_MD modify_VB the_ATI process_NN of_IN atherogenesis_NN and_CC lesion_NN development_NN the_ATI susceptibility_NN of_IN LDL_NP to_TO lipid_VB oxidation_NN in_IN vitro_NN is_BEZ associated_VBN with_IN the_ATI severity_NN of_IN atherosclerosis_NN probucol_RB , a_AT drug_NN found_VBN to_TO lower_JJR LDL_NP cholesterol_NN independent_NN of_IN the_ATI LDL_NP receptor_NN , also_RB has_HVZ lipophilic_JJ antioxidant_NN activity_NN that_CS appears_VBZ to_TO delay_VB lipid_NN peroxidation_NN and_CC reduce_VB atherosclerotic_JJ lesion_NN development_NN (_( independent_NN of_IN its_PP$ effect_NN of_IN lowering_VBG cholesterol_NN levels_NNS )_) a_AT recent_JJ National_NP Institutes_NNS of_IN Health_NP consensus_NN conference_NN concluded_VBD that_CS clinical_JJ trials_NNS of_IN antioxidant_NN supplementation_NN should_MD be_BE encouraged_VBN based_VBN on_IN the_ATI promising_JJ evidence_NN now_RN available_JJ 198_CD the_ATI LDL_NP particle_NN can_MD also_RB carry_VB molecules_NNS of_IN vitamin_NN E_ZZ , beta-carotene_NN , and_CC coenzyme_NN Q_ZZ that_DT may_MD counteract_VB or_CC delay_NN lipid_NN peroxidation_NN vitamin_NN C_ZZ may_MD intercept_VB oxidants_NNS in_IN the_ATI aqueous_JJ phase_NN before_CS they_PP3AS can_MD attack_VB and_CC damage_NN lipids_NNS , and_CC it_PP3 can_MD also_RB modify_VB LDL_NP to_TO increase_NN its_PP$ resistance_NN to_TO metal_NN ion-dependent_NN oxidation_NN high-dose_NN tocopherol_NN (_( vitamin_NN E_ZZ )_) supplementation_NN (_( but_CC not_XNOT beta_NN carotene_NN )_) decreases_VBZ LDL_NP susceptibility_NN to_IN oxidation_NN in_IN vitro_NN 199_CD considerable_JJ synergism_NN exists_VBZ among_IN antioxidants_NNS for_IN example_NN , vitamin_NN C_ZZ helps_VBZ regenerate_JJ oxidized_JJ vitamin_NN E_ZZ back_RP to_IN its_PP$ reduced_VBD (_( antioxidant_NN )_) state_NN in_IN turn_NN , oxidized_JJ vitamin_NN C_ZZ can_MD itself_PPL be_BE regenerated_VBN via_IN glutathione_NN , using_VBG selenium_NN as_IN a_AT cofactor_NN ascorbic_JJ acid_NN supplementation_NN can_MD maintain_VB red_JJ blood_NN cell_NN glutathione_NN , an_AT important_JJ intracellular_NN antioxidant_NN , in_IN its_PP$ effective_JJ state_NN 200_CD observational_JJ and_CC epidemiologic_JJ studies_NNS strongly_RB suggest_VB , but_CC do_DO not_XNOT conclusively_RB prove_VB , that_CS antioxidant_NN intake_NN is_BEZ inversely_RB associated_VBN with_IN cardiovascular_NN disease_NN and_CC mortality_NN population_NN studies_NNS suggest_VB that_CS alpha-tocopherol_NN serum_NN levels_NNS show_VB a_AT stronger_JJR correlation_NN with_IN ischemic_JJ heart_NN disease_NN than_IN either_DTX cholesterol_NN levels_NNS or_CC diastolic_JJ blood_NN pressure_NN a_AT cohort_NN study_NN of_IN 11000_CD people_NNS found_VBN a_AT substantial_JJ reduction_NN in_IN cardiovascular_NN and_CC total_JJ deaths_NNS in_IN persons_NNS with_IN higher_JJR intakes_NNS of_IN vitamin_NN C_ZZ those_DTS persons_NNS who_WPR took_VBD ascorbic_JJ acid_NN supplements_NNS and_CC had_HVD a_AT reasonable_JJ dietary_JJ intake_NN of_IN vitamin_NN C_ZZ did_DOD better_JJR than_IN those_DTS who_WPR just_RB consumed_JJ vitamin_NN C_ZZ in_IN their_PP$ diet_NN a_AT 12-year_CD-CD follow-up_NN of_IN the_ATI Prospective_NP Basel_NP (_( Switzerland_NP )_) Study_NP found_VBD that_CS either_DTX low_JJ plasma_NN carotene_NN or_CC vitamin_NN C_ZZ levels_NNS are_BER associated_VBN with_IN a_AT significant_JJ increase_NN in_IN the_ATI risk_NN for_IN ischemic_JJ heart_NN disease_NN and_CC , if_CS both_ABX are_BER low_JJ , cerebrovascular_JJB stroke_NN 201_CD 15_CD in_IN an_AT 8-year_JJ follow-up_NN of_IN 80000_CD women_NNS in_IN the_ATI Nurses'_NNS$ Health_NP Study_NP , those_DTS in_IN the_ATI top_NN fifth_OD of_IN the_ATI cohort_NN with_IN respect_NN to_TO vitamin_NN E_ZZ intake_NN (_( averaging_VBG 200_CD IU_d_NP , mostly_RB consumed_VBN as_IN a_AT supplement_NN )_) had_HVD a_AT relative_JJ risk_NN for_IN major_JJ coronary_JJ artery_NN disease_NN of_IN 0.66_CD after_IN adjusting_VBG for_IN age_NN and_CC smoking_VBG , compared_VBD with_IN those_DTS in_IN the_ATI lowest_JJT fifth_OD (_( consuming_VBG about_RB 3_CD IU_d_NP )_) as_CS expected_VBN , there_EX was_BEDZ little_JJ apparent_JJ benefit_NN to_IN the_ATI short-term_JJB use_NN of_IN tocopherol_NN , but_CC those_DTS who_WPR took_VBD supplements_VBZ for_IN more_QL than_IN 2_CD years_NNS had_HVD a_AT relative_JJ risk_NN of_IN 0.59_NP although_CS not_XNOT statistically_RB significant_JJ , there_EX were_BED trends_NNS toward_IN a_AT reduction_NN in_IN risk_NN for_IN mortality_NN from_IN cardiovascular_NN causes_NNS and_CC ischemic_JJ stroke_NN , as_QL well_RB as_IN decreased_VBD risk_NN for_IN coronary_JJ artery_NN surgery_NN and_CC overall_JJB mortality_NN 202_CD 16_CD an_AT evaluation_NN involving_VBG almost_RB 40000_CD men_NNS in_IN the_ATI Health_NP Professionals_NPT Follow-up_NP Study_NP after_IN 5_CD years_NNS found_VBN a_AT lower_JJR risk_NN for_IN coronary_JJ disease_NN among_IN men_NNS with_IN higher_JJR vitamin_NN E_ZZ intakes_NNS those_DTS consuming_VBG more_AP than_IN 60_CD IU_d_NP of_IN vitamin_NN E_ZZ had_HVD a_AT relative_JJ risk_NN of_IN 0.64_NP compared_VBN with_IN those_DTS consuming_VBG less_AP than_IN 7.5_JJ IU_d_NP compared_VBN with_IN men_NNS who_WPR did_DOD not_XNOT take_VB tocopherol_NN supplements_NNS , men_NNS who_WPR took_VBD at_RB least_RB 100_CD IU_d_NP for_IN at_RB least_RB 2_CD years_NNS had_HVD a_AT relative_JJ risk_NN of_IN coronary_JJ disease_NN of_IN 0.63_NP Without_NP supplements_NNS , the_ATI top_JJB quintile_NN of_IN the_ATI cohort_NN consumed_VBN only_RB 8_CD IU_d_NP of_IN vitamin_NN E._NP carotene_NN intake_NN was_BEDZ inversely_RB associated_VBN with_IN the_ATI risk_NN for_IN coronary_JJ heart_NN disease_NN in_IN current_JJ or_CC former_AP smokers_NNS but_CC not_XNOT among_IN those_DTS who_WPR had_HVD never_RB smoked_VBN a_AT high_JJ intake_NN of_IN vitamin_NN C_ZZ was_BEDZ not_XNOT associated_VBN with_IN a_AT lower_JJR risk_NN for_IN coronary_JJ disease_NN in_IN either_DTX this_DT study_NN or_CC the_ATI Nurses'_NNS$ Health_NP Study_NP 203_CD 17_CD among_IN 333_CD physicians_NNS participating_VBG in_IN the_ATI Physicians'_NNS$ Health_NP Study_NP who_WPR had_HVD evidence_NN of_IN coronary_JJ artery_NN disease_NN (_( chronic_JJ stable_JJ angina_NN or_CC coronary_JJ revascularization_NN , but_CC no_ATI prior_RB myocardial_JJ infarction_NN or_CC stroke_NN )_) , preliminary_JJ analysis_NN has_HVZ found_VBN that_CS the_ATI group_NN taking_NN beta_NN carotene_NN supplements_NNS (_( 50_CD mg_NNU every_AT other_AP day_NN )_) had_HVD 40%_NP fewer_AP coronary_JJ events_NNS than_IN the_ATI control_NN group_NN 204_CD 18_CD while_CS antioxidants_NNS appear_VB to_TO be_BE protective_JJ against_IN cardiovascular_NN disease_NN , prooxidants_NNS likely_JJ increase_NN the_ATI risk_NN the_ATI best_JJT example_NN is_BEZ iron_JJ iron_NN is_BEZ intimately_RB associated_VBN with_IN aerobic_JJ metabolism_NN It_NP is_BEZ necessary_JJ in_IN the_ATI transport_NN , storage_NN , and_CC use_NN of_IN oxygen_NN , as_QL well_RB as_CS being_BEG an_AT essential_JJ part_NN of_IN oxidases_NNS , oxygenases_NNS , and_CC antioxidant_NN enzymes_NNS however_RB , it_PP3 also_RB has_HVZ the_ATI ability_NN to_TO generate_VB oxidants_NNS (_( Figure_NP 1_CD1 )_) , and_CC therefore_RB the_ATI body_NN tries_VBZ to_TO sequester_VB iron_NN in_IN poorly_RB reactive_JJ forms_NNS (_( eg_NN , transferrin_NN , hemosiderin_NN , and_CC ferritin_NN )_) the_ATI exact_JJ role_NN of_IN iron_NN in_IN coronary_JJ heart_NN disease_NN remains_VBZ controversial_JJ however_RB , ferritin_NN levels_NNS do_DO reflect_VB the_ATI body's_NN$ iron_NN load_NN , and_CC a_AT high_JJ ferritin_NN level_NN has_HVZ been_BEN found_VBN to_TO be_BE associated_VBN with_IN an_AT increased_VBN relative_JJ risk_NN for_IN myocardial_JJ infarction_NN a_AT recent_JJ analysis_NN of_IN the_ATI ongoing_NN Health_NP Professionals_NP Follow-up_NP Study_NP found_VBD that_CS heme_NN iron_NN intake_NN , but_CC not_XNOT total_JJ iron_NN intake_NN , was_BEDZ associated_VBN with_IN an_AT increased_JJ serum_NN level_NN of_IN ferritin_NN as_QL well_RB as_IN increased_JJ incidence_NN of_IN fatal_JJ coronary_JJ disease_NN and_CC nonfatal_JJ myocardial_JJ infarction_NN one_CD1 reason_NN that_CS women_NNS are_BER protected_VBN from_IN cardiovascular_NN disease_NN until_IN after_IN menopause_NN may_MD be_BE their_PP$ low_JJ iron_NN stores_NNS resulting_JJ from_IN menstruation_NN 205_CD 19_CD AGE-ASSOCIATED_NPT EYE_NPT DISEASE_NP 206_NP 20_CD the_ATI prevalence_NN of_IN cataract_NN formation_NN in_IN the_ATI lens_NN of_IN the_ATI eye_NN increases_NNS with_IN age_NN senile_JJ cataract_NN is_BEZ found_VBN in_RP over_IN 45%_NN of_IN persons_NNS above_IN 75_CD years_NNS of_IN age_NN and_CC may_MD be_BE associated_VBN with_IN markedly_RB decreased_VBD vision_NN and_CC quality_NN of_IN life_NN cataract_NN removal_NN is_BEZ also_RB one_CD1 of_IN the_ATI most_QL commonly_RB performed_VBN surgical_JJ procedures_NNS in_IN the_ATI United_NP States_NP oxidation_NN may_MD cause_VB or_CC be_BE associated_VBN with_IN cortical_JJ and_CC nuclear_JJ cataract_NN , possibly_RB owing_IN to_IN the_ATI formation_NN of_IN free_JJ radicals_NNS from_IN the_ATI hydrogen_NN peroxide_NN present_NN in_IN aqueous_JJ humor_NN , near-ultraviolet_NN radiation_NN , and_or_CC glucose_NN oxidation_NN in_IN diabetes_NN mellitus_JJ 207_CD 21_CD glutathione_NN and_CC vitamin_NN C_ZZ are_BER present_NN in_IN the_ATI lens_NN of_IN the_ATI eye_NN , as_IN are_BER the_ATI antioxidant_NN enzymes_NNS glutathione_NN peroxidase_NN , catalase_NN , and_CC superoxide_NN dismutase_NN animal_NN studies_NNS suggest_VB an_AT age-related_JJ decline_NN in_IN ascorbate_NN levels_NNS in_IN the_ATI lens_NN levels_NNS of_IN ascorbic_JJ acid_NN are_BER low_JJ or_CC absent_JJ in_IN cataractous_JJ lenses_NNS there_EX is_BEZ a_AT statistical_JJ association_NN between_IN supplementary_JJ ascorbic_JJ acid_NN and_CC tocopherol_NN intake_NN over_IN the_ATI previous_JJ 5_CD years_NNS and_CC decreased_VBD risk_NN for_IN senile_JJ cataract_NN of_IN 2_CD 1_2_CD times_NNS persons_NNS who_WPR consume_VB more_AP than_IN 300_CD mg_d_NN of_IN ascorbic_JJ acid_NN or_CC 400_CD IU_d_NP of_IN tocopherol_NN have_HV about_IN one_CD1 third_OD the_ATI risk_NN of_IN developing_VBG cataracts_NNS Persons_NP who_WPR consumed_VBD less_AP than_IN 125_CD mg_d_NN of_IN ascorbic_JJ acid_NN over_IN the_ATI previous_JJ year_NN have_HV a_AT fourfold_NN greater_JJR probability_NN of_IN having_HVG any_DTI cataract_NN and_CC an_AT 11_CD times_NNS greater_JJR risk_NN for_IN having_HVG a_AT posterior_JJ subcapsular_NN cataract_NN than_IN those_DTS who_WPR consumed_VBD more_AP than_IN 490_CD mg_d_NN of_IN ascorbic_JJ acid_NN low_JJ serum_NN concentrations_NNS of_IN alpha-tocopherol_NN and_CC beta- carotene_NN are_BER also_RB associated_VBN with_IN an_AT increased_JJ incidence_NN of_IN senile_JJ cataract_NN similar_JJ associations_NNS have_HV been_BEN found_VBN with_IN vitamin_NN A_ZZ , carotenoids_NNS , and_CC multivitamins_NNS and_CC consumption_NN of_IN fewer_AP than_IN 3_CD 1_2_CD servings_NNS of_IN fruits_NNS and_CC vegetables_NNS daily_JJ 208_NP 22_CD not_XNOT all_ABN studies_NNS find_VB the_ATI same_AP associations_NNS an_AT analysis_NN of_IN the_ATI Nurses'_NNS$ Health_NP Study_NP found_VBD that_CS long-term_JJB multivitamin_NN intake_NN was_BEDZ not_XNOT protective_JJ against_IN cataracts_NNS , but_CC long-term_JJB vitamin_NN C_ZZ intake_NN (_( } 10_CD years_NNS )_) was_BEDZ , perhaps_RB because_CS multivitamins_NNS contain_VB relatively_RB low_JJ levels_NNS of_IN vitamin_NN C._NP since_IN spinach_NN consumption_NN , but_CC not_XNOT carrot_NN intake_NN , was_BEDZ associated_VBN with_IN a_AT lower_JJR relative_JJ risk_NN , carotenoids_NNS other_AP than_IN beta-carotene_NN may_MD be_BE more_QL protective_JJ 209_NP a_AT study_NN of_IN patients_NNS with_IN neovascular_JJ age-related_JJ macular_NN degeneration_NN found_VBN that_CS persons_NNS with_IN higher_JJR carotenoid_NN levels_NNS had_HVD one_CD1 half_ABN to_TO one_CD1 third_OD the_ATI risk_NN of_IN macular_NN degeneration_NN compared_VBN with_IN control_NN patients_NNS while_CS no_ATI statistically_RB significant_JJ protective_JJ effect_NN was_BEDZ found_VBN for_IN vitamins_NNS C_ZZ or_CC E_ZZ or_CC selenium_NN individually_RB , an_AT antioxidant_NN index_NN combining_VBG all_ABN micronutrients_NNS showed_VBD significant_JJ reductions_NNS in_IN risk_NN with_IN increasing_JJ levels_NNS of_IN the_ATI index_NN in_IN addition_NN , persons_NNS with_IN age-related_JJ macular_NN degeneration_NN have_HV much_RB lower_JJR levels_NNS of_IN several_AP antioxidant_NN enzymes_NNS in_IN their_PP$ cells_NNS compared_VBD with_IN age-matched_JJ controls_NNS 210_CD on_IN the_ATI other_AP hand_NN , increased_JJ levels_NNS of_IN copper_NN and_CC iron_NN , reported_VBD in_IN aging_VBG lenses_NNS and_CC cataracts_NNS , may_MD oxidize_VB ascorbate_VB and_CC produce_VB metabolites_NNS that_WPR induce_VB cataract_NN formation_NN therefore_RB , under_IN certain_JJ conditions_NNS , the_ATI antioxidant-prooxidant_NN balance_NN can_MD tip_VB , and_CC ascorbate_NN may_MD increase_VB protein_NN modifications_NNS that_WPR produce_VB cataracts_NNS 211_CD CARCINOGENESIS_NP 212_CD free_JJ radicals_NNS and_CC oxidant_NN damage_NN appear_VB to_TO play_VB a_AT major_JJ role_NN in_IN some_DTI forms_NNS of_IN cancer_NN epidemiologic_JJ studies_NNS have_HV generally_RB shown_VBN a_AT protective_JJ effect_NN of_IN consumption_NN of_IN fruits_NNS and_CC vegetables_NNS , foods_NNS rich_JJ in_IN vitamin_NN C_ZZ and_CC beta-carotene_NN , on_IN many_AP kinds_NNS of_IN cancers_NNS to_TO what_WDT degree_NN the_ATI antioxidant_JJ properties_NNS of_IN vitamins_NNS are_BER specifically_RB responsible_JJ for_IN these_DTS effects_NNS is_BEZ unclear_JJ for_IN example_NN , ascorbate_NN , unrelated_JJ to_IN its_PP$ antioxidant_NN capabilities_NNS , may_MD inhibit_VB stomach_VB cancer_NN by_IN reducing_VBG levels_NNS of_IN nitrous_JJ acid_NN and_CC inhibiting_JJ the_ATI formation_NN of_IN carcinogenic_JJ N-nitroso_NP compounds_NNS in_IN the_ATI gastrointestinal_JJ tract_NN because_CS carotenoids_NNS , folic_JJ acid_NN , vitamin_NN C_ZZ , soluble_JJ and_CC insoluble_JJ fiber_NN , and_CC various_JJ phytochemicals_NNS are_BER frequently_RB in_IN the_ATI same_AP foods_NNS , it_PP3 is_BEZ difficult_JJ to_TO document_NN which_WDTR dietary_JJ factor_NN is_BEZ most_QL responsible_JJ or_CC how_WRB synergetic_JJ the_ATI interactions_NNS are_BER in_IN addition_NN , persons_NNS who_WPR consume_VB this_DT type_NN of_IN diet_NN may_MD have_HV other_AP lifestyle_NN behaviors_NNS that_CS also_RB lower_JJR their_PP$ risk_NN 213_CD beta-Carotene_NN and_or_CC preformed_JJ vitamin_NN A_ZZ intake_NN have_HV been_BEN most_QL strongly_RB associated_VBN with_IN a_AT decreased_VBD risk_NN for_IN lung_NN cancer_NN and_CC upper_JJB gastrointestinal_JJ tract_NN cancers_NNS the_ATI association_NN is_BEZ less_QL consistent_JJ with_IN prostate_NN and_CC breast_NN cancer_NN a_AT 12-year_CD-CD follow-up_NN of_IN almost_RB 3000_CD men_NNS in_IN Basel_NP revealed_VBD a_AT significant_JJ inverse_JJ relationship_NN between_IN carotene_NN levels_NNS on_IN entering_VBG the_ATI study_NN and_CC subsequent_JJ cancer_NN , particularly_RB lung_NN and_CC stomach_NN cancers_NNS a_AT prospective_JJ study_NN of_IN nearly_RB 90000_CD female_JJ registered_JJ nurses_NNS found_VBN that_CS large_JJ intakes_NNS of_IN vitamin_NN C_ZZ or_CC E_ZZ did_DOD not_XNOT protect_VB women_NNS from_IN breast_NN cancer_NN , but_CC a_AT low_JJ intake_NN of_IN all_ABN forms_NNS of_IN vitamin_NN A_ZZ (_( {_( 6630_CD IU_d_NP )_) was_BEDZ associated_VBN with_IN an_AT increased_JJ risk_NN for_IN the_ATI disease_NN women_NNS who_WPR consumed_VBD little_JJ vitamin_NN A_ZZ from_IN food_NN , but_CC who_WPR took_VBD at_IN least_RB 10000_CD IU_NP from_IN supplements_NNS , had_HVD about_IN half_ABN the_ATI risk_NN of_IN women_NNS who_WPR did_DOD not_XNOT take_VB supplements_NNS on_IN the_ATI other_AP hand_NN , an_AT analysis_NN combining_VBG the_ATI data_NNS of_IN 12_CD case-control_JJ studies_NNS of_IN diet_NN and_CC breast_NN cancer_NN found_VBN a_AT significant_JJ inverse_JJ association_NN between_IN vitamin_NN C_ZZ intake_NN and_CC breast_NN cancer_NN there_EX is_BEZ also_RB an_AT inverse_JJ relationship_NN between_IN vegetable_JJ consumption_NN and_CC the_ATI risk_NN for_IN breast_NN cancer_NN 214_CD antioxidant_NN vitamin_NN and_CC mineral_NN supplementation_NN over_IN a_AT 6- year_NN period_NN (_( beta_NN carotene_NN , 50_CD mg_NNU ; tocopherol_RB , 30_CD mg_NNU ; and_CC selenium_NN sulfide_NN , 50_CD micrograms_NNS )_) in_IN 15000_CD people_NNS in_IN rural_JJ China_NP , which_WDTR has_HVZ one_CD1 of_IN the_ATI world's_NN$ highest_JJT rates_NNS of_IN upper_JJB gastrointestinal_JJ tract_NN cancer_NN , was_BEDZ associated_VBN with_IN a_AT reduction_NN in_IN total_JJ mortality_NN , primarily_RB owing_IN to_IN a_AT decrease_NN in_IN stomach_NN cancer_NN the_ATI incidence_NN of_IN heart_NN disease_NN in_IN this_DT population_NN is_BEZ minuscule_JJ vitamin_NN C_ZZ has_HVZ also_RB been_BEN associated_VBN with_IN a_AT decreased_VBD risk_NN for_IN many_AP gastrointestinal_JJ tract_NN cancers_NNS , breast_NN cancer_NN , and_CC lung_NN cancer_NN 215_CD in_IN a_AT study_NN of_IN 209_NP individuals_NNS who_WPR were_BED followed_VBN up_RP for_IN an_AT average_JJ of_IN 18_CD months_NNS after_IN removal_NN of_IN adenomatous_JJ polyps_NNS and_CC randomized_VBN to_TO receive_VB antioxidant_NN vitamins_NNS (_( axerophthol_NN palmitate_NN , equivalent_JJ to_IN 30000_CD IU_d_NP of_IN vitamin_NN A_ZZ activity_NN ; ascorbic_JJ acid_NN , 1_CD1 g_d_NN ; and_CC dl-alpha-tocopherol_NN , 70_CD mg_d_NN )_) , 20_CD g_d_NN of_IN lactulose_NN , or_CC nothing_PN , percentages_NNS of_IN recurrences_NNS of_IN adenomas_NNS were_BED 5.7%_NN for_IN the_ATI vitamin_NN group_NN , 14.7%_CD for_IN the_ATI lactulose_NN group_NN , and_CC 35.9%_CD for_IN the_ATI untreated_JJ group_NN 216_CD not_XNOT all_ABN studies_NNS are_BER uniformly_RB positive_JJ some_DTI studies_NNS have_HV reported_VBN a_AT relationship_NN between_IN vitamin_NN E_ZZ status_NN alone_JJ and_CC certain_JJ cancers_NNS , although_CS this_DT has_HVZ not_XNOT been_BEN uniform_JJ for_IN example_NN , an_AT inverse_JJ association_NN has_HVZ been_BEN found_VBN between_IN vitamin_NN E_ZZ status_NN and_CC lung_NN cancer_NN occurrence_NN in_IN nonsmokers_NNS but_CC not_XNOT among_IN smokers_NNS results_NNS from_IN one_CD1 recent_JJ case-control_NN study_NN examining_VBG dietary_JJ factors_NNS and_CC lung_NN cancer_NN in_IN nonsmokers_NNS suggest_VB that_CS dietary_JJ beta-carotene_NN (_( but_CC not_XNOT retinol_VB )_) , raw_JJ (_( not_XNOT processed_VBN )_) fruits_NNS and_CC vegetables_NNS , and_CC tocopherol_NN supplements_NNS are_BER significantly_RB associated_VBN with_IN risk_NN reduction_NN 217_CD a_AT randomized_VBN , double-blind_NN , placebo-controlled_JJ primary_JJ prevention_NN trial_NN of_IN white_JJ male_JJ smokers_NNS (_( aged_JJ 50_CD to_IN 69_CD years_NNS )_) undergoing_VBG analysis_NN following_JJ 5_CD to_IN 8_CD years_NNS of_IN supplementation_NN found_VBN no_ATI protective_JJ effect_NN of_IN 20_CD mg_d_NN of_IN beta_NN carotene_NN and_CC 50_CD IU_d_NP of_IN alpha- tocopherol_NN this_DT study_NN was_BEDZ surprising_JJ in_IN that_DT it_PP3 showed_VBD a_AT higher_JJR incidence_NN of_IN lung_NN cancer_NN and_CC ischemic_JJ heart_NN disease_NN among_IN men_NNS who_WPR received_JJ beta_NN carotene_NN but_CC fewer_AP cases_NNS of_IN prostate_NN cancer_NN in_IN those_DTS who_WPR received_JJ alpha-tocopherol_NN other_AP long-term_JJB prospective_JJ studies_NNS are_BER now_RN in_IN progress_NN to_TO look_VB at_IN vitamin_NN chemoprevention_NN (_( including_IN natural_JJ and_CC synthetic_JJ analogues_NNS )_) in_IN cancer_NN 218_CD VITAMIN_NP TOXICITY_NP 219_CD it_PP3 should_MD be_BE expected_VBN , because_CS diseases_NNS can_MD have_HV multifactorial_JJ causes_NNS , that_CS some_DTI vitamin_NN intervention_NN studies_NNS have_HV ambiguous_JJ results_NNS or_CC have_HV not_XNOT shown_VBN a_AT positive_JJ influence_NN indeed_RB , some_DTI animal_NN and_CC human_JJ studies_NNS have_HV even_RB shown_VBN a_AT disease-enhancing_NN , prooxidant_NN effect_NN for_IN some_DTI vitamins_NNS under_IN some_DTI conditions_NNS this_DT should_MD temper_NN unbridled_JJ enthusiasm_NN but_CC is_BEZ usually_RB ignored_VBN by_IN proponents_NNS of_IN vitamin_NN supplementation_NN Vitamins_NNS do_DO have_HV known_JJ toxicity_NN of_IN all_ABN the_ATI antioxidant_NN vitamins_NNS , vitamin_NN A_ZZ is_BEZ easily_RB the_ATI most_QL dangerous_JJ hypervitaminosis_NN A_ZZ can_MD occur_VB both_ABX acutely_RB and_CC after_IN long-term_JJB ingestion_NN acute_JJ toxic_JJ effects_NNS present_JJ as_IN headaches_NNS , drowsiness_NN , irritability_NN , dizziness_NN , nausea_NN , vomiting_NN , and_CC diarrhea_NN elderly_JJ people_NNS with_IN normal_JJ kidney_NN and_CC liver_NN functions_NNS may_MD tolerate_VB a_AT daily_JJ dose_NN of_IN 50000_CD retinol_NN equivalents_NNS (_( RE_NP )_) for_IN up_RP to_IN 6_CD months_NNS , while_CS younger_JJR adults_NNS have_HV taken_VBN 300000_CD RE_d_NP (_( as_IN retinyl_NN palmitate_NN )_) for_IN 12_CD months_NNS with_IN few_AP adverse_JJ effects_NNS .=20_CD 220_CD however_RB , toxic_JJ effects_NNS have_HV been_BEN seen_VBN in_IN intakes_NNS of_IN as_QL little_JJ as_IN 15_CD 000_CD RE_d_NP chronic_JJ toxic_JJ effects_NNS may_MD classically_RB , and_CC nonspecifically_RB , present_JJ as_IN desquamation_NN and_CC redness_NN of_IN the_ATI skin_NN and_CC mucous_JJ membranes_NNS , disturbed_JJ hair_NN growth_NN , loss_NN of_IN appetite_NN , fatigue_NN , irritability_NN , thyroid_JJ suppression_NN , cerebrospinal_JJ fluid_NN pressure_NN elevation_NN (_( producing_VBG symptoms_NNS similar_JJ to_IN those_DTS of_IN pseudotumor_NN cerebri_NN )_) , and_CC elevation_NN of_IN liver_NN enzyme_NN levels_NNS toxic_JJ effects_NNS increase_VB in_IN the_ATI presence_NN of_IN renal_JJ failure_NN and_CC preexisting_VBG hepatic_JJ dysfunction_NN and_CC decrease_NN in_IN the_ATI presence_NN of_IN excess_JJ levels_NNS of_IN vitamin_NN E._NP hypercalcemia_NN and_CC a_AT negative_JJ calcium_NN balance_NN similar_JJ to_TO that_CS seen_VBN with_IN hypervitaminosis_NN D_ZZ may_MD occur_VB , but_CC excess_JJ retinol_NN levels_NNS affect_VB the_ATI organic_JJ bone_NN matrix_NN , whereas_CS excess_JJ vitamin_NN D_ZZ levels_NNS cause_NN dissolution_NN of_IN the_ATI mineral_NN matrix_NN 221_CD toxic_JJ effects_NNS of_IN vitamin_NN E_ZZ may_MD present_JJ as_IN diarrhea_NN or_CC fatigue_NN , but_CC even_RB huge_JJ intakes_NNS are_BER usually_RB well_RB tolerated_VBN the_ATI major_JJ potential_JJ side_NN effect_NN may_MD be_BE that_CS vitamin_NN E_ZZ can_MD potentiate_VB warfarin_VB sodium_NN (_( Coumadin_NP )_) and_CC increase_VB the_ATI risk_NN for_IN bleeding_NN in_IN persons_NNS receiving_VBG this_DT anticoagulant_NN under_IN certain_JJ circumstances_NNS , vitamin_NN E_ZZ has_HVZ been_BEN found_VBN to_TO promote_VB skin_NN tumorigenesis_NN in_IN animal_NN studies_NNS therefore_RB , prolonged_JJ topical_JJ exposure_NN to_IN antioxidants_NNS like_IN vitamin_NN E_ZZ should_MD be_BE discouraged_VBN until_CS more_QL is_BEZ known_VBN 222_CD vitamin_NN C_ZZ can_MD increase_VB the_ATI absorption_NN of_IN iron_NN , and_CC supplementation_NN should_MD not_XNOT be_BE recommended_VBN in_IN persons_NNS at_IN risk_NN of_IN iron_NN overload_NN (_( eg_NN , persons_NNS with_IN thalassemia_NN or_CC hemohromatosis_NN )_) without_IN close_RB supervision_NN It_NP is_BEZ possible_JJ that_CS , in_IN the_ATI presence_NN of_IN appropriate_JJ levels_NNS of_IN copper_NN or_CC iron_NN , vitamin_NN C_ZZ may_MD act_VB as_IN a_AT prooxidant_NN ; whether_CS this_DT finding_VBG is_BEZ clinically_RB significant_JJ is_BEZ unknown_JJ however_RB , in_IN general_JJ , ascorbic_JJ acid_NN supplementation_NN causes_VBZ no_ATI problems_NNS , even_RB in_IN older_JJR persons_NNS vitamin_NN C_ZZ may_MD also_RB affect_VB results_NNS of_IN fecal_JJ occult_NN blood_NN tests_NNS as_QL well_RB as_IN some_DTI urinary_NN and_CC blood_NN glucose_NN tests_NNS abruptly_RB discontinuing_VBG high_JJ vitamin_NN C_ZZ intake_NN may_MD make_VB some_DTI persons_NNS deficient_JJ , but_CC this_DT result_NN is_BEZ probably_RB rare_JJ there_EX are_BER few_AP acute_JJ toxic_JJ effects_NNS of_IN high-dose_NN vitamin_NN C_ZZ ingestion_NN ; occasionally_RB diarrhea_JJ can_MD occur_VB 223_CD VITAMIN_NP A_ZZ AND_NP CAROTENE_NP 224_NN most_AP total_JJ vitamin_NN A_ZZ intake_NN in_IN the_ATI United_NP States_NP comes_VBZ from_IN liver_NN , carrots_NNS , eggs_NNS , vegetable-based_JJ soups_NNS , whole-milk_NN products_NNS , and_CC fortified_JJ food_NN products_NNS while_CS vitamin_NN A_ZZ intake_NN decreases_VBZ with_IN age_NN , hypovitaminosis_NN A_ZZ in_IN adults_NNS is_BEZ uncommon_JJ , even_RB in_IN the_ATI very_QL old_JJ there_EX is_BEZ evidence_NN that_CS vitamin_NN E_ZZ and_CC C_ZZ status_NN declines_VBZ in_IN many_AP older_JJR individuals_NNS , while_CS retinol_NN status_NN usually_RB does_DOZ not_XNOT 225_NN vitamin_NN A_ZZ may_MD refer_VB to_IN two_CD different_JJ groups_NNS of_IN substances_NNS one_CD1 is_BEZ retinol_NN , or_CC preformed_JJ vitamin_NN A_ZZ , found_VBD in_IN dairy_NN products_NNS and_CC animal_NN and_CC fish_NNS meats_NNS similar_JJ foms_NNS include_VB synthetic_JJ vitamin_NN A_ZZ analogues_NNS such_IN as_IN all-trans-retinoic_JJ acid_NN and_CC 13-cis-retinoic_CD-CD acid_NN , which_WDTR can_MD be_BE converted_VBN to_TO retinol_VB within_IN the_ATI body_NN vitamin_NN A_ZZ is_BEZ necessary_JJ for_IN maintaining_VBG the_ATI integrity_NN of_IN epithelial_JJ tissues_NNS (_( skin_NN , cornea_NN , gastrointestinal_JJ tract_NN , lungs_NNS , urinary_NN tract_NN , etc_RB )_) it_PP3 is_BEZ also_RB required_VBN for_IN proper_JJ retinal_JJ function_NN , immune_JJ function_NN , and_CC growth_NN 226_CD vitamin_NN A_ZZ activity_NN in_IN foods_NNS is_BEZ currently_RB expressed_VBN as_IN RE_NP ; 1_CD1 RE_NP is_BEZ defined_VBN as_CS 1_CD1 micrograms_NNS of_IN all-trans-retinol_NN and_CC roughly_RB estimated_VBN to_TO be_BE equivalent_JJ to_IN 6_CD micrograms_NNS of_IN all-trans-beta-carotene_NN or_CC 12_CD micrograms_NNS of_IN other_AP provitamin_NN A_ZZ carotenoids_NNS international_JJ units_NNS are_BER often_RB used_VBN for_IN both_ABX vitamin_NN A_ZZ and_CC the_ATI carotenoids_NNS and_CC are_BER frequently_RB confusing_JJ and_CC inaccurate_JJ one_CD1 RE_NP equals_NNS 3.33_CD IU_NP (_( or_CC IU_NP sub_NN a_AT )_) of_IN preformed_JJ vitamin_NN A_ZZ (_( retinol_NN )_) and_CC 10_CD IU_NP (_( or_CC IU_NP sub_NN c_ZZ )_) of_IN provitamin_NN A_ZZ carotenoids_NNS despite_IN this_DT , food_NN composition_NN tables_NNS often_RB assume_VB that_CS 1_CD1 IU_NP sub_NN a_AT equals_NNS 1_CD1 IU_NP sub_NN c._NN therefore_RB , consumers_NNS and_CC physicians_NNS should_MD use_VB food_NN composition_NN tables_NNS only_RB as_CS rough_JJ guides_NNS to_IN approximate_JJ vitamin_NN A_ZZ and_CC carotenoid_NN quantities_NNS in_IN specific_JJ foods_NNS 227_NN using_VBG the_ATI retinol_JJ equivalent_JJ to_TO determine_VB the_ATI antioxidant_NN activity_NN of_IN foods_NNS is_BEZ also_RB misleading_JJ , since_IN retinol_NN is_BEZ generally_RB not_XNOT an_AT antioxidant_NN the_ATI current_JJ RDA_NP is_BEZ 1000_CD micrograms_NP RE_NP in_IN men_NNS and_CC 800_CD micrograms_NP RE_NP in_IN women_NNS (_( Table1_CD )_) however_RB , it_PP3 has_HVZ been_BEN proposed_VBN that_CS the_ATI RDA_NP for_IN vitamin_NN A_ZZ is_BEZ too_QL high_JJ and_CC should_MD be_BE reduced_VBN to_IN 700_CD and_CC 600_CD micrograms_NP RE_NP for_IN men_NNS and_CC women_NNS , respectively_RB except_CS at_IN the_ATI extreme_JJ ranges_NNS , retinol_NN levels_NNS correlate_VB poorly_RB with_IN vitamin_NN A_ZZ status_NN and_CC are_BER affected_VBN by_IN many_AP nonnutritional_JJ diseases_NNS hepatic_JJ levels_NNS of_IN vitamin_NN A_ZZ appear_VB unchanged_JJ in_IN adults_NNS up_RP to_IN advanced_JJ age_NN retinol_NN absorption_NN increases_NNS with_IN age_NN in_IN some_DTI animals_NNS , but_CC it_PP3 is_BEZ not_XNOT known_VBN whether_CS the_ATI absorption_NN rate_NN in_IN humans_NNS changes_NNS with_IN age_NN 228_NN preformed_JJ vitamin_NN A_ZZ enters_VBZ the_ATI intestinal_JJ cell_NN by_IN a_AT carrier-mediated_JJ mechanism_NN in_IN contrast_NN , carotenoids_NNS are_BER passively_RB absorbed_VBN vitamin_NN A_ZZ is_BEZ transported_VBN via_IN the_ATI lymphatics_NNS to_IN the_ATI liver_NN and_CC stored_VBN as_IN the_ATI retinyl_NN ester_NN from_IN the_ATI liver_NN , which_WDTR contains_VBZ 95%_NN of_IN the_ATI body's_NN$ vitamin_NN A_ZZ stores_NNS , it_PP3 can_MD be_BE released_VBN as_IN retinol_NN bound_VBN to_TO retinol-binding_NN protein_NN and_CC prealbumin_NN and_CC transported_VBD to_IN various_JJ tissues_NNS 229_NN the_ATI other_AP form_NN of_IN vitamin_NN A_ZZ is_BEZ carotene_JJ (_( provitamin_NN A_ZZ )_) , found_VBD primarily_RB in_IN plants_NNS , especially_RB carrots_VBZ and_CC dark_JJ green_JJ leafy_JJ vegetables_NNS The_NP color_JJ intensity_NN of_IN a_AT fruit_NN or_CC vegetable_JJ , however_RB , does_DOZ not_XNOT reliably_RB indicate_VB its_PP$ provitamin_NN A_ZZ content_NN beta-Carotene_NN usually_RB makes_VBZ up_RP the_ATI largest_JJT fraction_NN of_IN provitamin_NN A_ZZ in_IN foods_NNS carotene_NN is_BEZ also_RB found_VBN in_IN yellow_JJ animal_NN fat_NN and_CC dairy_NN products_NNS of_IN the_ATI approximately_RB 500_CD or_CC so_PN carotenoids_NNS , only_RB 50_CD to_IN 60_CD are_BER known_VBN to_IN be_BE precursors_NNS of_IN vitamin_NN A_ZZ , but_CC many_AP more_QL may_MD act_VB as_IN antioxidants_NNS it_PP3 is_BEZ difficult_JJ to_TO interpret_VB tables_NNS of_IN carotenoid_JJ contents_NNS of_IN foods_NNS since_CS neither_DTX REs_NNS nor_CC beta- carotene_NN content_NN may_MD fully_RB reflect_VB the_ATI significant_JJ biologic_JJ antioxidant_NN activity_NN In_NP fact_NN , gamma-carotene_NN is_BEZ a_AT better_JJR antioxidant_NN than_IN beta-carotene_NN There_NP are_BER no_ATI RDAs_NP for_IN the_ATI carotenoids_NNS because_CS of_IN their_PP$ many_AP conjugated_VBD double_JJ bonds_NNS , carotenoids_NNS can_MD act_VB as_CS antioxidants_NNS by_IN quenching_VBG the_ATI unpaired_JJ electrons_NNS of_IN free_JJ radicals_NNS and_CC diverting_VBG free_JJ radical_JJ damage_NN to_TO themselves_PPLS rather_RB than_IN other_AP molecules_NNS (_( like_IN LDL_NP cholesterol_NN )_) beta-Carotene_NN and_CC other_AP carotenoids_NNS like_IN lycopenes_NNS may_MD be_BE protective_JJ of_IN the_ATI body_NN independent_NN of_IN any_DTI provitamin_NN A_ZZ role_NN beta-Carotene_NN can_MD be_BE converted_VBN to_IN retinoic_JJ acid_NN without_IN being_BEG converted_VBN into_IN retinol_NN this_DT retinoid_NN effect_NN may_MD promote_VB cell_NN differentiation_NN by_IN binding_JJ to_TO and_CC turning_VBG on_IN genes_NNS beta-Carotene_NN may_MD also_RB improve_VB cell-cell_NN communication_NN 230_CD only_RB about_RB 15%_CD of_IN beta-carotene_NN is_BEZ absorbed_VBN by_IN the_ATI body_NN , and_CC only_RB 20%_NP of_IN that_DT absorbed_VBN is_BEZ ultimately_RB converted_VBN to_TO retinol_VB therefore_RB , except_IN for_IN reversible_JJ carotenodermia_NN , an_AT orange- yellow_JJ skin_NN discoloration_NN most_QL prominent_JJ in_IN palms_NNS and_CC soles_NNS but_CC not_XNOT sclera_VB , which_WDTR may_MD be_BE seen_VBN with_IN an_AT ingestion_NN of_IN 30_CD mg_d_NN of_IN beta-carotene_NN , side_NN effects_NNS of_IN beta-carotene_NN ingestion_NN are_BER rare_JJ most_AP of_IN the_ATI beta-carotene_NN in_IN the_ATI blood_NN is_BEZ associated_VBN with_IN LDL_NP cholesterol_NN and_CC stored_VBD primarily_RB in_IN fat_NN rather_RB than_CS in_IN the_ATI liver_NN 231_CD VITAMIN_NP C_ZZ 232_CD the_ATI current_JJ RDA_NP for_IN vitamin_NN C_ZZ in_IN adults_NNS is_BEZ 60_CD mg_NNU (_( Table_NP 1_CD1 )_) it_PP3 has_HVZ been_BEN argued_VBN that_CS this_DT amount_NN could_MD be_BE safely_RB reduced_VBN in_IN contrast_NN , body_NN pools_NNS are_BER saturated_VBN at_IN 100_CD to_IN 150_CD mg_d_NN in_IN men_NNS and_CC 80_CD to_IN 100_CD mg_d_NN in_IN women_NNS , suggesting_VBG to_IN some_DTI that_CS the_ATI RDA_NP should_MD be_BE higher_JJR the_ATI RDA_NP for_IN vitamin_NN C_ZZ was_BEDZ not_XNOT formulated_VBN with_IN respect_NN to_IN its_PP$ antioxidant_NN properties_NNS Vitamin_NP C_ZZ deficiency_NN is_BEZ common_NN in_IN general_JJ malnutrition_NN and_CC many_AP frail_JJ , elderly_JJ populations_NNS .=20_CD 233_CD the_ATI pharmacokinetics_NNS of_IN vitamin_NN C_ZZ do_DO not_XNOT appear_VB to_TO change_VB with_IN age_NN , although_CS higher_JJR intakes_NNS of_IN ascorbic_JJ acid_NN are_BER needed_VBN in_IN older_JJR men_NNS than_IN older_JJR women_NNS to_TO attain_VB the_ATI same_AP plasma_NN concentrations_NNS , probably_RB owing_IN to_TO higher_JJR renal_JJ tubular_JJ reabsorption_NN in_IN women_NNS 234_CD tables_NNS from_IN the_ATI US_NP Department_NP of_IN Agriculture_NP provide_VB L-ascorbate_NP content_NN only_RB ; biologically_RB active_JJ dehydroascorbate_JJ present_NN in_IN foods_NNS may_MD provide_VB an_AT unrecognized_JJ additional_JJ vitamin_NN C_ZZ source_NN vegetables_NNS and_CC fruits_NNS contain_VB the_ATI highest_JJT concentrations_NNS of_IN vitamin_NN C_ZZ ; meats_NNS , fish_NNS , poultry_NN , eggs_NNS , and_CC dairy_NN products_NNS contain_VB some_DTI ; and_CC grains_NNS contain_VB none_PN In_NP the_ATI United_NP States_NP , most_QL ascorbate_NN is_BEZ supplied_VBN by_IN citrus_NN fruits_NNS , potatoes_NNS , and_CC other_AP vegetables_NNS vitamin_NN C_ZZ is_BEZ easily_RB destroyed_VBN by_IN heat_NN and_CC oxygen_NN or_CC lost_VBD in_IN cooking_NN water_NN 235_CD bioavailability_NN of_IN vitamin_NN C_ZZ is_BEZ inversely_RB related_VBN to_IN the_ATI amount_NN as_CS well_RB as_IN the_ATI form_NN ingested_VBN sustained-release_NN capsules_NNS allow_VB higher_JJR absorption_NN than_IN standard_NN pills_NNS smoking_VBG lowers_NNS vitamin_NN C_ZZ levels_NNS , and_CC smokers_NNS require_VB a_AT higher_JJR intake_NN to_TO achieve_VB plasma_NN levels_NNS comparable_JJ with_IN those_DTS of_IN nonsmokers_NNS , perhaps_RB because_CS of_IN increased_JJ metabolism_NN Absorption_NN does_DOZ not_XNOT appear_VB to_TO change_VB with_IN age_NN 236_CD VITAMIN_NP E_ZZ 237_CD 51_CD vitamin_NN E_ZZ is_BEZ the_ATI generic_JJ term_NN for_IN a_AT group_NN of_IN chemicals_NNS (_( tocopherols_NNS and_CC tocotrienols_NNS )_) originally_RB discovered_VBN to_TO affect_VB reproduction_NN in_IN the_ATI rat_NN it_PP3 was_BEDZ given_VBN the_ATI letter_NN E_ZZ to_TO follow_VB vitamin_NN D_ZZ and_CC the_ATI name_NN tocopherol_NN from_IN the_ATI Greek_JNP word_NN tokos_NNS , for_IN childbirth_NN , and_CC pherin_NN , to_TO bring_VB forth_RP alpha-Tocopherol_NN is_BEZ considered_VBN the_ATI most_QL active_JJ compound_JJ , but_CC other_AP forms_NNS of_IN tocopherols_NNS may_MD also_RB have_HV significant_JJ biologic_JJ functions_NNS the_ATI RDA_NP for_IN vitamin_NN E_ZZ is_BEZ 10_CD mg_NNU (_( natural_JJ alphatocopherol_NN equivalents_NNS )_) for_IN men_NNS and_CC 8_CD mg_NNU for_IN women_NNS (_( Table_NP 1_CD1 )_) Although_NP the_ATI synthetic_JJ form_NN of_IN alpha-tocopherol_NN has_HVZ 74%_NN of_IN the_ATI activity_NN of_IN naturally_RB occurring_VBG vitamin_NN E_ZZ , both_ABX the_ATI natural_JJ and_CC synthetic_JJ forms_NNS provide_VB equal_JJ antioxidant_NN protection_NN to_IN LDL_NP international_JJ units_NNS are_BER still_RB frequently_RB used_VBN ; 1_CD1 mg_NNU of_IN natural_JJ alpha-tocopherol_NN (_( one_CD1 alpha-tocopherol_JJ equivalent_JJ )_) equals_NNS about_RB 1.1_CD to_IN 1.5_CD IU_NP , while_CS 1_CD1 mg_NNU of_IN synthetic_JJ alpha-_NN tocopherol_NN equals_NNS 1_CD1 IU_NP beta-Tocopherol_NN has_HVZ one_CD1 half_ABN of_IN the_ATI activity_NN of_IN natural_JJ alpha-tocopherol_NN ; gamma-tocopherol_NN has_HVZ one_CD1 tenth_OD of_IN the_ATI activity_NN 238_CD large_JJ losses_NNS of_IN tocopherols_NNS can_MD occur_VB during_IN processing_NN , storage_NN , and_CC preparation_NN of_IN food_NN the_ATI richest_JJT sources_NNS in_IN the_ATI American_JNP diet_NN are_BER common_JJ vegetable_JJ oils_NNS and_CC products_NNS made_VBN from_IN them_PP3OS (_( eg_NN , margarine_NN and_CC shortening_VBG )_) western_JJ diets_NNS contain_VB much_AP more_QL gamma-tocopherol_JJ than_IN alpha-tocopherol_NN , but_CC alpha-tocopherol_NN appears_VBZ to_TO be_BE much_RB better_JJR absorbed_VBN and_CC accounts_NNS for_IN most_AP of_IN the_ATI total_JJ serum_NN vitamin_NN E_ZZ concentration_NN meats_NNS , fish_NNS , animal_NN fats_NNS , fruits_NNS , and_CC vegetables_NNS have_HV little_JJ vitamin_NN E._NP 239_CD vitamin_NN E_ZZ decreases_VBZ platelet_NN adhesion_NN , which_WDTR does_DOZ not_XNOT depend_VB on_IN its_PP$ antioxidant_NN properties_NNS and_CC may_MD be_BE protective_JJ in_IN thromboembolic_JJ disease_NN It_NP also_RB enhances_VBZ cell-mediated_JJ immunity_NN in_IN healthy_JJ elderly_JJ persons_NNS , and_CC antioxidants_NNS may_MD retard_VB some_DTI of_IN the_ATI age-related_JJ changes_NNS in_IN the_ATI immune_JJ system_NN the_ATI role_NN of_IN vitamin_NN E_ZZ in_IN intermittent_JJ claudication_NN syndromes_NNS remains_VBZ unclear_JJ 240_CD clinical_JJ vitamin_NN E_ZZ deficiency_NN syndromes_NNS are_BER not_XNOT well_RB recognized_VBN in_IN adults_NNS , although_CS peripheral_JJ neuropathy_NN , hand_NN myopathy_NN , and_CC cardiomyopathy_NN may_MD occur_VB in_IN association_NN with_IN severe_JJ fat_NN malabsorption_NN 241_CD TO_NPT SUPPLEMENT_NPT OR_NP NOT_NP ? 242_CD the_ATI RDAs_NP were_BED developed_VBN to_TO prevent_VB classic_JJ vitamin_NN deficiencies_NNS and_CC deliberately_RB do_DO not_XNOT reflect_VB other_AP possible_JJ health-promoting_JJ benefits_NNS of_IN vitamins_NNS therefore_RB , they_PP3AS cannot_NN be_BE used_VBN as_IN a_AT gold_NN standard_NN regarding_IN vitamin_NN use_NN to_TO optimize_VB health_NN the_ATI Second_NPT National_NP Health_NP and_CC Nutrition_NN Examination_JJ Survey_NP of_IN about_RB 12000_CD adults_NNS found_VBN that_CS 17%_CD had_HVD eaten_VBN no_ATI vegetables_NNS and_CC 41%_CD no_ATI fruit_NN on_IN the_ATI date_NN of_IN the_ATI survey_NN ; only_RB one_CD1 fourth_OD had_HVD eaten_VBN a_AT fruit_NN or_CC vegetable_JJ rich_JJ in_IN vitamin_NN A_ZZ or_CC C_ZZ ; and_CC only_RB 10%_CD consumed_VBN the_ATI recommended_VBN five_CD daily_JJ servings_NNS of_IN fruits_NNS and_CC vegetables_NNS On_NP the_ATI other_AP hand_NN , many_AP vegetarians_NNS and_CC nonvegetarians_NNS consume_VB nutritional_JJ supplements_NNS with_IN few_AP adverse_JJ consequences_NNS 243_CD while_CS the_ATI data_NNS so_QL far_RB support_VB the_ATI association_NN of_IN antioxidant_NN consumption_NN with_IN positive_JJ health_NN benefits_NNS , many_AP questions_NNS remain_VB unanswered_JJ , particularly_RB about_IN supplementation_NN for_IN skeptics_NNS , increasing_JJ consumption_NN of_IN fruits_NNS and_CC vegetables_NNS and_CC decreasing_VBG saturated_VBN fat_NN intake_NN (_( and_CC perhaps_RB partially_RB hydrogenated_JJ fat_NN intake_NN as_CS well_RB )_) would_MD be_BE the_ATI most_QL conservative_JJ approach_NN however_RB , experienced_JJ clinicians_NNS know_VB the_ATI difficulty_NN of_IN changing_VBG people_NNS 's_BEZ eating_VBG habits_NNS therefore_RB , this_DT approach_NN is_BEZ also_RB likely_JJ to_TO be_BE the_ATI least_RB acceptable_JJ or_CC possible_JJ or_CC successful_JJ for_IN many_AP high- risk_NN individuals_NNS recent_JJ surveys_NNS in_IN the_ATI media_NNS have_HV suggested_VBN that_CS people_NNS are_BER increasingly_RB reversing_JJ previously_RB healthy_JJ diets_NNS and_CC lifestyles.=20_CD 244_CD for_IN clinicians_NNS who_WPR consider_VB nutritional_JJ supplementation_NN a_AT reasonable_JJ additional_JJ intervention_NN , risk_NN factors_NNS for_IN diseases_NNS most_QL likely_JJ to_TO respond_VB to_IN antioxidants_NNS , as_QL well_RB as_CS potential_JJ toxic_JJ effects_NNS , should_MD be_BE explored_VBN with_IN each_DT patient_NN to_IN tailor_NN supplements_NNS appropriately_RB and_CC reinforce_VB the_ATI importance_NN of_IN other_AP risk_NN factor_NN interventions_NNS (_( eg_NN , exercise_NN , fat_NN reduction_NN , weight_NN control_NN , and_CC reduction_NN of_IN environmental_JJ toxin_NN exposures_NNS such_IN as_IN alcohol_NN and_CC tobacco_NN use_NN )_) there_EX are_BER many_AP intervention_NN studies_NNS in_IN progress_NN that_WPR will_MD continue_VB to_TO clarify_VB new_JJ roles_NNS for_IN all_ABN vitamins- not_NN just_RB those_DTS with_IN antioxidant_NN properties-and_VB the_ATI most_QL appropriate_JJ uses_VBZ for_IN supplementation_NN physicians_NNS , dietitians_NNS , and_CC other_AP health_NN care_NN professionals_NNS need_NN to_TO continually_RB reinforce_VB the_ATI importance_NN of_IN good_JJ nutrition_NN in_IN health_NN promotion_NN and_CC to_TO use_VB nutritional_JJ interventions_NNS appropriately_RB in_IN high-risk_NN patients_NNS 245_CD POTENTIAL_NPT ROLES_NPT FOR_NP ANTIOXIDANTS_NP 246_CD ANTIOXIDANTS_NPT AND_NPT CENTRAL_NPT NERVOUS_NPT SYSTEM_NP INJURY_NP 247_CD the_ATI brain_NN may_MD be_BE particularly_RB vulnerable_JJ to_IN oxidative_JJ stressors_NNS because_CS of_IN its_PP$ limited_JJ capacity_NN for_IN regeneration_NN , high_JJ concentrations_NNS of_IN polyunsaturated_VBN fatty_JJ acids_NNS and_CC iron_NN , and_CC a_AT relative_JJ deficiency_NN in_IN antioxidant_JJ protective_JJ mechanisms_NNS it_PP3 has_HVZ been_BEN postulated_JJ that_CS some_DTI neurodegenerative_JJ disorders_NNS , such_IN as_IN Parkinson's_NP$ disease_NN , may_MD be_BE slowed_VBN by_IN the_ATI use_NN of_IN antioxidants_NNS however_RB , a_AT multicenter_JJ study_NN of_IN l-deprenyl_NN (_( selegiline_NN hydrochloride_NN , an_AT inhibitor_NN of_IN monoamine_NN oxidase_NN B_ZZ that_CS decreases_VBZ hydrogen_NN peroxidase_NN production_NN during_IN brain_NN monoamine_NN catabolism_NN )_) and_CC vitamin_NN E_ZZ did_DOD not_XNOT find_VB that_CS oral_JJ vitamin_NN E_ZZ at_IN high_JJ doses_NNS (_( 2000_CD IU_d_NP )_) slowed_VBD functional_JJ decline_NN or_CC clinically_RB improved_JJ patients_NNS with_IN Parkinson's_NP$ disease_NN 248_CD however_RB , a_AT familial_JJ variant_NN of_IN amyotrophic_JJ lateral_JJ sclerosis_NN is_BEZ linked_VBN to_IN defective_JJ synthesis_NN of_IN the_ATI endogenous_JJ antioxidant_NN , superoxide_NN dismutase_NN , suggesting_VBG that_CS this_DT chronic_JJ neurodegenerative_JJ disease_NN may_MD be_BE related_VBN to_IN the_ATI production_NN of_IN reactive_JJ oxidant_NN metabolites_NNS in_IN the_ATI brain_NN In_NP addition_NN , high_JJ doses_NNS of_IN vitamin_NN E_ZZ (_( 1600_CD IU_d_NP )_) may_MD be_BE useful_JJ in_IN treating_VBG tardive_JJ dyskinesia_NN 249_CD acute_JJ central_JJ nervous_JJ system_NN injury_NN can_MD be_BE exacerbated_VBN by_IN oxygen_NN radical_JJ formation_NN from_IN arachidonic_JJ acid_NN , catecholamine_NN and_CC hemoglobin_NN oxidation_NN , leaking_JJ mitochondria_NN , and_CC infiltrating_VBG neutrophils_NNS these_DTS free_JJ radicals_NNS , in_IN turn_NN , can_MD initiate_VB peroxidation_NN of_IN neuronal_JJ , glial_JJ , and_CC vascular_NN cell_NN membranes_NNS and_CC myelin_NN , catalyzed_VBN by_IN the_ATI presence_NN of_IN iron_NN there_EX is_BEZ a_AT strong_JJ correlation_NN between_IN the_ATI ability_NN to_TO inhibit_VB central_JJ nervous_JJ system_NN tissue_NN peroxidation_NN and_CC neurologic_JJ recovery_NN the_ATI steroid_NN methylprednisolone_NN has_HVZ antioxidant_NN efficacy_NN independent_NN of_IN its_PP$ glucocorticoid_NN action_NN and_CC , when_WRB administered_VBN in_IN high_JJ amounts_NNS , has_HVZ improved_JJ recovery_NN after_IN spinal_JJ cord_NN injury_NN novel_NN 21-aminosteroids_CD-CD now_RN being_BEG developed_VBN have_HV antioxidant_NN activity_NN surpassing_JJ methylprednisolone_NN and_CC have_HV been_BEN shown_VBN to_TO be_BE quite_RB effective_JJ in_IN animal_JJ models_NNS of_IN brain_NN and_CC spinal_JJ cord_NN injury_NN 250_CD REPERFUSION_NP INJURY_NP 251_CD postischemic_JJ tissue_NN injury_NN results_NNS from_IN the_ATI additive_JJ effects_NNS of_IN both_ABX the_ATI ischemia_NN and_CC subsequent_JJ reperfusion_NN the_ATI reperfusion_NN that_CS follows_VBZ tissue_NN ischemia_NN (_( eg_NN , heart_NN or_CC bowel_NN infarction_NN or_CC organ_NN transplantation_NN )_) generates_NNS large_JJ quantities_NNS of_IN toxic_JJ oxygen_NN metabolites_NNS , such_IN as_IN superoxide_NN anion_NN (_( Figure_NP 1_CD1 )_) , from_IN activated_VBN inflammatory_JJ cells_NNS , xanthine_NN oxidase_NN , heme_NN protein_NN , and_CC disrupted_VBN mitochondria_NN this_DT overwhelms_NNS antioxidant_NN defense_NN mechanisms_NNS , paradoxically_RB producing_VBG further_JJB injury_NN (_( including_IN capillary_JJ permeability_NN and_CC endothelial_JJ cell_NN lysis_NN )_) the_ATI prostaglandin_NN synthesis_NN and_CC the_ATI autoxidation_NN of_IN catecholamines_NNS accompanying_JJ reperfusion_NN may_MD also_RB generate_VB free_JJ radicals_NNS Studies_NP are_BER in_IN progress_NN to_TO examine_VB whether_CS tissue_NN injury_NN can_MD be_BE moderated_VBN by_IN preventing_VBG free_JJ radical_JJ generation_NN , directly_RB scavenging_VBG free_JJ radicals_NNS , or_CC preventing_VBG increased_JJ tissue_NN damage_NN by_IN neutrophils_NNS JIMMUE_NP Gram-positive_JJ Organisms_NNS and_CC Sepsis_NP 2_CD at_IN present_NN , it_PP3 is_BEZ widely_RB believed_VBN that_CS sepsis_NN is_BEZ caused_VBN predominantly_RB by_IN gram-negative_JJ organisms_NNS , and_CC endotoxin_NN , a_AT substance_NN produced_VBN by_IN these_DTS organisms_NNS , is_BEZ often_RB posited_VBN to_TO be_BE the_ATI primary_JJ initiator_NN of_IN sepsis_NN three_CD arguments_NNS are_BER generally_RB put_VB forth_RP to_TO support_VB this_DT supposition_NN 3_CD many_AP patients_NNS with_IN sepsis_NN have_HV gram-negative_JJ infections_NNS , and_CC at_RB least_RB some_DTI of_IN those_DTS who_WPR have_HV other_AP types_NNS of_IN underlying_JJ infections_NNS demonstrate_VB the_ATI presence_NN of_IN endotoxin_NN in_IN their_PP$ blood_NN 4_CD endotoxin_NN can_MD initiate_VB the_ATI cascade_NN of_IN inflammatory_JJ mediators_NNS that_DT is_BEZ believed_VBN to_TO underlie_VB sepsis_NN 5_CD administration_NN of_IN antibodies_NNS to_TO endotoxin_VB prevents_VBZ the_ATI onset_NN of_IN sepsis_NN if_CS given_VBN before_CS endotoxin_NN challenge_NN , and_CC the_ATI administration_NN of_IN endotoxin_NN antiserum_NN reduces_VBZ mortality_NN in_IN patients_NNS with_IN gram-negative_JJ bacteremia_NN also_RB , monoclonal_JJ antibodies_NNS to_TO endotoxin_VB improve_VB survival_NN in_IN some_DTI patients_NNS with_IN gram-negative_JJ sepsis_NN or_CC gram- negative_JJ bacteremia_NN 6_CD it_PP3 is_BEZ now_RN becoming_VBG clear_JJ , however_RB , that_CS undue_JJ emphasis_NN has_HVZ been_BEN placed_VBN on_IN gram-negative_JJ organisms_NNS in_IN the_ATI origin_NN of_IN sepsis_NN a_AT wealth_NN of_IN recent_JJ evidence_NN indicates_VBZ that_CS the_ATI prevalence_NN of_IN gram-positive_JJ infections_NNS has_HVZ risen_VBN markedly_RB in_IN the_ATI last_AP decade_NN , and_CC there_EX has_HVZ also_RB been_BEN an_AT increase_NN in_IN the_ATI prevalence_NN of_IN gram-positive_JJ sepsis_NN in_IN many_AP reports_NNS , gram-positive_JJ organisms_NNS are_BER now_RN as_QL common_JJ as_CS , if_CS not_XNOT more_QL common_JJ than_IN , gram-negative_JJ organisms_NNS in_IN causing_VBG sepsis_NN newly_RB developed_VBN definitions_NNS for_IN sepsis_NN and_CC related_JJ disorders_NNS (_( Table_NP 1_CD1 )_) underscore_VB the_ATI fact_NN that_CS gram- negative_JJ bacteria_NNS are_BER only_RB one_CD1 of_IN many_AP possible_JJ causes_NNS of_IN these_DTS diseases_NNS 7_CD there_EX are_BER at_RB least_RB two_CD reasons_NNS for_IN the_ATI undue_JJ emphasis_NN on_IN gram-negative_JJ organisms_NNS the_ATI first_OD is_BEZ epidemiologic_JJ sepsis_NN became_VBD clinically_RB important_JJ in_IN the_ATI 1960s_CDS , after_IN a_AT number_NN of_IN advances_NNS in_IN our_PP$ ability_NN to_TO keep_VB severely_RB ill_JJ or_CC injured_JJ patients_NNS alive_JJ at_IN that_DT time_NN , however_RB , another_DT major_JJ change_NN occurred_VBD : the_ATI incidence_NN of_IN gram-negative_JJ infections_NNS rose_VBD markedly_RB after_IN the_ATI introduction_NN of_IN antibiotics_NNS because_CS the_ATI increasing_JJ incidence_NN of_IN sepsis_NN seemed_VBD to_TO mirror_NN the_ATI increasing_JJ incidence_NN of_IN gram-negative_JJ infection_NN , a_AT causal_JJ relationship_NN between_IN the_ATI two_CD was_BEDZ often_RB suggested-but_JJ it_PP3 is_BEZ possible_JJ that_CS the_ATI relationship_NN was_BEDZ essentially_RB coincidental_JJ (_( this_DT issue_NN will_MD be_BE explored_VBN in_IN greater_JJR detail_NN below_IN )_) 8_CD the_ATI second_OD reason_NN for_IN the_ATI emphasis_NN on_IN gram-negative_JJ organisms_NNS is_BEZ experimental_JJ a_AT single_JJ component_NN of_IN the_ATI gram-negative_JJ organism_NN (_( endotoxin_NN )_) is_BEZ believed_VBN to_TO be_BE involved_VBN in_IN inciting_VBG sepsis_NN endotoxin_NN is_BEZ relatively_RB easy_JJ to_TO purify_VB and_CC inject_NN , and_CC , because_CS it_PP3 is_BEZ a_AT single_JJ substance_NN , the_ATI mechanisms_NNS by_IN which_WDTR gram-negative_JJ organisms_NNS cause_NN sepsis_NN can_MD be_BE mapped_VBD fairly_RB simply_RB in_IN contrast_NN , a_AT gram-positive_JJ organism_NN contains_VBZ a_AT number_NN of_IN different_JJ substances_NNS that_DT can_MD initiate_VB sepsis_VB , an_AT issue_NN that_WPR will_MD also_RB be_BE discussed_VBN in_IN more_QL detail_NN below_RI 9_CD if_CS present_JJ trends_NNS continue_VB , gram-positive_JJ organisms_NNS may_MD predominate_VB as_IN the_ATI cause_NN of_IN sepsis_NN within_IN the_ATI next_AP few_AP years_NNS thus_RB , it_PP3 seems_VBZ reasonable_JJ to_TO explore_VB the_ATI implications_NNS of_IN the_ATI increase_NN in_IN gram-positive_JJ sepsis_NN I_PP1A do_DO not_XNOT mean_VB to_TO suggest_VB that_CS sepsis_NN is_BEZ essentially_RB a_AT gram-positive_JJ disorder_NN , just_RB that_CS it_PP3 should_MD not_XNOT be_BE thought_VBN of_IN as_CS strictly_RB a_AT gram-negative_JJ (_( or_CC endotoxic_JJ )_) problem_NN 10_CD BACKGROUND_NP 11_CD to_TO understand_VB the_ATI rising_JJ incidence_NN of_IN gram-positive_JJ sepsis_NN , it_PP3 is_BEZ helpful_JJ to_TO reexamine_VB certain_JJ infectious_JJ disease_NN patterns_NNS during_IN the_ATI last_AP several_AP decades_NNS at_IN the_ATI outset_NN , however_RB , it_PP3 must_MD be_BE remembered_VBN that_CS the_ATI term_NN sepsis_NN did_DOD not_XNOT exist_VB 30_CD years_NNS ago_RB however_RB , the_ATI clinical_JJ findings_NNS of_IN _** sepsis_NN _** are_BER ancient_JJ , and_CC before_IN the_ATI 1960s_CDS there_EX were_BED undoubtedly_RB patients_NNS who_WPR suffered_VBD from_IN conditions_NNS that_DT would_MD be_BE defined_VBN as_IN sepsis_NN today_NR but_CC there_EX was_BEDZ no_ATI clinically_RB recognized_JJ syndrome_NN , and_CC therefore_RB little_JJ or_CC no_ATI information_NN was_BEDZ gathered_VBN on_IN its_PP$ incidence-or_NN its_PP$ cause_NN Consequently_NP , our_PP$ search_NN must_MD be_BE somewhat_RB indirect_JJ 12_CD as_CS noted_VBN above_IN , the_ATI incidence_NN of_IN gram-negative_JJ infections- particularly_RB nosocomial_JJ gram-negative_JJ bacteremia-increased_JJ markedly_RB in_IN the_ATI l950s_NNS and_CC 1960s_CDS until_IN the_ATI 1940s_CDS , bacteremia_NN was_BEDZ comparatively_RB rare_JJ and_CC most_QL often_RB resulted_VBD from_IN gram-positive_JJ infection_NN beginning_NN in_IN the_ATI 1950s_CDS , however_RB , the_ATI incidence_NN of_IN bacteremia_NN rose_VBD substantially_RB because_CS of_IN a_AT dramatic_JJ upsurge_NN in_IN the_ATI incidence_NN of_IN gram-negative_JJ bacteremia_NN by_IN the_ATI early_JJ 1970s_CD , gram-negative_JJ bacilli_NN were_BED responsible_JJ for_IN most_QL cases_NNS of_IN bacteremia_NN in_IN adults_NNS 13_CD during_IN the_ATI 1970s_CD and_CC 1980s_CD , however_RB , prevalence_NN patterns_NNS for_IN nosocomial_JJ infections_NNS changed_VBN again_RB there_EX was_BEDZ a_AT marked_JJ resurgence_NN in_IN gram-positive_JJ infections_NNS , including_IN gram-positive_JJ bacteremia_NN and_CC gram-positive_JJ sepsis_NN this_DT change_NN was_BEDZ first_OD noted_VBN in_IN the_ATI early_JJ 1980s_CD In_NP its_PP$ 1984_CD surveillance_NN survey_NN , the_ATI Centers_NP for_IN Disease_NP Control_NP found_VBD that_CS gram-positive_JJ organisms_NNS were_BED responsible_JJ for_IN less_AP than_IN 30%_NP of_IN all_ABN nosocomial_JJ infections_NNS , but_CC that_CS they_PP3AS caused_VBD 37%_CD of_IN all_ABN bloodstream_NN infections_NNS coagulase-negative_JJ staphylococci_NN were_BED the_ATI single_JJ most_QL frequent_JJ cause_NN of_IN bacteremia_NN in_IN a_AT slightly_RB later_RBR survey_NN (_( 1986_CD through_IN 1989_CD )_) , the_ATI Centers_NP for_IN Disease_NP Control_NP found_VBD that_CS gram-positive_JJ organisms_NNS were_BED implicated_VBN in_IN at_RB least_RB 55%_NN of_IN all_ABN cases_NNS of_IN nosocomial_JJ bacteremia_NN coagulase-negative_JJ staphylococci_JJ alone_RB accounted_VBN for_IN 27%_NN of_IN these_DTS cases_NNS 14_CD it_PP3 is_BEZ important_JJ to_TO note_VB that_CS the_ATI incidence_NN of_IN gram- negative_JJ nosocomial_JJ bacteremia_NN did_DOD not_XNOT decline_VB during_IN the_ATI 1980s_CD there_EX was_BEDZ , however_RB , a_AT marked_JJ increase_NN in_IN the_ATI overall_JJB number_NN of_IN cases_NNS of_IN nosocomial_JJ bacteremia__JJ much_AP of_IN the_ATI increase_NN was_BEDZ due_JJ to_IN the_ATI rising_JJ incidence_NN of_IN gram-positive_JJ bacteremia_NN (_( the_ATI incidence_NN of_IN fungemia_NN , primarily_RB candidemia_NN , also_RB rose_VBD substantially_RB during_IN this_DT period_NN )_) 15_CD at_IN this_DT point_NN , two_CD caveats_NNS should_MD be_BE raised_VBN first_OD , sepsis_NN is_BEZ not_XNOT always_RB a_AT nosocomial_JJ infection_NN , and_CC the_ATI causes_NNS of_IN sepsis_NN are_BER not_XNOT identical_JJ to_IN the_ATI causes_NNS of_IN nosocomial_JJ infection_NN nevertheless_RB , the_ATI link_NN between_IN sepsis_NN and_CC nosocomial_JJ infection_NN is_BEZ sufficiently_RB strong_JJ that_CS a_AT knowledge_NN of_IN prevalence_NN patterns_NNS can_MD often_RB help_VB to_TO pinpoint_VB the_ATI cause_NN of_IN sepsis_NN second_OD , sepsis_NN and_CC bacteremia_NN should_MD not_XNOT be_BE used_VBN as_CS interchangeable_JJ terms_NNS not_XNOT all_ABN patients_NNS with_IN sepsis_NN are_BER bacteremic_JJ , and_CC not_XNOT all_ABN bacteremic_JJ patients_NNS have_HV systemic_JJ consequences_NNS however_RB , most_AP early_JJ studies_NNS of_IN sepsis_NN were_BED performed_VBN in_IN bacteremic_JJ patients__NN in_IN fact_NN , the_ATI terms_NNS gram-negative_JJ bacteremia_NN and_CC gram-negative_JJ sepsis_NN were_BED often_RB used_VBN synonymously_RB thus_RB , there_EX is_BEZ some_DTI merit_NN in_IN mapping_NN the_ATI prevalence_NN patterns_NNS for_IN bacteremia_NN (_( while_CS simultaneously_RB recognizing_VBG the_ATI differences_NNS between_IN sepsis_NN and_CC bacteremia_NN )_) the_ATI new_JJ definitions_NNS presented_VBN in_IN Table_NP 1_CD1 help_VB clarify_VB the_ATI distinction_NN between_IN sepsis_NN and_CC bacteremia_NN 16_CD INCIDENCE_NPT OF_NPT GRAM-POSITIVE_NP SEPSIS_NP 17_CD no_ATI large_JJ studies_NNS of_IN patients_NNS with_IN sepsis_NN have_HV been_BEN conducted_VBN specifically_RB to_TO ascertain_VB causative_JJ organisms_NNS thus_RB , this_DT information_NN must_MD be_BE derived_VBN from_IN other_AP sources_NNS four_CD large_JJ multicenter_NN trials_NNS (_( two_CD corticosteroid_NN studies_NNS and_CC two_CD studies_NNS of_IN monoclonal_JJ antibodies_NNS to_TO endotoxin_NN )_) reported_VBN causative_JJ organisms_NNS in_IN at_RB least_RB some_DTI patients_NNS in_IN the_ATI methyprednisolone_NN study_NN , information_NN about_IN causative_JJ organisms_NNS was_BEDZ given_VBN only_RB for_IN patients_NNS with_IN bacteremia_NN (_( 179_CD of_IN the_ATI 382_CD patients_NNS enrolled_VBN )_) among_IN these_DTS patients_NNS , 115_CD (_( 64%_NN )_) had_HVD gram-negative_JJ infections_NNS , 59_CD (_( 33%_CD )_) had_HVD gram-positive_JJ infections_NNS , and_CC five_CD (_( 3%_CD )_) had_HVD fungal_JJ infections_NNS the_ATI incidence_NN of_IN gram-positive_JJ bacteremia_NN was_BEDZ even_RB higher_JJR in_IN the_ATI Veterans_NNS Affairs_NNS systemic_JJ sepsis_NN study_NN of_IN the_ATI 90_CD cases_NNS of_IN bacteremia_NN documented_VBN in_IN that_DT study_NN (_( among_IN 223_CD patients_NNS enrolled_VBN )_) , 51_CD (_( 56%_NN ) _) were_BED gram-negative_VBN in_IN origin_NN , 36_CD (_( 40%_NP )_) were_BED gram-positive_JJ , and_CC three_CD (_( 3%_CD )_) were_BED fungal_JJ neither_DTX of_IN these_DTS studies_NNS provided_VBN information_NN about_IN the_ATI causes_NNS of_IN nonbacteremic_JJ sepsis__NN however_RB , the_ATI Veterans_NNS Affairs_NNS study_NN did_DOD note_NN that_CS evidence_NN of_IN gram-negative_JJ infection_NN could_MD be_BE documented_VBN in_IN only_RB 83_CD patients_NNS (_( 37%_CD )_) given_VBN that_CS both_ABX of_IN these_DTS studies_NNS were_BED conducted_VBN in_IN the_ATI early_JJ to_IN middle_JJB 1980s_CD , they_PP3AS probably_RB underrepresent_VB the_ATI incidence_NN of_IN gram-positive_JJ sepsis_NN for_IN that_DT period_NN 18_CD in_IN trials_NNS of_IN two_CD different_JJ monoclonal_JJ antibodies_NNS against_IN endotoxin_NN , the_ATI incidence_NN of_IN gram-positive_JJ infection_NN was_BEDZ much_RB lower_JJR in_IN the_ATI HA-1A_CD-CD trial_NN (_( 9%_NN )_) and_CC was_BEDZ not_XNOT reported_VBN in_IN the_ATI study_NN of_IN E5_NP both_ABX of_IN these_DTS studies_NNS specifically_RB sought_VBD patients_NNS with_IN gram-negative_JJ sepsis_NN , however_RB Thus_JJ , the_ATI low_JJ incidence_NN of_IN gram-positive_JJ infection_NN is_BEZ not_XNOT surprising_JJ 19_CD several_AP smaller_JJR , more_QL recent_JJ studies_NNS may_MD better_JJR reflect_VB the_ATI current_JJ incidence_NN of_IN gram-positive_JJ sepsis_NN although_CS these_DTS studies_NNS were_BED not_XNOT performed_VBN specifically_RB to_TO elucidate_VB causative_JJ organisms_NNS , they_PP3AS did_DOD include_VB consecutive_JJ series_NN of_IN patients.=20_CD 20_CD table_NN 2_CD outlines_VBZ the_ATI prevalence_NN of_IN organisms_NNS in_IN these_DTS studies__NN in_IN all_ABN but_CC one_CD1 , the_ATI incidence_NN of_IN gram-positive_JJ sepsis_NN equaled_VBN or_CC exceeded_VBD that_CS of_IN gram- negative_JJ sepsis_NN 21_CD on_IN the_ATI basis_NN of_IN this_DT evidence_NN , it_PP3 seems_VBZ reasonable_JJ to_TO conclude_VB that_CS between_IN one_CD1 third_OD and_CC one_CD1 half_ABN of_IN all_ABN cases_NNS of_IN sepsis_NN are_BER currently_RB caused_VBN by_IN gram-positive_JJ organisms_NNS , and_CC that_CS the_ATI incidence_NN of_IN gram- positive_JJ sepsis_NN should_MD continue_VB to_TO rise_VB for_IN at_RB least_RB the_ATI next_AP few_AP years_NNS the_ATI overall_JJB incidence_NN of_IN sepsis_NN is_BEZ unknown_JJ , but_CC it_PP3 has_HVZ been_BEN estimated_VBN that_CS about_RB 400000_CD cases_NNS occur_VB each_DT year_NN in_IN the_ATI United_NP States_NP Thus_JJ , at_RB least_RB 133000-and_CD-CD possibly_RB more_AP than_IN 200000- Americans_NNS will_MD suffer_VB from_IN gram-positive_JJ sepsis_NN this_DT year_NN 22_CD RISK_NP FACTORS_NP 23_CD a_AT number_NN of_IN factors_NNS are_BER known_VBN to_TO place_VB patients_NNS at_IN risk_NN for_IN sepsis__NN these_DTS include_VB the_ATI aggressive_JJ use_NN of_IN catheters_NNS and_CC other_AP invasive_JJ equipment_NN , the_ATI implantation_NN of_IN prosthetic_JJ devices_NNS , and_CC the_ATI administration_NN of_IN chemotherapy_NN or_CC immunosuppressive_JJ agents_NNS in_IN addition_NN , elderly_JJ persons_NNS , trauma_NN and_CC burn_VB victims_NNS , and_CC patients_NNS with_IN metabolic_JJ , neoplastic_JJ , or_CC immunodeficiency_NN disorders_NNS are_BER at_IN increased_VBN risk_NN none_PN of_IN these_DTS risk_NN factors_NNS is_BEZ specific_JJ for_IN gram- positive_JJ sepsis_NN However_NP , coagulase-negative_JJ staphylococci_NN are_BER the_ATI leading_JJ cause_NN of_IN infections_NNS related_VBN to_IN Hickman_NP catheters_NNS , central_JJ venous_JJ nutrition_NN catheters_NNS , peripheral_JJ intravenous_JJ catheters_NNS , and_CC prosthetic_JJ heart_NN valves_NNS coagulase-negative_JJ staphylococci_NN have_HV also_RB been_BEN linked_VBN to_IN infections_NNS from_IN intravenous_JJ administration_NN of_IN lipid_NN emulsions_NNS 24_CD two_CD recent_JJ studies_NNS reported_VBN a_AT high_JJ incidence_NN of_IN staphylococcal_JJ sepsis_NN in_IN patients_NNS receiving_VBG interleukin_NN 2_CD snydman_NN et_&FW al_APS found_VBN that_CS sepsis_NN developed_VBN in_IN 20_CD of_IN 107_CD patients_NNS with_IN cancer_NN treated_VBN with_IN interleukin_NN 2__NN 13_CD cases_NNS resulted_VBD from_IN Staphylococcus_&FW aureus_&FW infection_NN and_CC five_CD from_IN Staphylococcus_&FW epidermidis_NN infection_NN Lim_NP et_&FW al_APS detected_VBN four_CD episodes_NNS of_IN septicemia_NN in_IN 10_CD patients_NNS with_IN lymphoma_NN given_VBN interleukin_NN 2__NN three_CD episodes_NNS were_BED staphylococcal_JJ in_IN origin_NN 25_CD injecting_VBG drug_NN use_NN may_MD be_BE another_DT risk_NN factor_NN for_IN gram-positive_JJ sepsis_NN in_IN the_ATI study_NN by_IN Jafri_NP et_&FW al_APS , nine_CD of_IN 23_CD patients_NNS with_IN sepsis_NN were_BED injecting_VBG drug_NN users__NN all_ABN nine_CD had_HVD gram-positive_JJ sepsis_NN the_ATI association_NN between_IN gram-positive_JJ infection_NN and_CC injecting_VBG drug_NN use_NN has_HVZ been_BEN noted_VBN by_IN others_APS crane_NN et_&FW al_APS found_VBN that_CS gram-positive_JJ organisms_NNS were_BED implicated_VBN (_( exclusively_RB or_CC in_IN part_NN )_) in_IN 90%_NP of_IN 180_CD cases_NNS of_IN bacteremia_NN in_IN narcotic_JJ addicts_NNS the_ATI most_AP common_JJ pathogens_NNS were_BED methicillin-sensitive_JJ S_ZZ aureus_&FW , methicillin-resistant_NN S_ZZ aureus_&FW , and_CC streptococci_NN 26_CD overall_JJB , however_RB , the_ATI increasing_JJ incidence_NN of_IN gram-positive_JJ sepsis_NN may_MD result_VB less_AP from_IN an_AT increase_NN in_IN the_ATI number_NN of_IN new_JJ risk_NN factors_NNS for_IN sepsis_NN than_CS from_IN the_ATI increasing_JJ prevalence_NN of_IN known_JJ risk_NN factors_NNS in_IN clinical_JJ practice_NN , coupled_VBN with_IN changes_NNS in_IN gram-positive_JJ organisms_NNS themselves_PPLS for_IN example_NN , the_ATI number_NN of_IN strains_NNS of_IN S_ZZ aureus_&FW and_CC coagulase-negative_JJ staphylococci_JJ resistant_JJ to_IN conventional_JJ antibiotics_NNS keeps_VBZ growing_JJ resistance_NN has_HVZ also_RB been_BEN found_VBN in_IN strains_NNS of_IN Streptococcus_JJ pneumoniae_NN and_CC group_NN A_ZZ streptococci_NN 27_CD evidence_NN also_RB suggests_VBZ an_AT increase_NN in_IN virulence_NN in_IN recent_JJ years_NNS , there_EX has_HVZ been_BEN a_AT resurgence_NN of_IN acute_JJ rheumatic_JJ fever_NN the_ATI discovery_NN of_IN toxic_JJ shock_NN syndrome_NN and_CC related_VBD streptococcal_JJ disorders_NNS further_JJB supports_VBZ this_DT idea_NN pyrogenic_JJ exotoxin_NN A_ZZ (_( the_ATI scarlet_JJ fever_NN toxin_NN )_) has_HVZ reappeared_VBD 28_CD HOW_NPT GRAM-POSITIVE_NPT ORGANISMS_NPT CAUSE_NP SEPSIS_NP 29_CD sepsis_NN is_BEZ believed_VBN to_TO result_VB from_IN a_AT complex_JJ mechanism_NN involving_VBG activation_NN of_IN a_AT number_NN of_IN cells_NNS , most_QL notably_RB monocytes_VBZ , T_ZZ cells_NNS , neutrophils_NNS , and_CC platelets_NNS cytokines_NNS (_( especially_RB tumor_JJ necrosis_NN factor_NN (_( TNF_NP )_) and_CC various_JJ interleukins_NNS )_) are_BER released_VBN , arachidonic_JJ acid_NN is_BEZ metabolized_VBN , the_ATI complement_NN and_CC coagulation_NN systems_NNS are_BER activated_VBN , and_CC toxic_JJ oxygen_NN species_NN are_BER produced_VBN the_ATI result_NN is_BEZ widespread_JJ endothelial_JJ inflammation_NN and_CC , ultimately_RB , increased_VBD endothelial_JJ permeability_NN (_( Figure_NP 1_CD1 )_) 30_CD a_AT number_NN of_IN reports_NNS suggest_VB that_CS gram-positive_JJ organisms_NNS can_MD prompt_JJ release_NN of_IN the_ATI inflammatory_JJ mediators_NNS that_CS underlie_NN sepsis_NN and_CC can_MD also_RB reproduce_VB the_ATI clinical_JJ signs_NNS and_CC symptoms_NNS of_IN sepsis_NN how_WRB this_DT occurs_VBZ is_BEZ not_XNOT yet_RB entirely_RB clear_JJ , although_CS a_AT number_NN of_IN recent_JJ discoveries_NNS have_HV greatly_RB increased_VBN our_PP$ understanding_NN of_IN this_DT area_NN both_ABX constituents_NNS of_IN the_ATI gram-positive_JJ cell_NN wall_NN and_CC toxins_NNS released_VBN by_IN these_DTS organisms_NNS may_MD be_BE involved_VBN furthermore_RB , toxins_NNS and_CC cell_NN wall_NN components_NNS may_MD not_XNOT always_RB act_NN independently__NN evidence_NN suggests_VBZ that_CS toxins_NNS may_MD accelerate_VB the_ATI effects_NNS of_IN cell_NN wall_NN products_NNS 31_CD so_QL many_AP new_JJ discoveries_NNS are_BER being_BEG made_VBN about_IN the_ATI effects_NNS of_IN gram-positive_JJ organisms_NNS that_CS it_PP3 is_BEZ beyond_IN the_ATI scope_NN of_IN this_DT article_NN to_TO review_NN them_PP3OS all_ABN however_RB , I_PP1A will_MD attempt_VB to_IN present_JJ enough_QLP data_NNS to_TO show_VB that_CS gram-positive_JJ organisms_NNS are_BER as_CS capable_JJ of_IN inciting_VBG sepsis_NN as-and_NN perhaps_RB even_RB more_QL powerful_JJ than-gram-negative_JJ organisms_NNS I_PP1A will_MD concentrate_VB my_PP$ discussion_NN on_IN the_ATI organisms_NNS responsible_JJ for_IN most_QL cases_NNS of_IN gram-positive_JJ sepsis_NN : S_ZZ aureus_&FW , coagulase-negative_JJ staphylococci_NN , pneumococci_NN , and_CC streptococci_NN for_IN a_AT more_AP complete_JJ discussion_NN of_IN how_WRB gram-positive_JJ organisms_NNS cause_NN sepsis_NN , see_VB Bone_NP 32_CD effects_NNS of_IN Cell_NPT Wall_NP Components_NP 33_CD one_CD1 of_IN the_ATI chief_JJB difficulties_NNS in_IN elucidating_VBG how_WRB gram-positive_JJ organisms_NNS cause_NN sepsis_NN is_BEZ that_CS there_EX are_BER considerable_JJ differences_NNS in_IN cell_NN wall_NN composition_NN among_IN various_JJ gram-positive_JJ species_NN (_( Figure_NP 2_CD )_) Specific_NP components_NNS of_IN the_ATI cell_NN wall_NN may_MD be_BE structurally_RB different_JJ from_IN species_NN to_TO species_NN , or_CC even_RB within_IN the_ATI same_AP species_NN also_RB , the_ATI composition_NN of_IN these_DTS components_NNS may_MD change_VB during_IN maturation_NN of_IN the_ATI organism_NN nevertheless_RB , a_AT number_NN of_IN different_JJ cell_NN wall_NN constituents_NNS from_IN a_AT variety_NN of_IN gram-positive_JJ organisms_NNS have_HV been_BEN shown_VBN to_IN prompt_JJ the_ATI release_NN of_IN inflammatory_JJ mediators_NNS 34_CD humoral_JJ Effects_NNS both_ABX peptidoglycans_NNS and_CC teichoic_JJ acids_NNS can_MD activate_VB the_ATI alternate_JJ complement_NN pathway_NN pneumococcal_JJ cell_NN wall_NN components_NNS have_HV been_BEN shown_VBN to_TO interact_VB with_IN arachidonic_JJ acid_NN metabolism_NN , although_CS how_WRB this_DT occurs_VBZ is_BEZ not_XNOT yet_RB understood_VBN it_PP3 may_MD be_BE related_VBN to_TO complement_VB activation_NN , to_TO cytokine_VB production_NN , or_CC to_IN an_AT as_CS yet_RB unidentified_JJ mechanism_NN 35_CD staphylococcal_JJ peptidoglycan_NN induces_VBZ platelet_NN aggregation_NN when_WRB in_IN the_ATI presence_NN of_IN protein_NN A_ZZ pneumococcal_JJ lipoteichoic_JJ acid_NN is_BEZ structurally_RB similar_JJ to_TO platelet_VB activating_VBG factor_NN __*- it_PP3 is_BEZ unclear_JJ , however_RB , whether_CS the_ATI two_CD behave_VB similarly_RB 36_CD peptidoglycan_NN precursors_NNS from_IN penicillin-treated_JJ Streptococcus_JJ faecalis_NN and_CC staphylococcal_JJ lipoteichoic_JJ acids_NNS can_MD stimulate_VB interleukin_VB 1_CD1 release_NN from_IN human_JJ monocytes_NNS other_AP studies_NNS have_HV also_RB demonstrated_VBN that_CS human_JJ monocytes_NNS can_MD produce_VB interleukin_VB 1_CD1 in_IN response_NN to_TO stimulation_NN with_IN cell_NN wall_NN components_NNS from_IN a_AT wide_JJ variety_NN of_IN gram-positive_JJ organisms_NNS these_DTS studies_NNS , however_RB , produce_VB conflicting_JJ evidence_NN as_CS to_TO whether_CS lipoteichoic_JJ acids_NNS and_CC other_AP cell_NN wall_NN products_NNS can_MD elicit_VB TNF_NP production_NN in_IN human_JJ monocytes_NNS 37_CD several_AP explanations_NNS can_MD be_BE given_VBN for_IN these_DTS discordant_NN results_NNS __*- these_DTS explanations_NNS are_BER not_XNOT mutually_RB exclusive_JJ 38_CD it_PP3 may_MD be_BE possible_JJ that_CS gram-positive_JJ organisms_NNS do_DO not_XNOT act_VB identically_RB in_IN producing_VBG inflammation_NN or_CC inciting_VBG sepsis_NN the_ATI highly_RB variable_JJ nature_NN of_IN gram-positive_JJ cell_NN walls_NNS supports_VBZ this_DT argument_NN 39_CD the_ATI highly_RB evanescent_JJ nature_NN of_IN TNF_NP makes_VBZ it_PP3 difficult_JJ to_TO study_VB 40_CD experiments_NNS with_IN cell_NN wall_NN products_NNS may_MD simply_RB not_XNOT reflect_VB the_ATI clinical_JJ situation_NN adequately_RB in_IN patients_NNS with_IN sepsis_NN , a_AT number_NN of_IN other_AP nearby_JJB bacterial_JJ products_NNS or_CC inflammatory_JJ mediators_NNS might_MD well_RB alter_VB the_ATI effects_NNS of_IN cell_NN wall_NN components_NNS 41_CD clinical_JJ Effects_NNS clinical_JJ reactions_NNS after_IN administration_NN of_IN cell_NN wall_NN products_NNS have_HV also_RB been_BEN studied_VBN intratracheal_JJ instillation_NN of_IN either_DTX peptidoglycan_NN or_CC teichoic_JJ acids_NNS from_IN pneumococcal_JJ cell_NN walls_NNS produces_VBZ leukocytosis_NN and_CC elevated_VBD protein_NN concentrations_NNS in_IN rabbit_NN bronchoalveolar_NN lavage_NN fluid__VB the_ATI two_CD agents_NNS together_RB produce_VB a_AT greater_JJR inflammatory_JJ effect_NN than_IN does_DOZ either_DTX independently_RB 42_CD in_IN guinea_NN pigs_NNS , staphylococcal_JJ peptidoglycan_NN has_HVZ been_BEN shown_VBN to_TO induce_VB disseminated_VBN intravascular_NN coagulation_NN platelet_NN counts_VBZ and_CC fibrinogen_NN concentrations_NNS are_BER decreased__NN prothrombin_NN times_NNS , activated_VBD partial_JJ thromboplastin_NN times_NNS , and_CC fibrin_NN degradation_NN product_NN levels_NNS are_BER increased_VBN in_IN the_ATI same_AP animal_NN model_NN , staphylococcal_JJ peptidoglycan_NN causes_NNS leukopenia_NN and_CC thrombocytopenia_NN 43_CD effects_NNS of_IN Toxins_NNS 44_CD enterotoxins_NNS and_CC exotoxins_NNS released_VBN by_IN gram-positive_JJ organisms_NNS may_MD also_RB be_BE involved_VBN in_IN the_ATI pathogenesis_NN of_IN sepsis_NN these_DTS toxins_NNS may_MD be_BE able_JJ to_TO initiate_VB the_ATI inflammatory_JJ cascade_NN through_IN their_PP$ direct_JJ effects_NNS on_IN macrophages_NNS and_CC other_AP cells_NNS , as_QL well_RB as_IN through_IN their_PP$ ability_NN to_TO act_VB as_CS _** superantigens_NNS , _** substances_NNS that_CS profoundly_RB affect_VB T-cell_NP function_NN , thereby_RB interfering_VBG with_IN the_ATI body's_NN$ immune_JJ response_NN 45_CD humoral_JJ Effects_NNS toxic_JJ shock_NN syndrome_NN toxin_NN 1_CD1 (_( TSST-1_CD-CD )_) has_HVZ been_BEN shown_VBN to_TO be_BE more_QL potent_JJ than_IN endotoxin_NN in_IN prompting_NN human_JJ monocytes_NNS to_TO release_NN interleukin_NN 1_CD1 the_ATI TSST-1_CD-CD can_MD also_RB stimulate_VB TNF_NP release_NN from_IN human_JJ monocytes_NNS in_IN addition_NN , human_JJ monocytes_NNS have_HV been_BEN shown_VBN to_TO secrete_NN interleukin_NN 1_CD1 after_IN stimulation_NN with_IN S_ZZ aureus_&FW alpha-toxin_NN and_CC to_TO produce_VB TNF_NP after_IN exposure_NN to_IN staphylococcal_JJ enterotoxins_NNS B_ZZ or_CC C1_CD , or_CC streptococcal_JJ pyrogenic_JJ exotoxin_NN A_ZZ 46_CD a_AT number_NN of_IN toxins_NNS have_HV also_RB been_BEN shown_VBN to_TO metabolize_VB arachidonic_JJ acid_NN via_IN either_DTX the_ATI lipoxygenase_NN or_CC cyclo-oxygenase_NN pathways_NNS Streptolysin_NP O_ZZ has_HVZ also_RB been_BEN shown_VBN to_TO activate_VB the_ATI classic_JJ complement_NN pathway_NN staphylococcal_JJ alpha-toxin_NN is_BEZ known_VBN to_TO alter_VB platelet_NN function_NN after_IN exposure_NN to_IN this_DT toxin_NN , platelets_NNS copiously_RB secrete_JJ granule_NN constituents_NNS , such_IN as_IN factor_NN V_ZZ and_CC platelet_NN factor_NN 4_CD in_IN turn_NN , these_DTS cause_NN prothrombinase_JJ complex_JJ generation_NN and_CC thrombin_NN generation__NN disseminated_VBN intravascular_NN coagulation_NN may_MD ensue_VB 47_CD staphylococcal_JJ enterotoxins_NNS , TSST-1_CD-CD , and_CC streptococcal_JJ exotoxins_NNS form_VB the_ATI group_NN known_VBN as_CS superantigens_NNS and_CC are_BER among_IN the_ATI most_QL potent_JJ stimulators_NNS of_IN T_ZZ cells_NNS known_VBN superantigens_NNS bind_VB directly_RB to_TO class_VB II_NP major_JJ histocompatibility_NN molecules_NNS to_TO form_VB a_AT complex_JJ that_CS , in_IN turn_NN , attaches_VBZ to_IN an_AT unusual_JJ V_ZZ beta_NN region_NN on_IN a_AT T_ZZ cell's_NN$ antigen_NN receptor_NN Superantigens_NP have_HV two_CD somewhat_RB contradictory_JJ effects_NNS : they_PP3AS exert_VB an_AT extremely_RB powerful_JJ proliferative_JJ effect_NN on_IN T_ZZ cells_NNS , but_CC they_PP3AS can_MD produce_VB a_AT profound_JJ state_NN of_IN T-cell_NP unresponsiveness_JJ or_CC even_RB T-cell_NP death_NN as_IN a_AT consequence_NN , the_ATI body_NN may_MD have_HV first_OD too_QL many_AP , and_CC then_RN too_QL few_AP , T_ZZ cells_NNS to_TO fight_VB infection_NN (_( it_PP3 should_MD be_BE noted_VBN that_CS TSST-1_CD-CD , staphylococcal_JJ enterotoxins_NNS , and_CC streptococcal_JJ exotoxins_NNS are_BER not_XNOT the_ATI only_AP superantigens__NN others_APS include_VB an_AT exoprotein_NN of_IN Mycoplasma_NP arthritidis_NN , a_AT Clostridium_NP perfringens_NNS enterotoxin_NN , an_AT antigen_NN from_IN Yersinia_NP enterocolitica_NN , and_CC a_AT nucleocapsid_NN of_IN the_ATI rabies_NNS virus_NN superantigens_NNS may_MD also_RB be_BE encoded_VBN in_IN a_AT number_NN of_IN retroviruses_NNS , possibly_RB including_IN the_ATI acquired_JJ immunodeficiency_NN virus_NN for_IN more_AP information_NN about_IN superantigens_NNS , see_VB Johnson_NP et_&FW al_APS and_CC Fleischer_NP )_) 48_CD another_DT mechanism_NN by_IN which_WDTR gram-positive_JJ toxins_NNS cause_NN sepsis_NN may_MD be_BE through_IN an_AT increase_NN in_IN membrane_NN permeability_NN many_AP of_IN these_DTS toxins_NNS produce_VB pores_NNS that_WPR permit_VB rapid_JJ transmembrane_JJ flux_NN of_IN ions_NNS and_CC small_JJ molecules_NNS , especially_RB calcium_NN ionic_JJ disequilibrium_NN may_MD also_RB cause_VB functional_JJ derangements_NNS within_IN endothelial_JJ contractile_NN microfilaments_NNS , thereby_RB creating_VBG intercellular_NN gaps_NNS within_IN the_ATI endothelium_NN exposure_NN of_IN the_ATI endothelium_NN to_IN low_JJ doses_NNS of_IN staphylococcal_JJ alpha-toxin_NN produce_NN such_ABL gaps_NNS , permitting_VBG free_JJ passage_NN of_IN molecules_NNS 49_CD clinical_JJ Effects_NNS it_PP3 is_BEZ well_RB known_VBN that_CS TSST-1_CD-CD and_CC the_ATI scarlet_JJ fever_NN toxins_NNS of_IN Streptococcus_JJ pyogenes_NNS can_MD cause_VB fever_NN and_CC shock_NN it_PP3 may_MD be_BE less_QL well_RB known_VBN that_CS staphylococcal_JJ enterotoxins_NNS are_BER also_RB extremely_RB pyrogenic__NN enterotoxin_NN A_ZZ is_BEZ markedly_RB more_QL potent_JJ than_IN TSST-1_CD-CD in_IN producing_VBG fever_NN , cachexia_NN , multiple_JJ organ_NN system_NN dysfunction_NN , and_CC death_NN enterotoxin_NN B_ZZ can_MD also_RB cause_VB fever_NN , shock_NN , and_CC death_NN 50_CD the_ATI TSST-1_CD-CD can_MD also_RB directly_RB inhibit_VB myocardial_JJ function_NN __*- 51_CD a_AT similar_JJ effect_NN on_IN myocardial_JJ function_NN can_MD be_BE caused_VBN by_IN purified_VBN alpha-toxin_NN from_IN C_ZZ perfringens_NNS injection_NN of_IN staphylococcal_JJ alpha-toxin_NN to_IN rabbit_NN lungs_NNS results_NNS in_IN a_AT dose-dependent_NN increase_NN in_IN pulmonary_NN artery_NN pressure_NN , and_CC also_RB pulmonary_JJ edema_NN and_CC elevated_VBD ventilation_NN pressure_NN 52_CD INFLAMMATORY_NPT MEDIATORS_NPT IN_NPT PATIENTS_NPT WITH_NPT GRAM-POSITIVE_NP SEPSIS_NP 53_CD information_NN on_IN the_ATI serum_NN levels_NNS of_IN inflammatory_JJ mediators_NNS in_IN patients_NNS with_IN gram-positive_JJ sepsis_NN is_BEZ limited_JJ most_AP studies_NNS of_IN inflammatory_JJ mediators_NNS in_IN sepsis_NN do_DO not_XNOT report_VB causative_JJ organisms_NNS or_CC do_DO not_XNOT report_VB levels_NNS separately_RB for_IN gram-positive_JJ and_CC gram-negative_JJ infections_NNS at_RB least_RB three_CD studies_NNS , however_RB , have_HV reported_VBN this_DT information_NN 54_CD in_IN a_AT study_NN by_IN Debets_NP et_&FW al_APS , detectable_JJ TNF_NP levels_NNS were_BED present_NN in_IN 11_CD of_IN 43_CD patients_NNS with_IN sepsis_NN the_ATI TNF_NP was_BEDZ present_NN in_IN four_CD of_IN 13_CD patients_NNS with_IN gram-positive_JJ sepsis_NN and_CC four_CD of_IN 19_CD patients_NNS with_IN gram-negative_JJ infections_NNS mean_VB TNF_NP levels_NNS were_BED markedly_RB higher_JJR in_IN the_ATI patients_NNS with_IN gram-positive_JJ sepsis_NN than_CS in_IN those_DTS with_IN gram-negative_JJ infection_NN (_( 54_CD vs_IN 25_CD pg_mL_NN , respectively_RB )_) 55_CD marks_NNS et_&FW al_APS found_VBN only_RB a_AT slight_JJ difference_NN in_IN mean_NN peak_NN TNF_NP levels_NNS between_IN patients_NNS with_IN gram- positive_JJ and_CC gram-negative_JJ sepsis_NN in_IN this_DT study_NN , measurable_JJ TNF_NP levels_NNS were_BED found_VBN in_IN 12_CD of_IN 32_CD patients_NNS with_IN gram-positive_JJ sepsis_NN (_( mean_VB peak_NN value_NN , 196_CD pg_mL_NN )_) and_CC in_IN nine_CD of_IN 25_CD patients_NNS with_IN gram-negative_JJ infection_NN (_( mean_VB peak_NN value_NN , 167_CD pg_mL_NN )_) 56_CD in_IN the_ATI study_NN by_IN Guidet_NP et_&FW al_APS , all_ABN 11_CD patients_NNS with_IN gram-negative_JJ sepsis_NN , and_CC seven_CD of_IN nine_CD patients_NNS with_IN gram-positive_JJ sepsis_NN , had_HVD measurable_JJ TNF_NP levels_NNS patients_NNS with_IN gram-positive_JJ sepsis_NN had_HVD lower_JJR mean_VB initial_JJ TNF_NP levels_NNS than_IN did_DOD those_DTS with_IN gram-negative_JJ infections_NNS (_( 196_CD vs_IN 455_NN pg_mL_NN , respectively_RB )_) 57_CD my_PP$ colleagues_NNS and_CC I_PP1A have_HV found_VBN measurable_JJ levels_NNS of_IN TNF_NP , interleukin_NN 1_CD1 , and_CC interleukin_NN 6_CD in_IN patients_NNS with_IN gram-positive_JJ sepsis_NN elevated_VBD levels_NNS of_IN these_DTS cytokines_NNS have_HV also_RB been_BEN detected_VBN in_IN patients_NNS with_IN gram-positive_JJ meningitis_NN __*- increased_JJ interleukin_NN 6_CD levels_NNS are_BER also_RB demonstrable_JJ in_IN patients_NNS with_IN gram-positive_JJ septic_JJ arthritis_NN 58_CD CONCLUSIONS_NP 59_CD if_CS gram-positive_JJ organisms_NNS are_BER capable_JJ of_IN causing_VBG sepsis_NN , three_CD questions_NNS must_MD be_BE addressed_VBN : what_WDT role_NN , if_CS any_DTI , does_DOZ endotoxin_NN have_HV in_IN the_ATI pathogenesis_NN of_IN gram-positive_JJ sepsis_NN ? does_DOZ the_ATI underlying_JJ organism_NN alter_VB the_ATI outcome_NN in_IN sepsis_NN ? what_WDT implications_NNS do_DO these_DTS findings_NNS have_HV for_IN the_ATI treatment_NN of_IN sepsis_NN ? 60_CD role_NN of_IN Endotoxin_NP 61_CD a_AT study_NN by_IN Natanson_NP et_&FW al_APS provides_VBZ confirmation_NN that_CS endotoxin_NN is_BEZ not_XNOT required_VBN for_IN the_ATI onset_NN of_IN sepsis_NN these_DTS authors_NNS injected_VBD endotoxin_NN into_IN dogs_NNS and_CC found_VBN that_CS it_PP3 reproduced_VBN the_ATI cardiovascular_NN changes_NNS characteristic_NN of_IN septic_JJ shock_NN however_RB , injection_NN of_IN S_ZZ aureus_&FW into_IN other_AP dogs_NNS reproduced_VBN these_DTS changes_NNS natanson_NN et_&FW al_APS thus_RB concluded_VBD that_CS endotoxin_NN is_BEZ sufficient_JJ , but_CC not_XNOT necessary_JJ , to_TO produce_VB sepsis_NN 62_CD perhaps_RB the_ATI strongest_JJT argument_NN for_IN endotoxin_NN as_IN the_ATI primary_JJ initiator_NN of_IN sepsis_NN comes_VBZ from_IN the_ATI discovery_NN that_CS a_AT large_JJ proportion_NN of_IN patients_NNS with_IN non-gram-negative_JJ sepsis_NN have_HV endotoxemia_NN this_DT finding_VBG is_BEZ actually_RB not_XNOT surprising__VB bacterial_JJ translocation_NN may_MD allow_VB endotoxin_VB to_IN leak_NN across_IN the_ATI gut_NN , and_CC the_ATI incidence_NN of_IN polymicrobial_JJ infections_NNS may_MD be_BE higher_JJR than_IN realized_VBN nevertheless_RB , I_PP1A would_MD argue_VB that_CS in_IN this_DT setting_VBG , the_ATI primary_JJ problem_NN is_BEZ not_XNOT endotoxemia_VB 63_CD what_WDT impact_NN endotoxemia_NN has_HVZ on_IN the_ATI course_NN of_IN gram- positive_JJ sepsis_NN is_BEZ not_XNOT known_VBN there_EX is_BEZ evidence_NN that_CS the_ATI presence_NN of_IN endotoxin_NN in_IN the_ATI bloodstream_NN may_MD exacerbate_VB the_ATI effects_NNS of_IN gram- positive_JJ bacteria_NNS __*- it_PP3 is_BEZ equally_RB possible_JJ that_CS the_ATI presence_NN of_IN gram-positive_JJ organisms_NNS worsens_NNS the_ATI impact_NN of_IN endotoxin_NN however_RB , given_VBN the_ATI considerable_JJ evidence_NN that_CS gram-positive_JJ organisms_NNS can_MD cause_VB sepsis_VB by_IN themselves_PPLS , there_EX is_BEZ no_ATI reason_NN to_TO assume_VB that_CS the_ATI presence_NN of_IN endotoxin_NN is_BEZ required_VBN in_IN other_AP words_NNS , endotoxin_NN is_BEZ an_AT initiator_NN , but_CC not_XNOT the_ATI initiator_JJ , of_IN sepsis_NN 64_CD effect_NN of_IN the_ATI Underlying_NP Organism_NP 65_CD there_EX has_HVZ never_RB been_BEN consensus_NN on_IN whether_CS the_ATI underlying_JJ organism_NN alters_VBZ outcome_NN in_IN sepsis_NN wiles_NNS et_&FW al_APS found_VBN that_CS the_ATI hyperdynamic_JJ cardiovascular_NN response_NN was_BEDZ similar_JJ , regardless_RB of_IN whether_CS patients_NNS had_HVD gram-positive_JJ , gram-negative_JJ , or_CC fungal_JJ sepsis_NN however_RB , it_PP3 has_HVZ often_RB been_BEN said_VBD that_CS shock_NN is_BEZ more_QL common_JJ and_CC the_ATI mortality_NN higher_JJR in_IN patients_NNS with_IN gram-negative_JJ sepsis_NN in_IN the_ATI absence_NN of_IN a_AT large_JJ study_NN directly_RB comparing_VBG outcome_NN in_IN different_JJ types_NNS of_IN sepsis_NN , it_PP3 is_BEZ difficult_JJ to_TO confirm_VB or_CC refute_VB this_DT assumption_NN however_RB , several_AP recent_JJ reports_NNS demonstrate_VB that_CS patients_NNS with_IN gram-positive_JJ and_CC gram-negative_JJ sepsis_NN have_HV comparable_JJ disease_NN severity_NN scores_NNS and_CC similar_JJ mortality_NN other_AP studies_NNS show_VB that_CS patients_NNS with_IN septic_JJ shock_NN are_BER as_CS likely_JJ to_TO have_HV gram-positive_JJ as_IN gram-negative_JJ infection_NN 66_CD it_PP3 is_BEZ unlikely_JJ that_CS gram-positive_JJ organisms_NNS , as_IN a_AT group_NN , are_BER any_DTI more_QL or_CC less_QL likely_JJ to_TO produce_VB an_AT adverse_JJ outcome_NN than_IN are_BER gram-negative_JJ organisms_NNS individual_JJ strains_NNS , however_RB , may_MD be_BE especially_RB virulent_JJ or_CC have_HV other_AP factors_NNS that_WPR make_VB them_PP3OS particularly_RB deadly__JJ this_DT may_MD help_VB explain_VB the_ATI resurgence_NN of_IN gram- positive_JJ sepsis_NN for_IN example_NN , a_AT recent_JJ report_NN documents_NNS a_AT new_JJ , highly_RB virulent_JJ clone_NN of_IN Spyogenes_NP that_DT is_BEZ characterized_VBN by_IN the_ATI presence_NN of_IN an_AT invasive_JJ 67_CD restriction-fragment_NN profile_NN and_CC the_ATI presence_NN of_IN the_ATI speA_NN gene_NN (_( the_ATI gene_NN for_IN the_ATI scarlet_JJ fever_NN toxin_NN ) _) this_DT clone_NN was_BEDZ present_NN in_IN 17_CD of_IN 19_CD patients_NNS with_IN S_ZZ pyogenes-caused_JJ sepsis_NN , but_CC in_IN only_RB 20_CD of_IN the_ATI 48_CD patients_NNS with_IN less_QL severe_JJ forms_NNS of_IN S_ZZ pyogenes_NNS infection_NN 68_CD implications_NNS for_IN Treatment_NP 69_CD until_CS recently_RB , the_ATI only_AP available_JJ treatments_NNS for_IN sepsis_NN were_BED directed_VBN at_IN the_ATI underlying_JJ infection_NN or_CC were_BED purely_RB supportive_JJ soon_RB , however_RB , a_AT variety_NN of_IN new_JJ treatments_NNS may_MD become_VB available_JJ to_TO make_VB best_JJT use_NN of_IN these_DTS new_JJ agents_NNS (_( as_QL well_RB as_CS current_JJ therapies_NNS )_) , we_PP1AS must_MD recognize_VB three_CD things_NNS : first_OD , in_IN the_ATI absence_NN of_IN culture_NN results_NNS , there_EX is_BEZ currently_RB no_ATI way_NN to_TO ascertain_VB rapidly_RB the_ATI cause_NN of_IN sepsis_NN second_OD , the_ATI predominant_JJ causes_NNS of_IN sepsis_NN probably_RB change_NN over_IN time_NN and_CC may_MD vary_VB from_IN institution_NN to_IN institution_NN third_OD , there_EX is_BEZ usually_RB no_ATI reason_NN to_TO assume_VB that_CS the_ATI cause_NN of_IN sepsis_NN is_BEZ a_AT gram-negative_JJ organism_NN 70_CD these_DTS three_CD points_NNS are_BER not_XNOT as_QL obvious_JJ as_CS they_PP3AS may_MD appear_VB in_IN the_ATI studies_NNS of_IN E5_NP and_CC HA-1A_CD-CD , almost_RB one_CD1 third_OD of_IN patients_NNS did_DOD not_XNOT have_HV gram-negative_JJ sepsis_NN , despite_IN the_ATI fact_NN that_CS these_DTS studies_NNS sought_VBD to_TO include_VB only_RB patients_NNS with_IN gram-negative_JJ infection_NN this_DT is_BEZ one_CD1 of_IN the_ATI major_JJ factors_NNS limiting_JJ the_ATI use_NN of_IN these_DTS agents_NNS although_CS both_ABX ES_NP and_CC HA-1A_CD-CD were_BED effective_JJ in_IN lowering_VBG mortality_NN in_IN specific_JJ subgroups_NNS of_IN patients_NNS , there_EX is_BEZ currently_RB no_ATI reliable_JJ way_NN to_TO identify_VB those_DTS subgroups_NNS in_IN advance_NN 71_CD what_WDT may_MD prove_VB more_QL effective_JJ are_BER agents_NNS directed_VBN against_IN the_ATI cascade_NN of_IN endogenous_JJ inflammatory_JJ mediators_NNS , since_IN this_DT cascade_NN is_BEZ common_JJ to_IN all_ABN forms_NNS of_IN sepsis_NN among_IN the_ATI most_AP promising_JJ are_BER receptor_NN antagonists_NNS to_TO interleukin_VB 1_CD1 and_CC monoclonal_JJ antibodies_NNS to_IN TNF_NP a_AT recombinant_NN receptor_NN antagonist_NN to_TO interleukin_VB 1_CD1 has_HVZ been_BEN found_VBN to_TO improve_VB survival_NN in_IN a_AT variety_NN of_IN animal_JJ models_NNS of_IN sepsis_NN astudy_RB of_IN this_DT agent_NN in_IN patients_NNS with_IN sepsis_NN has_HVZ begun_VBN 72_CD in_IN a_AT phase_NN 1_CD1 study_NN , Exley_NP et_&FW al_APS administered_VBN murine_NN IgG_NP monoclonal_JJ antibodies_NNS raised_VBN against_IN recombinant_JJ human_JJ TNF_NP to_IN 14_CD patients_NNS with_IN severe_JJ septic_JJ shock_NN (_( causes_NNS of_IN sepsis_NN were_BED not_XNOT reported_VBN )_) mean_VB arterial_JJ pressure_NN increased_VBN markedly_RB after_IN the_ATI infusion_NN , and_CC there_EX were_BED no_ATI adverse_JJ reactions_NNS a_AT controlled_JJ trial_NN of_IN anti-TNF_NN antibodies_NNS is_BEZ now_RN under_IN way_NN 73_CD other_AP agents_NNS that_DT may_MD dampen_VB the_ATI inflammatory_JJ cascade_NN include_VB pentoxifylline_NN , a_AT substance_NN that_CS inhibits_VBZ neutrophil_NN behavior_NN and_CC decreases_VBZ the_ATI tendency_NN of_IN the_ATI blood_NN to_TO clot__VB cyclo-oxygenase_NN or_CC thromboxane_NN synthetase_NN inhibitors__NN and_CC monoclonal_JJ antibodies_NNS to_TO adhesion_NN molecules_NNS in_IN animal_NN models_NNS , each_DT of_IN these_DTS agents_NNS has_HVZ been_BEN shown_VBN to_TO counteract_VB successfully_RB the_ATI effects_NNS produced_VBN by_IN various_JJ gram-positive_JJ organisms_NNS 74_CD what_WDT is_BEZ important_JJ about_IN each_DT of_IN these_DTS agents_NNS is_BEZ not_XNOT just_RB that_CS it_PP3 worked_VBN in_IN models_NNS of_IN gram- positive_JJ sepsis_NN , but_CC that_CS it_PP3 also_RB was_BEDZ effective_JJ in_IN models_NNS of_IN gram-negative_JJ sepsis_NN if_CS results_NNS in_IN animal_NN studies_NNS are_BER confirmed_VBN in_IN clinical_JJ trials_NNS , we_PP1AS will_MD have_HV found_VBN a_AT means_NNS to_TO combat_VB sepsis_JJ regardless_RB of_IN the_ATI underlying_JJ cause_NN 75_CD as_CS these_DTS new_JJ agents_NNS are_BER introduced_VBN , however_RB , we_PP1AS should_MD not_XNOT overlook_VB the_ATI importance_NN of_IN appropriate_JJ antibiotic_JJ therapy_NN and_CC drainage_NN of_IN purulent_NN material- the_NN first_OD lines_NNS of_IN treatment_NN for_IN sepsis_NN if_CS we_PP1AS continue_VB to_TO assume_VB that_CS sepsis_NN is_BEZ predominantly_RB a_AT gram-negative_JJ problem_NN , we_PP1AS risk_VB selecting_VBG the_ATI wrong_JJ empiric_JJ antibiotics_NNS the_ATI best_JJT approach_NN may_MD be_BE to_TO combine_VB information_NN from_IN the_ATI patient_NN history_NN , knowledge_NN of_IN the_ATI prevalence_NN patterns_NNS for_IN nosocomial_JJ infection_NN at_IN our_PP$ own_AP institutions_NNS , and_CC recognition_NN that_CS sepsis_NN may_MD result_VB from_IN any_DTI of_IN a_AT number_NN of_IN organisms_NNS 76_CD ultimately_RB , a_AT combination_NN of_IN agents_NNS will_MD probably_RB be_BE required_VBN to_TO combat_NN sepsis_NN effectively_RB we_PP1AS are_BER fortunate_JJ that_CS enough_QLP agents_NNS are_BER under_IN active_JJ investigation_NN that_CS several_AP should_MD withstand_VB the_ATI test_NN of_IN controlled_VBN clinical_JJ trials_NNS , even_CS if_CS the_ATI results_NNS of_IN recent_JJ trials_NNS have_HV been_BEN disappointing_JJ in_IN the_ATI not_XNOT too_QL distant_JJ future_NN , we_PP1AS may_MD finally_RB be_BE able_JJ to_TO improve_VB outcome_NN in_IN patients_NNS with_IN sepsis_JJ resulting_JJ from_IN gram-positive_JJ as_QL well_RB as_CS gram-negative_JJ bacteria_NNS 77_CD agranulocytosis_NN 78_CD a_AT 60-year-old_JJB man_NN with_IN moderately_RB severe_JJ congestive_JJ heart_NN failure_NN secondary_JJ to_TO cardiomyopathy_VB was_BEDZ treated_VBN with_IN an_AT experimental_JJ inotropic_JJ drug_NN , vesnarinone_NN (_( Otsuka_NP America_NP , Rockville_NP , Md_NP )_) , known_VBN to_TO be_BE associated_VBN with_IN agranulocytosis_NN blood_NN cell_NN counts_VBZ were_BED monitored_VBN weekly_JJ ten_CD weeks_NNS after_IN beginning_NN treatment_NN , the_ATI total_JJ white_JJ blood_NN cell_NN count_VB , previously_RB normal_JJ , was_BEDZ 2.6x10_CD sup_VB 9_L_NN with_IN an_AT absolute_JJ neutrophil_NN count_NN of_IN 1.282x10_CD sup_VB 9_L_NN the_ATI patient_NN was_BEDZ not_XNOT symptomatic_JJ the_ATI experimental_JJ drug_NN was_BEDZ discontinued_VBN two_CD days_NNS later_RBR the_ATI absolute_JJ neutrophil_NN count_NN was_BEDZ 0.396x10_CD sup_VB 9_L_NN the_ATI patient_NN was_BEDZ hospitalized_VBN for_IN observation_NN a_AT bone_NN marrow_NN aspirate_NN showed_VBD absence_NN of_IN mature_JJ granulocytes_NNS and_CC myeloid_NN precursor_NN cells_NNS the_ATI patient_NN was_BEDZ treated_VBN with_IN oral_JJ cephalexin_NN fever_NN occurred_VBD to_IN a_AT temperature_NN of_IN 38.6_CD degrees_NNS C_ZZ (_( 101.4_CD degrees_NNS F_ZZ )_) , leading_JJ to_IN withdrawal_NN of_IN an_AT intravenous_JJ catheter_NN Over_NP a_AT week_NN both_ABX total_JJ white_JJ blood_NN cell_NN and_CC neutrophil_NN numbers_NNS returned_VBD to_IN normal_JJ 79_CD a_AT 75-year-old_JJB woman_NN with_IN severe_JJ congestive_JJ heart_NN failure_NN due_JJ to_TO ischemic_JJ cardiomyopathy_NN received_VBN the_ATI same_AP cardiotonic_JJ drug_NN nine_CD weeks_NNS after_IN therapy_NN she_PP3A presented_VBD to_IN a_AT hospital_NN with_IN fever_NN to_IN 40_CD degrees_NNS C_ZZ (_( 104_CD degrees_NNS F_ZZ )_) the_ATI total_JJ white_JJ blood_NN cell_NN count_NN was_BEDZ 0.8x10_CD sup_VB 9_L_NN with_IN an_AT absolute_JJ neutrophil_JJ count_NN of_IN 0.016x10_CD sup_VB 9_L_NN the_ATI experimental_JJ drug_NN was_BEDZ withdrawn_VBN and_CC the_ATI patient_NN was_BEDZ admitted_VBN to_IN the_ATI hospital_NN for_IN broad- spectrum_JJ antibiotic_JJ treatment_NN a_AT bone_NN marrow_NN aspirate_NN showed_VBD absolute_JJ absence_NN of_IN all_ABN myeloid_NN cells.=20_CD 80_CD several_AP days_NNS later_RBR her_PP$ neutrophil_JJ count_NN was_BEDZ 0_CD , and_CC granulocyte_NN colony-stimulating_NN factor_NN (_( G-CSF_NP )_) at_IN 5_CD micrograms_kg_NN was_BEDZ added_VBN to_IN her_PP$ regimen_NNS fever_NN continued_VBD but_CC all_ABN bacterial_JJ cultures_NNS were_BED negative_JJ two_CD weeks_NNS after_IN entering_VBG the_ATI hospital_NN her_PP$ total_JJ white_JJ blood_NN cell_NN count_NN remained_VBD 1.0x10_CD sup_VB 9_L_NN and_CC neutrophils_NNS were_BED 0_CD she_PP3A developed_JJ confusion_NN ; ventricular_JJ arrhythmias_NNS were_BED noted_VBN , which_WDTR rapidly_RB degenerated_VBN into_IN ventricular_JJ fibrillation_NN resuscitation_NN was_BEDZ not_XNOT attempted_VBN due_JJ to_IN the_ATI patient_NN 's_BEZ previously_RB expressed_VBN wishes_VBZ an_AT autopsy_NN was_BEDZ not_XNOT performed_VBN 81_CD these_DTS case_NN histories_NNS span_VB the_ATI clinical_JJ spectrum_NN of_IN agranulocytosis_NN Agranulocytosis_NN in_IN both_ABX cases_NNS probably_RB resulted_VBD from_IN treatment_NN with_IN a_AT single_JJ drug_NN , and_CC both_ABX were_BED entered_VBN in_IN a_AT blood_NN count_NN monitoring_VBG program_NN The_NP first_OD patient_NN was_BEDZ asymptomatic_JJ and_CC agranulocytosis_JJ was_BEDZ detected_VBN only_RB as_IN a_AT result_NN of_IN monitoring_VBG ; the_ATI bone_NN marrow_NN recovered_VBN spontaneously_RB after_IN discontinuation_NN of_IN the_ATI incriminated_JJ agent_NN , and_CC the_ATI patient_NN did_DOD well_RB despite_IN treatment_NN with_IN oral_JJ antibiotics_NNS only_RB the_ATI second_OD patient's_NN$ course_RB was_BEDZ progressive_NN in_IN the_ATI face_NN of_IN appropriate_JJ treatment_NN with_IN broad-spectrum_JJ parenteral_JJ antibiotics_NNS and_CC a_AT hematopoietic_JJ growth_NN factor_NN 82_CD HISTORY_NP 83_CD 7_CD agranulocytosis_NN was_BEDZ named_VBN by_IN Schultz_NP in_IN 1923_CD in_IN a_AT paper_NN presented_VBN before_IN the_ATI Berlin_NP Medical_NP Society_NP ; the_ATI title_NN may_MD be_BE translated_VBN as_CS _** On_NP a_AT Peculiar_NPT Throat_NP Disease_NP _** he_PP3A associated_VBN the_ATI severe_JJ local_JJ symptoms_NNS of_IN infection_NN in_IN the_ATI pharynx_NN with_IN the_ATI absence_NN of_IN granulocytes_NNS in_IN the_ATI blood_NN in_IN the_ATI following_JJ decade_NN in_IN the_ATI United_NP States_NP , Kracke_NP and_CC Parker_NP argued_VBD that_CS agranulocytosis_NN was_BEDZ a_AT new_JJ disease_NN , the_ATI result_NN of_IN the_ATI introduction_NN of_IN a_AT popular_JJ class_NN of_IN potent_JJ analgesics_NNS and_CC antipyretics_NNS derived_VBN from_IN amidopyrine_NN they_PP3AS successfully_RB campaigned_VBD to_TO restrict_VB exposure_NN to_IN these_DTS drugs_NNS by_IN requiring_VBG prescriptions_NNS for_IN their_PP$ use_NN in_IN the_ATI early_JJ 1930s_CDS , Madison_NP and_CC Squier_NP reproduced_VBN agranulocytosis_NN in_IN susceptible_JJ patients_NNS by_IN readministering_VBG the_ATI drug_NN , and_CC in_IN 1951_CD Moeschlin_NP and_CC Wagner_NP transferred_VBD the_ATI disease_NN to_IN normal_JJ volunteers_NNS by_IN using_VBG serum_NN from_IN affected_JJ patients_NNS , thus_RB offering_VBG an_AT immunologic_JJ mechanism_NN for_IN amidopyrine-induced_JJ agranulocytosis_NN in_IN the_ATI 1970s_CD , Pisciotta's_NP$ clinical_JJ and_CC laboratory_NN observations_NNS of_IN leukopenia_NN in_IN psychiatric_JJ patients_NNS treated_VBN with_IN phenothiazines_NNS characterized_VBN direct_JJ toxicity_NN as_IN a_AT second_OD mechanism_NN of_IN agranulocytosis_NN several_AP recent_JJ articles_NNS and_CC monographs_NNS review_VB the_ATI disease_NN 84_NN CLINICAL_NPT PRESENTATION_NPT AND_NPT DIFFERENTIAL_NP DIAGNOSIS_NP 85_CD in_IN the_ATI classical_JJ patient_NN , the_ATI presentation_NN is_BEZ severe_JJ sore_JJ throat_NN Older_NP case_NN reports_NNS describe_VB striking_JJ local_JJ evidence_NN of_IN edema_NN , necrosis_NN , and_CC obstruction_NN in_IN the_ATI pharynx_NN , followed_VBD within_IN days_NNS by_IN prostration_NN , coma_NN , and_CC death_NN when_WRB antibiotics_NNS are_BER used_VBN early_JJ , both_ABX the_ATI patient's_NN$ complaints_NNS and_CC the_ATI physical_JJ findings_NNS may_MD be_BE less_QL dramatic-fever_JJ may_MD be_BE the_ATI only_AP symptom_NN agranulocytosis_NN may_MD be_BE entirely_RB asymptomatic_JJ despite_IN absolute_JJ neutropenia_NN , especially_RB in_IN patients_NNS whose_WP$R blood_NN cell_NN counts_VBZ are_BER regularly_RB monitored_VBN during_IN drug_NN therapy_NN 86_CD the_ATI peripheral_JJ blood_NN findings_NNS are_BER of_IN absent_JJ neutrophil_NN and_CC band_NN forms_NNS the_ATI hemoglobin_NN and_CC platelet_NN counts_VBZ are_BER normal_JJ the_ATI bone_NN marrow_NN typically_RB shows_VBZ normal_JJ or_CC mildly_RB reduced_VBN total_JJ cellularity_NN but_CC a_AT striking_JJ absence_NN of_IN myeloid_NN precursor_NN cells_NNS a_AT more_AP restricted_JJ picture_NN of_IN decreased_VBD late_JJ granulocytic_JJ cells_NNS with_IN preserved_VBN immature_JJ forms_NNS to_TO the_ATI myelocyte_NN stage_NN is_BEZ described_VBN as_IN _** myeloid_NN arrest_NN , _** which_WDTR may_MD represent_VB either_DTX a_AT selective_JJ effect_NN on_IN later_RBR cells_NNS or_CC the_ATI recovery_NN phase_NN similarly_RB , myeloid_NN progenitor_NN cells_NNS (_( colony-forming_NN unit- granulocyte-macrophage_NN (_( CFU-GM_NP )_) or_CC colony-forming_NN unit- granulocyte_NN )_) , while_CS usually_RB greatly_RB depressed_VBN in_IN number_NN , may_MD also_RB be_BE normal_JJ for_IN patients_NNS receiving_VBG drugs_NNS like_IN procainamide_NN , an_AT antinuclear_NN antibody_NN test_NN result_NN may_MD also_RB be_BE positive_JJ 87_CD in_IN the_ATI appropriate_JJ setting_VBG the_ATI diagnosis_NN is_BEZ not_XNOT difficult_JJ isolated_JJ absolute_JJ neutropenia_NN has_HVZ a_AT limited_JJ number_NN of_IN causes_NNS (_( Table_NP 1_CD1 )_) , and_CC performance_NN of_IN a_AT bone_NN marrow_NN examination_NN will_MD further_JJB limit_VB diagnostic_JJ possibilities_NNS (_( Table_NP 2_CD )_) the_ATI most_AP important_JJ distinctions_NNS are_BER among_IN (_( 1_CD1 )_) immune_JJ neutropenia_NN that_WPR is_BEZ secondary_JJ to_IN peripheral_JJ destruction_NN of_IN polymorphonuclear_NN cells_NNS , also_RB often_RB drug_NN associated_VBN ; (_( 2_CD )_) neutropenia_NN that_DT is_BEZ secondary_JJ to_IN overwhelming_JJ sepsis_NN ; and_CC (_( 3_CD )_) neutropenia_NN appearing_VBG as_IN a_AT harbinger_NN of_IN more_QL generalized_JJ bone_NN marrow_JJ failure_NN of_IN hematologic_JJ cause_NN (_( for_IN example_NN , myelodysplasia_NN )_) 88_CD EPIDEMIOLOGY_NP 89_CD 13_CD the_ATI strong_JJ association_NN between_IN drug_NN use_NN and_CC agranulocytosis_NN has_HVZ been_BEN formally_RB confirmed_VBN in_IN an_AT extensive_JJ and_CC rigorous_JJ prospective_JJ survey_NN performed_VBN by_IN the_ATI International_NPT Aplastic_NP Anemia_NP and_CC Agranulocytosis_NN Study_NP (_( IAAAS_NP )_) in_IN Europe_NP and_CC Israel_NP from_IN 1980_CD to_IN 1986_CD both_ABX rate_NN and_CC specific_JJ risk_NN factors_NNS were_BED determined_VBN in_IN this_DT hospital-based_JJ study_NN by_IN identifying_VBG and_CC interviewing_NN all_ABN cases_NNS in_IN eight_CD metropolitan_JJ areas_NNS as_QL well_RB as_CS matched_JJ controls_NNS the_ATI overall_JJB incidence_NN of_IN agranulocytosis_NN was_BEDZ 3.4_CD per_NNU 1_CD1 million_CD population_NN the_ATI incidence_NN of_IN agranulocytosis_NN rose_VBD precipitously_RB with_IN age_NN ; only_RB 10%_CD of_IN cases_NNS occurred_VBD in_IN children_NNS and_CC young_JJ adults_NNS , and_CC more_AP than_IN half_ABN developed_VBN in_IN older_JJR persons_NNS agranulocytosis_NN was_BEDZ about_IN twice_RB as_CS frequent_JJ among_IN women_NNS as_IN men_NNS these_DTS associations_NNS may_MD only_RB reflect_VB more_QL frequent_JJ medication_NN use_NN among_IN women_NNS and_CC the_ATI elderly_JJ Confirmatory_NP results_NNS were_BED obtained_VBN for_IN US_NP populations_NNS from_IN examination_NN of_IN computerized_VBN Medicaid_NP billing_NN data_NNS in_IN the_ATI IAAAS_NP , most_QL cases_NNS of_IN agranulocytosis_NN were_BED linked_VBN to_TO suspect_VB drug_NN use_NN it_PP3 is_BEZ worth_IN noting_VBG that_CS the_ATI epidemiology_NN of_IN agranulocytosis_NN differs_VBZ from_IN that_DT of_IN aplastic_JJ anemia_NN : the_ATI rates_NNS of_IN the_ATI two_CD diseases_NNS are_BER inversely_RB correlated_VBN in_IN geographic_JJ regions_NNS , aplastic_JJ anemia_NN occurs_VBZ in_IN a_AT much_RB younger_JJR population_NN , and_CC only_RB a_AT minority_NN of_IN cases_NNS of_IN aplastic_JJ anemia_NN are_BER drug_NN related_VBN 90_CD 14_CD PATHOPHYSIOLOGY_NP 91_CD 15_CD clinical_JJ observations_NNS , studies_VBZ in_IN volunteers_NNS and_CC patients_NNS , and_CC laboratory_NN experiments_NNS have_HV suggested_VBN that_CS agranulocytosis_NN has_HVZ at_RB least_RB two_CD underlying_JJ mechanisms_NNS (_( Table_NP 3_CD )_) leukoagglutinins_NNS were_BED measured_VBN in_IN patients_NNS many_AP decades_NNS ago_RB , but_CC today_NR this_DT crude_JJ test_NN has_HVZ been_BEN replaced_VBN by_IN more_QL quantitative_JJ assays_NNS of_IN antibody_NN binding_JJ , often_RB to_TO surrogate_VB myeloid_NN cell_NN lines_NNS rather_RB than_IN bone_NN marrow_NN cells_NNS (_( Fig_NP 1_CD1 )_) Antineutrophil_NP antibodies_NNS have_HV been_BEN detected_VBN in_IN drug- associated_JJ agranulocytosis_NN for_IN example_NN , in_IN one_CD1 study_NN , IgG_NP or_CC IgM_NP antibodies_NNS were_BED detected_VBN in_IN 13_CD of_IN 13_CD cases_NNS of_IN drug-associated_JJ agranulocytosis_NN (_( with_IN hypoplastic_JJ bone_NN marrows_NNS )_) using_VBG enzyme-linked_JJ binding_JJ assays_NNS for_IN antibodies_NNS to_IN autologous_JJ or_CC normal_JJ granulocytes_NNS (_( antineutrophil_NN antibodies_NNS are_BER also_RB present_JJ in_IN other_AP types_NNS of_IN neutropenia_NN , including_IN pure_JJ white_JJ blood_NN cell_NN aplasia_NN , immune_JJ neutropenia_NN , Felty's_NP$ syndrome_NN , and_CC systemic_JJ lupus_JJ erythematosus_JJ )_) in_IN agranulocytosis_NN , antibody_NN binding_JJ to_TO target_NN cells_NNS usually_RB requires_VBZ the_ATI presence_NN of_IN a_AT drug_NN and_CC often_RB consumes_VBZ complement_NN sometimes_RB serum_NN reactivity_NN has_HVZ been_BEN enhanced_VBN by_IN addition_NN of_IN a_AT purified_VBN metabolite_NN or_CC metabolites_NNS in_IN the_ATI urine_NN of_IN treated_VBN patients_NNS to_TO the_ATI target_NN neutrophils_NNS failure_NN to_TO demonstrate_VB an_AT antibody_NN has_HVZ been_BEN blamed_VBN on_IN antibody_NN specificity_NN for_IN a_AT drug's_NN$ intermediate_JJ metabolite_NN (_( Fig_NP 2_CD )_) or_CC on_IN a_AT low_JJ antibody_NN titer_NN in_IN a_AP few_AP well-studied_JJ cases_NNS , antibody_NN binding_JJ to_IN a_AT myeloid_NN progenitor_NN cell_NN has_HVZ been_BEN inferred_VBN from_IN inhibition_NN by_IN a_AT patient's_NN$ serum_NN of_IN CFU-GM_NP derived_JJ colony_NN formation_NN in_IN clonogenic_JJ assays_NNS the_ATI relative_JJ specificity_NN of_IN a_AT putative_JJ serum_NN antibody_NN for_IN immature_JJ progenitors_NNS compared_VBN with_IN granulocytes_NNS was_BEDZ nicely_RB demonstrated_VBN for_IN a_AT case_NN of_IN chlorpropamide_NN agranulocytosis_NN , in_IN which_WDTR the_ATI patient's_NN$ serum_NN inhibited_VBN CFU-GM-derived_NP colony_NN formation_NN in_IN a_AT drug_NN dose-dependent_NN manner_NN , but_CC it_PP3 did_DOD not_XNOT inhibit_VB CFU-E- derived_NP or_CC mixed_JJ colonies_NNS , and_CC the_ATI serum_NN did_DOD not_XNOT bind_VB to_IN either_DTX neutrophils_NNS or_CC recognizable_JJ granulocytic_JJ precursor_NN cells_NNS 92_CD 16_CD drugs_NNS can_MD also_RB directly_RB damage_NN myeloid_NN precursors_NNS the_ATI complex_JJ enzymatic_JJ pathways_NNS present_NN in_IN myelopoietic_JJ cells_NNS for_IN digestion_NN of_IN microbial_JJ constituents_NNS can_MD also_RB be_BE applied_VBN to_IN drugs_NNS and_CC chemicals_NNS Detoxification_NN of_IN many_AP nonpolar_NN compounds_NNS , such_IN as_IN the_ATI benzene-based_JJ group_NN of_IN arene_NN oxides_NNS , requires_VBZ conversion_NN to_IN a_AT chemically_RB reactive_JJ intermediate_JJ prior_RB to_TO covalent_VB linkage_NN to_IN polar_JJ groups_NNS these_DTS short-lived_JJ , nucleophilic_JJ intermediate_JJ molecules_NNS are_BER also_RB available_JJ to_TO covalently_RB bind_VB to_IN nuclear_JJ material_NN or_CC cytoplasmic_JJ proteins_NNS , thereby_RB resulting_JJ in_IN either_DTX direct_JJ damage_NN to_IN the_ATI cell_NN or_CC induction_NN of_IN an_AT immunologic_JJ response_NN (_( Fig_NP 2_CD )_) the_ATI complex_JJ metabolic_JJ pathways_NNS that_CS detoxify_NN drugs_NNS and_CC chemicals_NNS are_BER genetically_RB regulated_VBN ; idiosyncratic_JJ susceptibility_NN can_MD thus_RB be_BE explained_VBN by_IN the_ATI presence_NN or_CC absence_NN of_IN genes_NNS for_IN enzymes_NNS that_WPR generate_VB or_CC destroy_VB toxic_JJ intermediate_JJ compounds_NNS Well-studied_NP examples_NNS include_VB arylhydroxylases_NNS for_IN hydrophobic_JJ cyclical_JJ aromatic_JJ hydrocarbons_NNS , epoxide_NN hydroxylases_NNS that_WPR convert_VB epoxides_NNS to_IN phenols_NNS , S- methylation_NN in_IN purine_NN metabolism_NN , and_CC N-acetylation_NN of_IN procainamide_NN 93_CD 17_CD SPECIFIC_NP DRUGS_NP 94_CD 18_CD case_NN reports_NNS show_VB that_CS a_AT large_JJ number_NN of_IN drugs_NNS have_HV been_BEN associated_VBN with_IN agranulocytosis_NN table_NN 4_CD represents_VBZ a_AT review_NN of_IN the_ATI medical_JJ literature_NN for_IN relatively_RB well-documented_JJ instances_NNS where_WRB blood_NN cell_NN counts_VBZ and_CC bone_NN marrow_JJ morphological_JJ features_NNS are_BER described_VBN and_CC the_ATI temporal_JJ relationship_NN to_TO drug_NN use_NN is_BEZ reasonable_JJ in_IN some_DTI series_NN of_IN patients_NNS from_IN specialty_NN clinics_NNS , agranulocytosis_NN rates_NNS for_IN some_DTI drugs_NNS have_HV been_BEN high_JJ : antibiotics_NNS (_( 6%_NN for_IN penicillin_NN in_IN one_CD1 orthopedic_JJ population_NN )_) , psychotropics_NNS (_( about_RB 1%_CD to_IN 3%_CD for_IN clozapine_NN )_) , and_CC procainamide_NN (_( about_IN 4%_NN in_IN patients_NNS recovering_VBG from_IN surgery_NN )_) 95_CD 19_CD for_IN a_JJ few_AP drugs_NNS , specific_JJ risk_NN factors_NNS have_HV been_BEN identified_VBN for_IN levamisole_NN , histocompatibility_NN antigens_NNS prevalent_JJ among_IN Jewish_JNP patients_NNS have_HV conferred_VBN greater_JJR risk_NN , a_AT finding_VBG that_CS suggests_VBZ genetically_RB based_VBN susceptibility_NN for_IN captopril_NN , patients_NNS with_IN renal_JJ failure_NN or_CC those_DTS concurrently_RB receiving_VBG probenecid_NN have_HV a_AT higher_JJR rate_NN of_IN agranulocytosis_NN , and_CC drug-associated_JJ agranulocytosis_NN may_MD occur_VB predominantly_RB in_IN patients_NNS with_IN underlying_JJ autoimmune_NN diseases_NNS , such_IN as_IN rheumatoid_NN arthritis_NN 96_CD 20_CD in_IN general_JJ , however_RB , apparently_RB high_JJ rates_NNS of_IN agranulocytosis_NN that_CS are_BER based_VBN on_IN biased_VBN collections_NNS of_IN patient_NN data_NNS have_HV not_XNOT been_BEN validated_VBN in_IN formal_JJ epidemiologic_JJ studies_NNS the_ATI IAAAS_NP compared_VBD drug_NN use_NN in_IN the_ATI week_NN before_CS hospitalization_NN for_IN cases_NNS and_CC controls_NNS relative_JJ risks_NNS were_BED especially_RB elevated_VBD for_IN certain_JJ groups_NNS of_IN medications_NNS , including_IN antithyroid_NN drugs_NNS , nonsteroidal_JJ anti-inflammatory_NN drugs_NNS , some_DTI cardiotonics_NNS , and_CC anticonvulsants_NNS (_( Table_NP 5_CD )_) however_RB , while_CS the_ATI relative_JJ risk_NN of_IN agranulocytosis_NN was_BEDZ elevated_VBD for_IN many_AP drugs_NNS , this_DT risk_NN translated_VBN into_IN far_RB smaller_JJR numbers_NNS than_IN those_DTS derived_VBN from_IN a_AT selection_NN of_IN cases_NNS in_IN clinics_NNS or_CC estimates_NNS based_VBN on_IN the_ATI quantity_NN of_IN case_NN reports_NNS in_IN the_ATI literature_NN in_IN addition_NN , the_ATI absolute_JJ increase_NN in_IN the_ATI number_NN of_IN cases_NNS in_IN the_ATI population_NN was_BEDZ small_JJ relative_JJ to_IN the_ATI extensive_JJ use_NN of_IN many_AP of_IN the_ATI agents_NNS 97_CD 21_CD PREVENTION_NPT AND_NP TREATMENT_NP 98_NN 22_CD due_JJ to_IN the_ATI lack_NN of_IN suitable_JJ assays_NNS , testing_NN to_TO detect_VB the_ATI rare_JJ individual_JJ who_WPR might_MD manifest_JJ drug_NN sensitivity_NN is_BEZ not_XNOT feasible_JJ early_JJ detection_NN of_IN a_AT change_NN in_IN neutrophil_NN counts_VBZ in_IN a_AT patient_NN receiving_VBG treatment_NN has_HVZ been_BEN used_VBN for_IN several_AP drugs_NNS , including_IN antithyroid_NN drugs_NNS , phenothiazines_NNS , carbamazepine_NN , and_CC most_QL recently_RB clozapine_JJ the_ATI benefit_NN of_IN monitoring_VBG is_BEZ uncertain_JJ , and_CC it_PP3 is_BEZ often_RB abandoned_VBN or_CC modified_VBN as_IN the_ATI low_JJ probability_NN of_IN agranulocytosis_NN is_BEZ appreciated_VBN early_JJ detection_NN is_BEZ desirable_JJ to_TO avoid_VB continued_VBD drug_NN exposure_NN and_CC to_IN alert_JJ the_ATI patient_NN and_CC the_ATI treating_NN physician_NN to_IN dangerous_JJ levels_NNS of_IN neutropenia_NN for_IN this_DT reason_NN , rapid_JJ and_CC accurate_JJ white_JJ blood_NN cell_NN levels_NNS and_CC differential_JJ counts_VBZ are_BER required_VBN there_EX is_BEZ sufficient_JJ laboratory_NN and_CC biological_JJ variability_NN in_IN these_DTS numbers_NNS so_CS that_CS the_ATI criteria_NNS for_IN discontinuing_VBG the_ATI drug_NN are_BER difficult_JJ to_TO set_VBN , and_CC patients_NNS may_MD be_BE required_VBN to_TO stop_VB and_CC start_VB the_ATI drug_NN repeatedly_RB the_ATI expense_NN of_IN such_ABL precautions_NNS is_BEZ enormous_JJ ; for_IN example_NN , it_PP3 is_BEZ estimated_VBN to_TO be_BE a_AT major_JJ proportion_NN of_IN the_ATI $10_CD 000_CD yearly_JJ cost_NN of_IN clozapine_NN , with_IN a_AT projected_JJ national_JJ cost-even_NN if_CS the_ATI drug_NN were_BED used_VBN only_RB for_IN refractory_JJ schizophrenia-in_JJ excess_NN of_IN $1_CD billion_CD the_ATI predictive_JJ value_NN of_IN a_AT positive_JJ antineutrophil_NN antibody_NN test_NN result_NN for_IN the_ATI development_NN of_IN agranulocytosis_NN is_BEZ not_XNOT known_VBN 99_CD 23_CD once_RB drug_NN exposure_NN stops_VBZ , recovery_NN should_MD follow_VB old_JJ age_NN , septicemia_NN , shock_NN , and_CC metabolic_JJ complications_NNS of_IN infection_NN like_IN renal_JJ failure_NN are_BER poor_JJ prognostic_JJ variables_NNS the_ATI severity_NN of_IN neutropenia_NN and_CC especially_RB its_PP$ duration_NN must_MD also_RB relate_VB negatively_RB to_IN outcome_NN in_IN patients_NNS with_IN agranulocytosis_NN who_WPR survive_VB , the_ATI time_NN to_IN recovery_NN of_IN granulocytes_NNS in_IN the_ATI blood_NN is_BEZ highly_RB variable_JJ (_( 3_CD to_IN 56_CD days_NNS in_IN one_CD1 series_NN , with_IN a_AT mean_NN of_IN about_RB 12_CD days_NNS )_) however_RB , the_ATI natural_JJ history_NN of_IN agranulocytosis_NN is_BEZ progression_NN of_IN the_ATI severe_JJ localized_JJ infection_NN to_TO sepsis_NN and_CC death_NN within_IN a_JJ few_AP days_NNS ; few_AP of_IN the_ATI patients_NNS in_IN the_ATI 1920s_CDS and_CC 1930s_CDS survived_VBN the_ATI disease_NN the_ATI introduction_NN of_IN sulfa_NN antibacterials_NNS and_CC penicillin_NN in_IN the_ATI 1940s_CDS much_AP improved_JJ the_ATI prognosis_NN the_ATI rapid_JJ utilization_NN of_IN broad-spectrum_JJ parenteral_JJ antibiotics_NNS for_IN fever_NN or_CC the_ATI first_OD sign_NN of_IN infection_NN is_BEZ the_ATI mainstay_NN of_IN treatment_NN of_IN agranulocytosis_NN due_JJ to_IN drugs_NNS as_CS it_PP3 is_BEZ for_IN fever_NN in_IN the_ATI setting_NN of_IN severe_JJ neutropenia_NN of_IN any_DTI cause_NN mortality_NN remains_VBZ at_IN about_RB 10%_CD , resulting_JJ at_RB least_RB in_IN part_NN from_IN the_ATI older_JJR age_NN of_IN the_ATI patients_NNS and_CC the_ATI presence_NN of_IN serious_JJ underlying_JJ diseases_NNS because_CS of_IN the_ATI high_JJ risk_NN of_IN death_NN during_IN agranulocytosis_NN , an_AT incriminated_JJ drug_NN should_MD not_XNOT be_BE readministered_VBN to_IN a_AT patient_NN , unless_CS there_EX is_BEZ doubt_NN about_IN its_PP$ culpability_NN among_IN other_AP suspected_VBD agents_NNS and_CC its_PP$ reintroduction_NN is_BEZ potentially_RB lifesaving_JJ 100_CD 24_CD hematopoietic_JJ growth_NN factors_NNS , such_ABL as_CS G-CSF_NP and_CC granulocyte-macrophage_NN colony-stimulating_NN factor_NN (_( GM-CSF_NP )_) , act_NN directly_RB on_IN progenitor_NN cells_NNS in_IN the_ATI bone_NN marrow_NN , and_CC their_PP$ administration_NN increases_NNS neutrophil_NN counts_VBZ in_IN normal_JJ individuals_NNS and_CC in_IN patients_NNS made_VBN neutropenic_JJ after_IN chemotherapy_NN or_CC bone_NN marrow_NN transplantation_NN rapid_JJ improvement_NN in_IN granulocyte_NN numbers_NNS has_HVZ been_BEN reported_VBN anecdotally_RB in_IN patients_NNS treated_VBN with_IN GM-CSF_NP and_CC G-CSF_NP , but_CC case_NN reports_NNS are_BER of_IN limited_JJ value_NN because_CS of_IN the_ATI enormous_JJ range_NN in_IN the_ATI time_NN to_TO granulocyte_VB recovery_NN after_IN an_AT offending_JJ agent_NN is_BEZ discontinued_VBN in_IN my_PP$ experience_NN with_IN a_AT single_JJ experimental_JJ drug_NN , for_IN which_WDTR the_ATI protocol_NN required_VBN careful_JJ weekly_JJ monitoring_VBG of_IN blood_NN cell_NN counts_VBZ , recovery_NN from_IN absolute_JJ neutropenia_NN occurred_VBD as_QL soon_RB as_IN 2_CD days_NNS to_TO as_QL long_JJ as_IN 3_CD weeks_NNS after_IN the_ATI drug_NN was_BEDZ stopped_VBN in_IN comparing_VBG about_IN a_AT dozen_CD patients_NNS who_WPR recovered_VBD spontaneously_RB with_IN a_AT similar_JJ number_NN who_WPR received_VBD G-CSF_NP (_( 130_CD mg_d_NN to_IN 750_CD mg_d_NN )_) , the_ATI mean_JJ duration_NN of_IN neutropenia_NN was_BEDZ shortened-but_NN not_XNOT significantly-by_VB about_RB 3_CD days_NNS (_( from_IN 9.5_CD days_NNS to_IN 6.5_CD days_NNS )_) observations_NNS in_IN other_AP patients_NNS have_HV suggested_VBN that_CS G- CSF_NP may_MD not_XNOT necessarily_RB shorten_VB recovery_NN time_NN a_AT rigorous_JJ therapeutic_JJ trial_NN in_IN which_WDTR the_ATI important_JJ variables_NNS of_IN drug_NN , monitoring_VBG , and_CC supportive_JJ care_NN are_BER all_ABN well_RB controlled_VBN is_BEZ desirable_JJ but_CC not_XNOT very_QL feasible_JJ granulocyte_NN colony-stimulating_NN factor_NN is_BEZ expensive_JJ but_CC minimally_RB toxic_JJ , and_CC most_QL patients_NNS with_IN agranulocytosis_NN likely_JJ will_MD receive_VB it_PP3 in_IN the_ATI future_NN (_( Table_NP 6_CD )_) 101_CD new_JJ Vaccine_NP Technologies_NNS 102_CD prevention_NN of_IN disease_NN is_BEZ a_AT tenet_NN of_IN all_ABN the_ATI various_JJ approaches_NNS to_TO health_NN care_NN reform_NN one_CD1 of_IN the_ATI most_QL effective_JJ medical_JJ interventions_NNS ever_RB devised_VBN are_BER vaccines_NNS , with_IN their_PP$ high_JJ level_NN of_IN benefit_NN and_CC cost-effectiveness_NN for_IN public_JJ health_NN there_EX has_HVZ never_RB been_BEN a_AT more_QL exciting_JJ time_NN for_IN vaccine_NN research_NN and_CC development_NN , largely_RB as_IN a_AT result_NN of_IN the_ATI implementation_NN and_CC refinement_NN of_IN a_AT variety_NN of_IN new_JJ technologies_NNS Several_NP new_JJ vaccines_NNS have_HV been_BEN licensed_JJ recently_RB in_IN different_JJ countries_NNS for_IN routine_NN use_NN , including_IN recombinant_NN hepatitis_NN B_ZZ (_( HB_NP )_) , Haemophilus_JJ influenzae_NN type_NN b_ZZ (_( Hib_NP )_) conjugate_NN , and_CC hepatitis_NN A_ZZ (_( HA_NP )_) vaccines_NNS Several_NP more_AP are_BER expected_VBN to_TO be_BE licensed_JJ throughout_IN the_ATI 1990s_CD , including_IN acellular_RB pertussis_JJ (_( for_IN infants_NNS )_) , varicella_NN , and_CC pneumococcal_JJ conjugate_NN vaccines_NNS of_IN potentially_RB greater_JJR importance_NN are_BER several_AP technological_JJ developments_NNS that_CS , if_CS successful_JJ , would_MD revolutionize_VB the_ATI way_NN in_IN which_WDTR vaccines_NNS are_BER produced_VBN and_CC used_VBN this_DT article_NN reviews_NNS three_CD such_ABL developments_NNS , each_DT of_IN which_WDTR is_BEZ being_BEG researched_VBN and_CC developed_VBN in_IN numerous_JJ academic_JJ and_CC industrial_JJ laboratories_NNS : combination_NN vaccines_NNS , new_JJ formulation_NN strategies_NNS (_( controlled_JJ delivery_NN and_CC adjuvants_NNS )_) , and_CC new_JJ vector_NN systems_NNS (_( live_VB vectors_NNS and_CC polynucleotide_NN vaccines_NNS )_) 103_CD COMBINATION_NP VACCINES_NP 104_CD a_AT combination_NN vaccine_NN contains_VBZ two_CD or_CC more_QL vaccines_NNS delivered_VBN in_IN a_AT single_JJ inoculation_NN because_CS infants_NNS and_CC young_JJ children_NNS sometimes_RB receive_VB three_CD or_CC four_CD separate_JJ injections_NNS at_IN a_AT single_JJ visit_NN , the_ATI availability_NN of_IN combination_NN vaccines_NNS can_MD avoid_VB such_ABL multiple_JJ injections_NNS by_IN providing_VBG as_CS many_AP different_JJ vaccines_NNS as_CS possible_JJ in_IN a_AT single_JJ inoculation_NN the_ATI following_JJ four_CD such_ABL vaccines_NNS have_HV been_BEN available_JJ for_IN at_RB least_RB 10_CD years_NNS for_IN routine_NN immunization_NN : (_( 1_CD1 )_) diphtheria_NN and_CC tetanus_JJ toxoids_NNS and_CC pertussis_NN vaccine_NN (_( DTP_NP )_) , which_WDTR is_BEZ an_AT inactivated_VBN bacterial_JJ vaccine_NN for_IN infants_NNS and_CC children_NNS ; (_( 2_CD )_) measles_NNS , mumps_NNS , and_CC rubella_NN (_( MMR_NP )_) virus_NN vaccine_NN (_( M-M- R_NP sub_NN II_NP )_) , which_WDTR is_BEZ a_AT live_VB attenuated_JJ viral_JJ vaccine_NN for_IN young_JJ children_NNS ; (_( 3_CD )_) oral_JJ polio_NN vaccine_NN (_( OPV_NP )_) , a_AT mixture_NN of_IN three_CD strains_NNS of_IN live_VB attenuated_JJ poliovirus_JJ for_IN infants_NNS and_CC children_NNS ; and_CC (_( 4_CD )_) pneumococcal_JJ vaccines_NNS (_( Pneumovax_NP 23_CD (_( Merck_NP )_) and_CC Pnu-Imune_NP 23_CD (_( Lederle_NP Laboratories_NNS , Pearl_NP River_NPL , NY_NP )_) )_) , which_WDTR are_BER mixtures_NNS of_IN 23_CD polysaccharides_NNS from_IN different_JJ pneumococcal_JJ strains_NNS for_IN older_JJR individuals_NNS these_DTS combination_NN vaccines_NNS have_HV established_VBN the_ATI principle_NN that_CS an_AT individual_JJ vaccine_NN effective_JJ at_IN preventing_VBG disease_NN can_MD be_BE similarly_RB effective_JJ when_WRB combined_VBN and_CC inoculated_JJ with_IN other_AP vaccines.=20_CD 105_CD the_ATI following_JJ are_BER three_CD ways_NNS in_IN which_WDTR vaccines_NNS can_MD be_BE combined_VBN : (_( 1_CD1 )_) by_IN mixing_NN in_IN a_AT vial_JJ at_IN the_ATI manufacturing_NN stage_NN ; (_( 2_CD )_) by_IN filling_VBG different_JJ vaccines_NNS in_IN separate_JJ chambers_NNS of_IN a_AT dual-chambered_JJ syringe_NN ; and_CC (_( 3_CD )_) by_IN mixing_NN vaccines_NNS from_IN separate_JJ vials_NNS in_IN the_ATI practitioner's_NP$ office_NN at_IN the_ATI time_NN of_IN administration_NN in_IN terms_NNS of_IN ease_NN of_IN use_NN , the_ATI manufacturer_NN seeks_VBZ to_TO develop_VB a_AT combination_NN vaccine_NN preferably_RB by_IN the_ATI first_OD option_NN or_CC alternatively_RB the_ATI second_OD ; the_ATI four_CD above-mentioned_JJ vaccines_NNS use_VB the_ATI first_OD option_NN 106_CD the_ATI first_OD issue_NN that_WPR must_MD be_BE considered_VBN in_IN creating_VBG new_JJ combination_NN vaccine_NN products_NNS is_BEZ that_CS each_DT component_NN vaccine_NN must_MD be_BE recommended_VBN for_IN administration_NN at_IN the_ATI same_AP age_NN this_DT can_MD be_BE established_VBN only_RB through_IN controlled_VBN clinical_JJ trials_NNS the_ATI DTP_NP vaccine_NN has_HVZ been_BEN the_ATI most_QL commonly_RB used_VBN inactivated_JJ vaccine_NN , being_BEG administered_VBN in_IN early_JJ childhood_NN at_IN 2_CD , 4_CD , 6_CD , and_CC 15_CD through_IN 18_CD months_NNS of_IN age_NN as_IN a_AT consequence_NN , it_PP3 is_BEZ desirable_JJ that_CS other_AP inactivated_VBN pediatric_JJ vaccines_NNS be_BE recommended_VBN at_IN these_DTS ages_NNS for_IN ultimate_JJ combination_NN with_IN DTP_NP similarly_RB , because_CS MMR_NP vaccine_NN is_BEZ administered_VBN at_IN 15_CD months_NNS , other_AP live_VB pediatric_JJ vaccines_NNS should_MD be_BE recommended_VBN , if_CS possible_JJ , for_IN administration_NN at_IN 15_CD months_NNS as_IN a_AT step_NN toward_IN ultimate_JJ combination_NN with_IN MMR_NP vaccine_NN 107_CD a_AT second_OD issue_NN is_BEZ that_CS the_ATI final_JJ product_NN must_MD be_BE pharmaceutically_RB stable_JJ and_CC acceptable_JJ in_IN terms_NNS of_IN physical_JJ interactions_NNS among_IN individual_JJ vaccines_NNS and_CC other_AP components_NNS in_IN the_ATI vial_JJ it_PP3 takes_VBZ considerable_JJ preclinical_JJ research_NN and_CC development_NN to_TO achieve_VB a_AT stable_JJ and_CC acceptable_JJ vaccine_NN formulation_NN , often_RB involving_VBG many_AP trial-and-error_NN attempts_NNS Furthermore_NP , the_ATI procedures_NNS that_WPR enable_VB a_AT particular_JJ combination_NN vaccine_NN to_TO be_BE formulated_VBN are_BER not_XNOT necessarily_RB applicable_JJ to_IN another_DT combination_NN vaccine_NN the_ATI final_JJ combination_NN vaccine_NN product_NN should_MD be_BE uniform_JJ and_CC stable_JJ for_IN as_QL long_JJ as_CS possible_JJ , preferably_RB 2_CD or_CC more_QL years_NNS at_IN the_ATI indicated_VBN storage_NN temperature_NN in_IN the_ATI field_NN (_( currently_RB refrigerated_VBN or_CC frozen_JJ )_) as_IN a_AT result_NN , the_ATI manufacture_NN and_CC quality_NN control_NN of_IN combination_NN vaccines_NNS can_MD be_BE very_QL complex_JJ 108_CD the_ATI third_OD key_NN issue_NN for_IN combination_NN vaccines_NNS is_BEZ clinical_JJ evaluation_NN , which_WDTR includes_VBZ the_ATI determination_NN of_IN local_JJ and_CC systemic_JJ tolerability_NN and_CC immunogenicity_NN in_IN well- controlled_JJ studies_NNS comparing_VBG the_ATI combination_NN with_IN its_PP$ licensed_JJ component_NN vaccines_NNS in_IN particular_JJ , the_ATI immunogenicity_NN of_IN each_DT vaccine_NN in_IN combination_NN should_MD be_BE as_CS good_JJ clinically_RB as_CS those_DTS of_IN the_ATI vaccines_NNS administered_VBN individually_RB , based_VBD on_IN well- defined_JJ serological_JJ assays_NNS for_IN antibodies_NNS specific_JJ to_IN each_DT vaccine_NN component_NN there_EX have_HV been_BEN reports_NNS of_IN inhibition_NN or_CC immunologic_JJ interference_NN among_IN components_NNS in_IN a_AT combination_NN , which_WDTR can_MD be_BE detected_VBN only_RB through_IN well-controlled_JJ clinical_JJ trials_NNS if_CS a_AT diminution_NN in_IN a_AT particular_JJ immune_JJ response_NN is_BEZ considered_VBN clinically_RB significant_JJ , the_ATI combination_NN vaccine_NN may_MD be_BE immunologically_RB unacceptable_JJ on_IN the_ATI other_AP hand_NN , there_EX has_HVZ been_BEN a_AT report_NN of_IN enhancement_NN of_IN immune_JJ responses_NNS associated_VBN with_IN a_AT combination_NN product_NN , which_WDTR highlights_NNS the_ATI unpredictability_NN of_IN responses_NNS to_TO such_ABL combination_NN vaccines_NNS the_ATI assessment_NN of_IN tolerability_NN and_CC side_NN effects_NNS of_IN the_ATI combination_NN product_NN relative_JJ to_IN its_PP$ individual_JJ vaccines_NNS is_BEZ complex_JJ and_CC requires_VBZ carefully_RB designed_VBN clinical_JJ studies_NNS for_IN proper_JJ assessment_NN 109_CD a_AT final_JJ issue_NN is_BEZ convenience_NN of_IN use_NN vaccines_NNS should_MD be_BE presented_VBN in_IN the_ATI simplest_JJT possible_JJ form_NN to_IN medical_JJ practitioners_NNS in_IN the_ATI private_JJ and_CC the_ATI public_NN sectors_NNS in_IN terms_NNS of_IN clear_JJ labeling_NN with_IN respect_NN to_TO age_NN of_IN administration_NN , identity_NN of_IN component_NN vaccines_NNS , and_CC compatibility_NN or_CC incompatibility_NN for_IN simultaneous_JJ administration_NN with_IN other_AP vaccines_NNS Moreover_NP , the_ATI number_NN of_IN overall_JJB combination_NN products_NNS should_MD be_BE limited_JJ to_TO avoid_VB confusion_NN regarding_IN age_NN of_IN administration_NN and_CC storage_NN in_IN medical_JJ offices_NNS and_CC clinics_NNS attention_NN to_IN these_DTS issues_NNS is_BEZ very_QL important_JJ in_IN increasing_JJ rates_NNS of_IN vaccination_NN 110_CD the_ATI available_JJ vaccines_NNS readily_RB combinable_JJ with_IN DTP_NP include_VB the_ATI following_JJ : (_( 1_CD1 )_) Hib_NP conjugate_NN vaccine_NN , which_WDTR has_HVZ been_BEN recommended_VBN for_IN infants_NNS since_IN 1990_CD ; (_( 2_CD )_) HB_NP vaccine_NN , which_WDTR has_HVZ been_BEN recommended_VBN for_IN infants_NNS since_IN 1992_CD ; and_CC (_( 3_CD )_) inactivated_JJ polio_NN vaccine_NN (_( IPV_NP )_) , which_WDTR may_MD replace_VB OPV_NP in_IN initial_JJ pediatric_JJ doses_NNS to_TO avoid_VB the_ATI rare_JJ cases_NNS of_IN vaccine-induced_JJ polio_NN in_IN vaccinees_NNS or_CC contacts_NNS of_IN vaccinees_NNS receiving_VBG OPV_NP in_IN 1993_CD , a_AT new_JJ combination_NN product_NN became_VBD available_JJ that_CS combines_VBZ DTP_NP with_IN Hib_NP (_( Tetramune_NP (_( Lederle_NP Laboratories_NNS )_) )_) other_AP combination_NN vaccine_NN products_NNS now_RN or_CC soon_RB to_TO be_BE in_IN clinical_JJ testing_NN include_VB DTP-IPV_NP , Hib-HB_NP , DTP-HB_NP , DTP-Hib-HB_NP , and_CC DTP-Hib-HB-IPV_NP the_ATI lattermost_NN vaccine_NN is_BEZ noteworthy_JJ in_IN that_DT it_PP3 would_MD combine_VB six_CD common_JJ pediatric_RB inactivated_VBN vaccines_NNS into_IN a_AT single_JJ injection_NN and_CC could_MD become_VB the_ATI most_QL widely_RB used_VBN combination_NN vaccine_NN in_IN the_ATI latter_AP part_NN of_IN the_ATI 1990s_CD subsequently_RB , HA_NP and_CC pneumococcal_JJ conjugate_NN vaccines_NNS eventually_RB might_MD be_BE combined_VBN with_IN these_DTS as_IN well_RB it_PP3 is_BEZ expected_VBN that_CS MMR_NP vaccine_NN could_MD be_BE combined_VBN with_IN varicella_NN (_( V_ZZ )_) vaccine_NN to_TO create_VB MMR- V_NP vaccine_NN , as_IN a_AT new_JJ pediatric_JJ combination_NN live_VB vaccine_NN 111_CD thus_RB , it_PP3 can_MD be_BE seen_VBN that_CS combining_VBG vaccines_NNS is_BEZ a_AT very_QL complex_JJ and_CC time-consuming_NN process_NN nevertheless_RB , the_ATI result_NN of_IN these_DTS programs_NNS , if_CS successful_JJ , would_MD be_BE a_AT reduction_NN in_IN the_ATI number_NN of_IN vaccine_NN needlesticks_NNS in_IN the_ATI first_OD 2_CD years_NNS of_IN life_NN from_IN approximately_RB 15_CD to_IN five_CD , which_WDTR should_MD result_VB in_IN increased_JJ immunization_NN rates_NNS in_IN the_ATI United_NP States_NP 112_CD NEW_NPT FORMULATION_NP STRATEGIES_NP 113_CD a_AT second_OD major_JJ technological_JJ development_NN is_BEZ that_CS of_IN new_JJ formulation_NN strategies_NNS , one_CD1 of_IN which_WDTR is_BEZ the_ATI application_NN of_IN controlled-release_NN delivery_NN systems_NNS to_IN vaccines.=20_CD 114_CD this_DT is_BEZ a_AT technology_NN not_XNOT yet_RB proven_VBN feasible_JJ , but_CC it_PP3 may_MD offer_VB the_ATI opportunity_NN to_TO convert_VB a_AT multidose_NN vaccination_NN regimen_NNS to_IN a_AT single-dose_NN vaccination_NN , which_WDTR is_BEZ the_ATI ultimate_JJ goal_NN for_IN the_ATI Children's_NP$ Vaccine_NP Initiative_NP of_IN the_ATI World_NP Health_NP Organization_NN the_ATI principle_NN involved_VBN is_BEZ the_ATI encapsulation_NN of_IN a_AT vaccine_NN antigen_NN in_IN a_AT polymer_NN that_CS provides_VBZ for_IN the_ATI controlled_JJ release_NN of_IN the_ATI antigen_NN this_DT would_MD result_VB in_IN a_AT longer_RBR period_NN of_IN immune_JJ stimulation_NN than_CS for_IN a_AT conventional_JJ vaccine_NN , thus_RB obviating_VBG the_ATI need_NN for_IN additional_JJ doses_NNS of_IN the_ATI vaccine_NN 115_CD most_AP of_IN the_ATI developmental_JJ efforts_NNS to_TO date_VB have_HV been_BEN with_IN tetanus_JJ toxoid_NN , which_WDTR offers_VBZ the_ATI advantages_NNS of_IN ready_JJ availability_NN and_CC relative_JJ structural_JJ simplicity_NN ; there_EX is_BEZ a_AT major_JJ worldwide_NN need_NN for_IN a_AT single-dose_NN tetanus_JJ vaccine_NN for_IN immunizing_VBG women_NNS for_IN the_ATI prevention_NN of_IN neonatal_JJ tetanus_JJ such_ABL polymers_NNS need_NN to_TO be_BE safe_JJ , biodegradable_JJ , stable_JJ during_IN long-term_JJB storage_NN , reproducible_JJ in_IN quality_NN , physically_RB compatible_JJ with_IN the_ATI particular_JJ vaccine_NN antigen_NN , and_CC permeable_JJ enough_QLP to_TO permit_VB slow_JJ release_NN of_IN the_ATI antigen_NN the_ATI polymer_NN and_CC vaccine_NN antigen_NN are_BER formulated_VBN in_IN microspheres_NNS or_CC microcapsules_NNS approximately_RB 10_CD to_IN 200_CD microns_NNS in_IN diameter_NN depending_VBG on_IN the_ATI precise_JJ formulation_NN , release_NN of_IN the_ATI antigen_NN occurs_VBZ through_IN degradation_NN of_IN the_ATI polymer_NN as_IN well_RB as_IN diffusion_NN through_IN pores_NNS in_IN the_ATI particles_NNS continuous-release_NN formulations_NNS may_MD enable_VB the_ATI vaccine_NN antigen_NN to_TO be_BE released_VBN during_IN a_AT range_NN of_IN time_NN from_IN a_JJ few_AP days_NNS to_TO a_AT year_NN or_CC more_QL pulse-release_NN formulations_NNS may_MD enable_VB the_ATI antigen_NN to_TO be_BE released_VBN at_IN discrete_JJ intervals_NNS that_WPR mimic_VB a_AT typical_JJ vaccination_NN schedule_NN to_TO accomplish_VB the_ATI latter_AP , it_PP3 may_MD be_BE possible_JJ to_TO formulate_VB different_JJ types_NNS of_IN microspheres_NNS that_DT would_MD release_VB the_ATI antigen_NN at_IN different_JJ time_NN intervals_NNS according_IN to_IN their_PP$ composition_NN (_( eg_NN , week_NN 1_CD1 , months_NNS 2_CD to_IN 3_CD , months_NNS 4_CD to_IN 5_CD , and_CC months_NNS 12_CD to_IN 15_CD )_) the_ATI mixture_NN of_IN these_DTS microspheres_NNS then_RN would_MD release_VB the_ATI antigen_NN in_IN intervals_NNS similar_JJ to_TO those_DTS of_IN an_AT actual_JJ vaccination_NN regimen_NNS (_( eg_NN , vaccination_NN at_IN 2_CD , 4_CD , 6_CD , and_CC 15_CD months_NNS of_IN age_NN )_) thus_RB , the_ATI reduction_NN to_IN five_CD injections_NNS achieved_VBN with_IN pediatric_JJ combination_NN vaccines_NNS conceivably_RB may_MD be_BE further_JJB reduced_VBN to_IN a_AT single_JJ injection_NN early_RB in_IN life_NN 116_CD there_EX remains_VBZ much_AP development_NN work_NN to_TO be_BE done_VBN for_IN preparing_VBG appropriate_JJ and_CC stable_JJ formulations_NNS and_CC proving_VBG their_PP$ efficacy_NN in_IN preclinical_JJ animal_NN models_NNS before_CS this_DT approach_NN is_BEZ widely_RB tested_VBN in_IN humans_NNS the_ATI principle_NN challenge_NN at_IN present_NN is_BEZ the_ATI development_NN of_IN consistent_JJ and_CC stable_JJ formulations_NNS using_VBG appropriate_JJ biodegradable_JJ components_NNS beyond_IN testing_NN for_IN efficacy_NN in_IN humans_NNS in_IN terms_NNS of_IN sustained_VBN immune_JJ responses_NNS , the_ATI immunologic_JJ consequences_NNS of_IN continual_JJ exposure_NN to_TO released_JJ antigens_NNS need_NN to_TO be_BE considered_VBN should_MD controlled-release_VB delivery_NN prove_VB to_TO be_BE well_RB tolerated_VBN and_CC efficacious_JJ in_IN humans_NNS , this_DT technology_NN could_MD greatly_RB simplify_VB vaccination_NN by_IN converting_VBG multidose_NN to_TO single-dose_NN regimens_NNS , thereby_RB significantly_RB improving_VBG compliance_NN and_CC reducing_VBG the_ATI overall_JJB expense_NN associated_VBN with_IN vaccination_NN 117_CD another_DT formulation_NN strategy_NN is_BEZ the_ATI use_NN of_IN novel_NN adjuvants_NNS , which_WDTR are_BER defined_VBN as_CS formulations_NNS that_WPR augment_VB humoral_JJ and_CC cell-mediated_JJ immune_JJ responses_NNS to_IN vaccine_NN antigens_NNS the_ATI formulation_NN is_BEZ made_VBN by_IN mixing_NN the_ATI vaccine_NN antigen_NN with_IN the_ATI adjuvant_NN , to_TO which_WDTR it_PP3 is_BEZ stably_RB bound_VBN this_DT is_BEZ a_AT long-standing_JJ field_NN in_IN that_DT aluminum_JJ salt-based_JJ adjuvants_NNS have_HV been_BEN used_VBN for_IN decades_NNS with_IN vaccines_NNS such_ABL as_CS DTP_NP and_CC also_RB are_BER used_VBN for_IN vaccines_NNS such_ABL as_CS HB_NP , IPV_NP , HA_NP , and_CC Hib_NP and_CC pneumococcal_JJ conjugates_NNS Although_NP aluminum_NN salts_NNS have_HV been_BEN widely_RB used_VBN in_IN vaccines_NNS and_CC have_HV been_BEN generally_RB well_RB tolerated_VBN , it_PP3 has_HVZ been_BEN recognized_VBN that_CS these_DTS adjuvants_NNS often_RB do_DO not_XNOT provide_VB sufficient_JJ augmentation_NN to_IN immune_JJ responses_NNS for_IN certain_JJ experimental_JJ vaccines_NNS therefore_RB , there_EX have_HV been_BEN many_AP investigations_NNS into_IN several_AP groups_NNS of_IN novel_NN adjuvants_NNS , which_WDTR include_VB liposomes_NNS , squalene_NN emulsions_NNS , and_CC immune-stimulating_NN complexes_NNS many_AP preclinical_JJ studies_NNS have_HV demonstrated_VBN that_CS such_ABL new_JJ adjuvant_NN formulations_NNS are_BER often_RB more_QL potent_JJ than_IN aluminum_NN salts_NNS for_IN stimulating_JJ immune_JJ responses_NNS to_IN certain_JJ vaccine_NN antigens_NNS some_DTI of_IN these_DTS new_JJ adjuvants_NNS also_RB have_HV been_BEN tested_VBN clinically_RB with_IN promising_JJ results_NNS Nevertheless_NN , extensive_JJ evaluations_NNS of_IN tolerability_NN will_MD be_BE required_VBN for_IN such_ABL adjuvants_NNS , given_VBN that_CS aluminum_JJ salt- based_JJ adjuvants_NNS have_HV been_BEN employed_VBN in_IN billions_NNS of_IN doses_NNS of_IN vaccines_NNS over_IN decades_NNS of_IN use_NN Furthermore_NP , it_PP3 may_MD be_BE anticipated_VBN that_CS considerable_JJ experience_NN would_MD need_VB to_TO be_BE gained_VBN with_IN novel_NN adjuvants_NNS in_IN adults_NNS before_IN they_PP3AS are_BER widely_RB used_VBN for_IN routine_NN vaccination_NN in_IN infants_NNS 118_CD NEW_NPT VECTOR_NP SYSTEMS_NP 119_CD a_AT third_OD major_JJ technological_JJ development_NN is_BEZ the_ATI application_NN of_IN new_JJ vector_NN systems_NNS to_IN the_ATI delivery_NN of_IN vaccine_NN antigens_NNS into_IN cells_NNS after_IN immunization_NN subunit_NN or_CC inactivated_JJ vaccines_NNS such_ABL as_CS those_DTS mentioned_VBN in_IN the_ATI preceding_JJ paragraph_NN do_DO not_XNOT replicate_VB in_IN the_ATI host_NN they_PP3AS are_BER recognized_VBN by_IN the_ATI host's_NP$ immune_JJ system_NN as_CS foreign_JJ and_CC typically_RB elicit_VB an_AT antibody-based_JJ immune_JJ response_NN on_IN the_ATI other_AP hand_NN , foreign_JJ antigens_NNS that_CS are_BER expressed_VBN in_IN cells_NNS (_( eg_NN , after_IN viral_JJ infection_NN )_) can_MD elicit_VB killer_NN T-cell_NP or_CC cytotoxic_JJ T-lymphocyte_NP (_( CTL_NP )_) activity_NN in_IN addition_NN to_IN antibodies_NNS therefore_RB , vaccine_NN antigens_NNS expressed_VBN in_IN cells_NNS typically_RB elicit_VB more_QL broadly_RB based_VBN immune_JJ responses_NNS than_IN subunit_NN or_CC inactivated_VBD vaccine_NN antigens_NNS in_IN the_ATI case_NN of_IN some_DTI pathogens_NNS , elicitation_NN of_IN CTL_NP responses_NNS may_MD be_BE required_VBN for_IN protection_NN against_IN infection_NN 120_CD there_EX are_BER several_AP vector_NN systems_NNS being_BEG applied_VBN to_IN the_ATI delivery_NN of_IN vaccine_NN antigens_NNS into_IN cells_NNS for_IN expression_NN two_CD of_IN these_DTS are_BER conceptually_RB similar_JJ and_CC involve_VB the_ATI use_NN of_IN live_VB viruses_NNS or_CC bacteria_NNS to_TO carry_VB vaccine_NN antigens_NNS for_IN other_AP pathogens_NNS all_ABN viruses_NNS and_CC some_DTI bacteria_NNS (_( eg_NN , Salmonella_NP typhimurium_NN and_CC Mycobacterium_NP tuberculosis_NN )_) replicate_NN intracellularly_RB if_CS the_ATI gene_NN encoding_NN a_AT vaccine_NN antigen_NN , such_ABL as_IN influenza_NN virus_NN nucleoprotein_NN (_( NP_NP )_) , is_BEZ inserted_VBN into_IN the_ATI genome_NN of_IN the_ATI virus_NN or_CC bacterium_NN by_IN means_NNS of_IN recombinant_NN DNA_NP technology_NN , then_RN the_ATI antigen_NN (_( NP_NP )_) is_BEZ expressed_VBN in_IN cells_NNS after_IN immunization_NN with_IN the_ATI recombinant_NN virus_NN or_CC bacterium_NN some_DTI of_IN the_ATI viruses_NNS that_CS have_HV been_BEN engineered_VBN into_IN live_VB vectors_NNS include_VB adenovirus_JJ and_CC vaccinia_JJ , herpes_NNS simplex_NN , varicella-zoster_NN , fowlpox_NN , and_CC canarypox_NN viruses_NNS , while_CS bacterial_JJ vector_NN systems_NNS include_VB S_ZZ typhimurium_NN and_CC the_ATI Mycobacterium_NP bovis_NN Calmette-Guerin_NP bacillus_JJ strain_NN the_ATI viruses_NNS or_CC bacteria_NNS that_CS are_BER used_VBN as_CS live_VB vectors_NNS have_HV been_BEN selected_VBN or_CC engineered_VBN to_TO be_BE attenuated_JJ in_IN their_PP$ infectivity_NN for_IN humans_NNS such_ABL that_CS they_PP3AS replicate_NN in_IN the_ATI host_NN without_IN causing_VBG disease_NN or_CC significant_JJ clinical_JJ symptoms_NNS the_ATI live_VB vectors_NNS have_HV undergone_VBN extensive_JJ preclinical_JJ evaluations_NNS , and_CC some_DTI of_IN these_DTS vectors_NNS carrying_VBG foreign_JJ antigens_NNS have_HV been_BEN or_CC are_BER planned_VBN to_TO be_BE tested_VBN in_IN humans_NNS extensive_JJ evaluations_NNS of_IN safety_NN and_CC efficacy_NN will_MD be_BE required_VBN for_IN such_ABL vaccines_NNS to_TO enjoy_VB widespread_JJ use_NN 121_CD the_ATI third_OD vector_NN system_NN is_BEZ quite_RB distinct_JJ from_IN the_ATI other_AP two_CD and_CC is_BEZ based_VBN on_IN the_ATI use_NN of_IN _** naked_JJ DNA_NP _** as_IN a_AT vaccine_NN , also_RB known_VBN as_IN the_ATI _** polynucleotide_NN vaccine_NN _** this_DT field_NN recently_RB was_BEDZ created_VBN from_IN the_ATI observation_NN that_CS injection_NN of_IN a_AT DNA_NP or_CC an_AT RNA_NP molecule_NN with_IN the_ATI complete_JJ genetic_JJ information_NN for_IN a_AT protein_NN product_NN into_IN mouse_NN skeletal_JJ muscle_NN elicited_VBN the_ATI synthesis_NN of_IN the_ATI particular_JJ protein_NN in_IN the_ATI injected_VBD muscle_NN cells_NNS furthermore_RB , protein_NN expression_NN from_IN injected_VBD DNA_NP was_BEDZ shown_VBN to_TO persist_VB in_IN mouse_NN muscle_NN for_IN up_RP to_IN 19_CD months_NNS , with_IN no_ATI evidence_NN for_IN the_ATI integration_NN of_IN the_ATI injected_VBD DNA_NP into_IN mouse_NN chromosomal_JJ DNA_NP as_IN a_AT result_NN of_IN these_DTS observations_NNS , the_ATI technology_NN of_IN naked_JJ DNA_NP injection_NN was_BEDZ seen_VBN to_TO have_HV potential_JJ utility_NN for_IN the_ATI fields_NNS of_IN gene_NN therapy_NN and_CC vaccine_NN development_NN the_ATI DNA_NP was_BEDZ termed_VBN _** naked_JJ _** because_CS no_ATI chemical_JJ carrier_NN was_BEDZ required_VBN in_IN addition_NN , the_ATI DNA_NP did_DOD not_XNOT need_VB to_TO be_BE part_NN of_IN a_AT virus_NN or_CC bacterium_NN to_TO function_VB as_IN a_AT vaccine_NN 122_CD the_ATI initial_JJ demonstration_NN of_IN the_ATI utility_NN of_IN the_ATI polynucleotide_NN vaccine_NN approach_NN was_BEDZ in_IN a_AT mouse_NN model_NN of_IN infection_NN with_IN influenza_NN virus_NN Injection_NN of_IN DNA_NP encoding_NN influenza_NN virus_NN NP_NP into_IN mouse_NN muscle_NN , which_WDTR induces_VBZ synthesis_NN of_IN NP_NP , elicited_VBD CTL_NP activity_NN against_IN influenza_NN virus_NN and_CC protection_NN against_IN infection_NN with_IN a_AT different_JJ (_( heterologous_JJ )_) strain_NN of_IN influenza_NN A_ZZ virus_NN than_IN that_DT from_IN which_WDTR the_ATI NP_NP DNA_NP was_BEDZ derived_VBN these_DTS results_NNS are_BER significant_JJ in_IN that_DT conventional_JJ influenza_NN vaccines_NNS elicit_VB no_ATI CTL_NP reactivity_NN and_CC fail_VB to_TO protect_VB against_IN heterologous_JJ influenza_NN virus_NN infections_NNS ; rather_RB , the_ATI conventional_JJ vaccine_NN protects_VBZ only_RB against_IN the_ATI same_AP (_( homologous_JJ )_) strains_NNS as_IN the_ATI vaccine_NN strains_NNS by_IN eliciting_VBG antibodies_NNS against_IN hemagglutinin_NN , a_AT highly_RB variable_JJ viral_JJ protein_NN based_VBN on_IN these_DTS results_NNS , it_PP3 may_MD be_BE possible_JJ to_TO develop_VB an_AT influenza_NN polynucleotide_NN vaccine_NN that_CS encodes_NNS internal_JJ proteins_NNS of_IN influenza_NN virus_NN , such_ABL as_CS NP_NP , which_WDTR are_BER conserved_VBN among_IN all_ABN influenza_NN strains_NNS such_ABL a_AT vaccine_NN may_MD protect_VB against_IN heterologous_JJ infection_NN by_IN means_NNS of_IN CTL_NP , as_CS can_MD be_BE tested_VBN in_IN ferret_NN or_CC primate_NN models_NNS of_IN infection_NN it_PP3 also_RB has_HVZ been_BEN shown_VBN that_CS DNA_NP encoding_NN hemagglutinin_NN elicits_NNS protective_JJ levels_NNS of_IN anti-hemagglutinin_NN antibodies_NNS in_IN animals_NNS this_DT means_VBZ that_CS polynucleotide_NN vaccines_NNS can_MD elicit_VB both_ABX CTL_NP and_CC antibody_NN responses_NNS , which_WDTR are_BER the_ATI two_CD major_JJ arms_NNS of_IN protective_JJ immunity_NN against_IN infectious_JJ agents_NNS depending_VBG on_IN the_ATI particular_JJ infectious_JJ agent_NN , either_DTX antibody-based_JJ immunity_NN or_CC CTL-based_NP immunity_NN may_MD be_BE important_JJ in_IN the_ATI efficacy_NN of_IN a_AT vaccine_NN if_CS both_ABX can_MD contribute_VB to_TO protection_NN or_CC enhanced_JJ recovery_NN , then_RN it_PP3 would_MD be_BE ideal_JJ to_TO include_VB both_ABX in_IN the_ATI design_NN of_IN a_AT polynucleotide_NN vaccine_NN this_DT strategy_NN may_MD offer_VB a_AT potential_JJ approach_NN to_IN agents_NNS that_CS have_HV not_XNOT yet_RB succumbed_VBD to_IN conventional_JJ vaccine_NN technology_NN , such_IN as_IN human_JJ immunodeficiency_NN virus_NN 123_CD there_EX are_BER other_AP potential_JJ advantages_NNS to_IN a_AT polynucleotide_NN vaccine_NN The_NP DNA_NP is_BEZ relatively_RB easier_JJR to_TO produce_VB , purify_VB , and_CC assure_VB quality_NN consistently_RB compared_VBN with_IN protein-based_JJ or_CC live_VB attenuated_JJ vaccines_NNS in_IN addition_NN , the_ATI demonstrated_VBN persistence_NN of_IN expression_NN of_IN a_AT protein_NN after_IN intramuscular_JJ injection_NN of_IN its_PP$ gene_NN (_( DNA_NP )_) may_MD lead_VB to_IN the_ATI maintenance_NN of_IN protective_JJ immune_JJ responses_NNS for_IN a_AT period_NN beyond_IN that_DT elicited_VBN by_IN some_DTI conventional_JJ vaccines_NNS nevertheless_RB , these_DTS exciting_JJ findings_NNS are_BER of_IN a_AT preliminary_JJ nature_NN with_IN regard_NN to_IN applicability_NN to_IN humans_NNS there_EX remain_VB significant_JJ challenges_VBZ to_IN the_ATI development_NN of_IN polynucleotide_NN vaccines_NNS , including_IN demonstrations_NNS of_IN efficacy_NN in_IN animal_NN models_NNS most_QL relevant_JJ to_TO human_JJ disease_NN , assurance_NN that_WPR injected_VBD DNA_NP does_DOZ not_XNOT readily_RB integrate_VB into_IN genomic_JJ DNA_NP as_CS diagnosed_VBN by_IN the_ATI highly_RB sensitive_JJ technique_NN of_IN polymerase_NN chain_NN reaction_NN , and_CC eventual_JJ human_JJ clinical_JJ studies_NNS of_IN short-_NN and_CC long-term_JJB side_NN effects_NNS and_CC efficacy_NN , which_WDTR are_BER expected_VBN during_IN the_ATI next_AP few_AP years_NNS if_CS these_DTS challenges_VBZ are_BER met_VBN , polynucleotide_NN vaccines_NNS would_MD have_HV the_ATI potential_JJ to_TO revolutionize_VB the_ATI field_NN of_IN vaccines_NNS 124_CD the_ATI net_JJB impact_NN of_IN these_DTS three_CD technologies_NNS , combination_NN vaccines_NNS , formulation_NN strategies_NNS , and_CC vector_NN systems_NNS , would_MD be_BE a_AT significant_JJ decrease_NN in_IN the_ATI number_NN of_IN needlesticks_NNS and_CC physician_NN appointments_NNS for_IN vaccination_NN , a_AT concomitant_NN increase_NN in_IN rates_NNS of_IN immunization_NN , and_CC the_ATI potential_JJ development_NN of_IN innovative_JJ vaccines_NNS 125_CD helicobacter_NN pylori_NN 126_CD helicobacter_NN pylori_NN is_BEZ the_ATI cause_NN of_IN chronic_JJ active_JJ gastritis_NN it_PP3 is_BEZ integral_JJ to_IN the_ATI pathogenesis_NN of_IN peptic_JJ ulcer_NN disease_NN and_CC is_BEZ epidemiologically_RB linked_VBN to_IN gastric_JJ cancer_NN and_CC lymphoma_NN helicobacter_NN pylori_NN can_MD be_BE detected_VBN through_IN a_AT variety_NN of_IN invasive_JJ (_( urease_NN testing_NN , culture_NN , or_CC histologic_JJ diagnosis_NN of_IN endoscopic_JJ biopsies_NNS )_) and_CC noninvasive_JJ (_( urease_NN breath_NN tests_NNS , serologic_JJ tests_NNS )_) diagnostic_JJ tests_NNS it_PP3 is_BEZ now_RN appropriate_JJ to_TO detect_VB and_CC eradicate_VB H_ZZ pylori_NN in_IN patients_NNS with_IN a_AT peptic_JJ ulcer_NN as_IN the_ATI natural_JJ history_NN of_IN peptic_JJ ulcer_NN disease_NN is_BEZ then_RN markedly_RB improved_JJ at_IN this_DT time_NN , there_EX is_BEZ no_ATI role_NN for_IN H_ZZ pylori_NN eradication_NN in_IN the_ATI prevention_NN of_IN gastric_JJ cancer_NN ; however_RB , this_DT concept_NN is_BEZ being_BEG actively_RB investigated.=20_CD 127_CD there_EX is_BEZ no_ATI indication_NN to_TO treat_VB patients_NNS who_WPR have_HV H_ZZ pylori_NN and_CC nonulcer_NN dyspepsia_NN or_CC gastritis_NN because_CS eradication_NN does_DOZ not_XNOT reliably_RB affect_VB their_PP$ symptoms_NNS current_JJ regimens_NNS for_IN eradication_NN include_VB bismuth_NN , antibiotics_NNS , and_CC antisecretory_NN agents_NNS complex_JJ and_CC poorly_RB tolerated_VBN regimens_NNS (_( triple_JJ therapy_NN )_) may_MD no_RB longer_RBR be_BE necessary_JJ , as_CS simpler_JJR regimens_NNS (_( omeprazole_NN and_CC amoxicillin_NN or_CC clarithromycin_NN )_) appear_VB to_TO be_BE as_CS effective_JJ and_CC better_JJR tolerated_VBN 128_CD helicobacter_NN pylori_NN was_BEDZ first_OD identified_VBN and_CC isolated_JJ nearly_RB a_AT decade_NN ago_RB since_IN that_DT time_NN , H_ZZ pylori_NN has_HVZ been_BEN proposed_VBN to_TO be_BE the_ATI causative_JJ factor_NN for_IN a_AT variety_NN of_IN gastrointestinal_JJ tract_NN maladies_NNS ranging_VBG from_IN nonulcer_NN dyspepsia_NN to_IN gastric_JJ cancer_NN the_ATI role_NN of_IN H_ZZ pylori_NN as_IN the_ATI major_JJ causative_JJ factor_NN of_IN _** environmental_JJ _** (_( nonautoimmune_NN )_) gastritis_NN and_CC peptic_JJ ulcer_NN disease_NN seems_VBZ beyond_IN refute_VB ; however_RB , its_PP$ association_NN with_IN other_AP gastroduodenal_JJ disorders_NNS remains_VBZ speculative_JJ This_NN review_NN is_BEZ meant_VBN to_TO provide_VB a_AT state-of-the-art_NN update_NN regarding_IN epidemiology_NN , pathogenesis_NN , diagnosis_NN , and_CC treatment_NN of_IN this_DT _** elusive_JJ _** organism_NN 129_CD BACTERIOLOGY_NP 130_CD the_ATI organism_NN was_BEDZ originally_RB named_VBN Campylobacter_NP pyloridis_NN because_CS of_IN its_PP$ structural_JJ similarity_NN to_TO other_AP Campylobacter_NP species_NN because_CS of_IN its_PP$ enteric_JJ nature_NN it_PP3 was_BEDZ renamed_VBN Campylobacter_NP pylori_NN to_TO correspond_VB to_TO the_ATI nomenclature_NN of_IN other_AP enteric_JJ pathogens_NNS in_IN 1989_CD it_PP3 was_BEDZ given_VBN the_ATI name_NN H_ZZ pylori_NN within_IN a_AT new_JJ genus_JJ , Helicobacter_NP , on_IN the_ATI basis_NN of_IN distinct_JJ functional_JJ and_CC enzymatic_JJ properties_NNS in_IN retrospect_NN , Helicobacter-like_NP organisms_NNS were_BED detected_VBN in_IN animal_NN mucosa_NN in_IN the_ATI 1800s_CD and_CC in_IN humans_NNS in_IN the_ATI earlier_RBR part_NN of_IN the_ATI 20th_OD century_NN however_RB , because_CS of_IN misconceptions_NNS and_CC faulty_JJ reasoning_NN , the_ATI organism_NN was_BEDZ ignored_VBN until_IN interest_NN in_IN it_PP3 was_BEDZ resurrected_VBN by_IN Marshall_NP and_CC Warren_NP in_IN 1983_CD 131_CD the_ATI organism_NN is_BEZ a_AT spiral-shaped_JJ , gram-negative_JJ rod_NN measuring_VBG 0.5x3.0_CD microns_NNS with_IN four_CD to_IN six_CD sheathed_JJ flagella_NN it_PP3 resides_NNS below_IN the_ATI mucous_JJ layer_NN in_IN apposition_NN to_IN gastric_JJ epithelium_NN in_IN any_DTI location_NN in_IN which_WDTR gastric_JJ epithelium_NN is_BEZ found_VBN , including_IN the_ATI stomach_NN and_CC such_ABL metaplastic_JJ locations_NNS as_IN the_ATI esophagus_JJ , duodenum_JJB , and_CC Meckel's_NP$ diverticulum_NN the_ATI organism_NN is_BEZ motile_JJ (_( via_IN its_PP$ flagella_NN )_) , and_CC because_CS of_IN this_DT motility_NN and_CC its_PP$ spiral_NN shape_NN , H_ZZ pylori_NN is_BEZ able_JJ to_TO burrow_VB through_IN and_CC reside_VB under_IN the_ATI mucous_JJ layer_NN the_ATI organism_NN also_RB possesses_VBZ a_AT high-_NN molecular-weight_NN urease_NN enzyme_NN that_CS allows_VBZ it_PP3 to_TO catalyze_VB urea_NN , thus_RB forming_VBG ammonium_NN and_CC bicarbonate_NN the_ATI ammonium_NN forms_NNS an_AT alkaline_JJ microenvironment_NN that_CS protects_VBZ H_ZZ pylori_NN from_IN gastric_JJ acid_NN , to_TO which_WDTR the_ATI organism_NN is_BEZ very_QL sensitive_JJ the_ATI bicarbonate_NN that_WPR is_BEZ produced_VBN by_IN the_ATI urease_NN reaction_NN can_MD be_BE used_VBN as_IN a_AT diagnostic_JJ test_NN , as_CS it_PP3 is_BEZ absorbed_VBN into_IN the_ATI blood_NN and_CC eventually_RB excreted_VBN as_IN carbon_NN dioxide_NN by_IN the_ATI lungs_NNS (_( see_VB the_ATI _** Diagnosis_NP _** section_NN )_) the_ATI organism_NN is_BEZ able_JJ to_TO attach_VB to_IN epithelial_JJ membranes_NNS , which_WDTR may_MD determine_VB pathogenicity_VB attachment_NN is_BEZ facilitated_VBN by_IN adherence_NN pedestals_NNS and_CC proteins_NNS that_CS are_BER similar_JJ to_IN those_DTS found_VBN in_IN enteropathogenic_JJ Escherichia_NP coli_&FW 132_CD the_ATI organism_NN demonstrates_VBZ considerable_JJ diversity_NN by_IN DNA_NP analysis_NN This_NN diversity_NN can_MD be_BE used_VBN to_TO type_VB various_JJ strains_NNS and_CC may_MD be_BE valuable_JJ in_IN epidemiologic_JJ studies_NNS a_AT minority_NN of_IN strains_NNS appear_VB to_TO possess_VB plasmids_NNS , although_CS their_PP$ role_NN in_IN pathogenesis_NN or_CC survival_NN is_BEZ unclear_JJ 133_CD transmission_NN appears_VBZ to_TO occur_VB via_IN human-to-human_NN spread_NN , as_IN no_ATI environmental_JJ reservoir_NN has_HVZ been_BEN identified_VBN humans_NNS appear_VB to_TO be_BE the_ATI only_RB major_JJ reservoir_NN of_IN infection_NN and_CC are_BER the_ATI probable_JJ vectors_NNS of_IN transmission_NN isolation_NN of_IN H_ZZ pylori_NN in_IN the_ATI stool_NN indicates_VBZ fecal-oral_JJ transmission_NN as_IN the_ATI likely_JJ route_NN human_JJ transmission_NN is_BEZ further_JJB supported_VBN by_IN the_ATI findings_NNS of_IN increased_JJ prevalence_NN of_IN H_ZZ pylori_NN in_IN family_NN members_NNS of_IN affected_JJ subjects_NNS 134_CD PATHOGENESIS_NP 135_CD the_ATI mechanisms_NNS by_IN which_WDTR H_ZZ pylori_NN produces_VBZ the_ATI inflammatory_JJ and_CC cellular_JJ destructive_JJ changes_NNS that_WPR accompany_VB its_PP$ infection_NN remain_VB unclear_JJ lack_NN of_IN availability_NN of_IN a_AT suitable_JJ animal_NN model_NN has_HVZ hindered_VBN research_NN in_IN this_DT area_NN , but_CC recent_JJ work_NN indicates_VBZ that_CS gnotobiotic_JJ piglets_NNS may_MD provide_VB a_AT suitable_JJ model_NN in_IN which_WDTR to_TO study_VB pathogenic_JJ mechanisms_NNS of_IN H_ZZ pylori_NN 136_CD tissue_NN invasion_NN by_IN the_ATI organism_NN is_BEZ extremely_RB rare_JJ and_CC is_BEZ probably_RB not_XNOT important_JJ to_TO pathogenesis_VB however_RB , the_ATI bacteria_NNS are_BER able_JJ to_TO penetrate_VB epithelial_JJ cell_NN junctions_NNS the_ATI role_NN that_CS this_DT process_NN plays_NNS in_IN pathogenesis_NN is_BEZ unclear_JJ , although_CS it_PP3 does_DOZ allow_VB the_ATI organism_NN to_TO reside_VB in_IN proximity_NN to_IN epithelial_JJ cell_NN membranes_NNS helicobacter_NN pylori_NN also_RB possesses_VBZ proteases_NNS , lipases_NNS , and_CC phospholipases_NNS , which_WDTR may_MD account_VB for_IN some_DTI of_IN its_PP$ pathogenic_JJ properties_NNS by_IN disrupting_VBG mucous_JJ lipids_NNS 137_CD cytotoxins_NNS have_HV been_BEN identified_VBN that_CS cause_NN vacuolization_NN in_IN tissue_NN culture_NN cell_NN lines_NNS , and_CC these_DTS cytotoxins_NNS appear_VB to_TO be_BE more_QL common_NN in_IN those_DTS patients_NNS who_WPR present_JJ with_IN duodenal_JJ ulcer_NN disease_NN further_JJB evidence_NN that_CS cytotoxins_NNS may_MD be_BE important_JJ to_TO pathogenesis_VB is_BEZ the_ATI finding_NN of_IN antibody_NN to_TO cytotoxin_VB in_IN the_ATI serum_NN of_IN affected_JJ patients_NNS purified_VBN toxin_NN has_HVZ some_DTI homology_NN to_TO transport_VB and_CC ion_NN channel_NN proteins_NNS , but_CC how_WRB this_DT affects_VBZ pathogenesis_NN is_BEZ unclear_JJ 138_CD the_ATI organism_NN also_RB has_HVZ the_ATI ability_NN to_TO adhere_VB to_IN epithelial_JJ cell_NN membranes_NNS via_IN attachment_NN pedestals_NNS or_CC adhesion_NN proteins_NNS this_DT ability_NN to_TO attach_VB probably_RB confers_VBZ some_DTI element_NN of_IN pathogenicity_NN to_IN the_ATI organism_NN , as_IN adhesion_NN is_BEZ not_XNOT essential_JJ for_IN colonization_NN it_PP3 also_RB appears_VBZ that_CS organisms_NNS that_CS are_BER motile_NN are_BER more_QL virulent_JJ , although_CS the_ATI mechanism_NN for_IN this_DT is_BEZ unclear_JJ 139_CD the_ATI existence_NN of_IN the_ATI potent_JJ , cell-bound_JJB urease_NN enzyme_NN allows_VBZ an_AT acid-labile_NN organism_NN to_TO survive_VB in_IN an_AT acid_NN environment_NN urease_NN may_MD produce_VB some_DTI of_IN the_ATI cellular_JJ injury_NN that_WPR is_BEZ observed_VBN either_DTX directly_RB or_CC through_IN the_ATI local_JJ production_NN of_IN ammonium_NN urease_NN may_MD act_VB directly_RB as_IN a_AT gastric_JJ cell_NN cytotoxin_NN or_CC may_MD disrupt_VB tight_JJ cell_NN junctions_NNS , resulting_JJ in_IN increased_VBN ionic_JJ flow_NN urease_NN also_RB acts_VBZ as_IN a_AT virulence_NN factor_NN , as_IN urease_NN is_BEZ necessary_JJ during_IN the_ATI initial_JJ steps_NNS of_IN colonization_NN before_IN the_ATI organism's_NP$ entry_NN into_IN the_ATI mucous_JJ layer_NN ammonia_NN production_NN impairs_NNS mitochondrial_JJ and_CC cellular_JJ respiration_NN , thus_RB decreasing_VBG cell_NN viability_NN and_CC leading_JJ to_IN mucosal_JJ damage_NN ammonia_NN also_RB disrupts_VBZ the_ATI mucous_JJ layer_NN and_CC may_MD be_BE a_AT direct_JJ cytotoxin_NN clarification_NN of_IN pathogenic_JJ factors_NNS and_CC their_PP$ mechanisms_NNS may_MD allow_VB the_ATI development_NN of_IN novel_JJ therapeutic_JJ agents_NNS or_CC agents_NNS or_CC vaccines_NNS that_DT will_MD prevent_VB infection_NN and_CC colonization_NN 140_CD PREVALENCE_NP 141_CD the_ATI prevalence_NN of_IN the_ATI organism_NN is_BEZ dependent_JJ on_IN socioeconomic_JJ class_NN , race_NN , and_CC whether_CS the_ATI subject_NN resides_NNS in_IN a_AT developing_VBG country_NN in_IN Western_NP countries_NNS , infection_NN before_IN the_ATI age_NN of_IN 20_CD years_NNS is_BEZ unusual_JJ , and_CC in_IN adulthood_NN prevalence_NN rates_NNS range_VB from_IN 40%_NP to_IN 60%_NP at_IN age_NN 60_CD years_NNS However_NP , in_IN the_ATI United_NP States_NP , Hispanics_NP and_CC blacks_NNS are_BER noted_VBN to_TO have_HV markedly_RB increased_JJ prevalence_NN rates_NNS compared_VBN with_IN that_DT of_IN whites_NNS lower_JJR socioeconomic_JJ class_NN and_CC crowding_NN seem_VB to_TO result_VB in_IN higher_JJR prevalence_NN rates_NNS additionally_RB , an_AT increased_JJ prevalence_NN (_( up_RP to_IN 80%_NP )_) is_BEZ found_VBN in_IN family_NN members_NNS of_IN an_AT affected_JJ patient_NN 142_CD in_IN developing_VBG countries_NNS , children_NNS are_BER colonized_VBN early_JJ , with_IN up_RP to_TO 80%_NP of_IN children_NNS under_IN 20_CD years_NNS of_IN age_NN being_BEG infected_VBN , compared_VBD with_IN less_AP than_IN 20%_NP of_IN children_NNS in_IN developed_JJ countries_NNS thus_RB , the_ATI age_NN of_IN acquisition_NN and_CC prevalence_NN of_IN infection_NN are_BER different_JJ between_IN populations_NNS , and_CC , more_QL importantly_RB , age_NN at_IN infection_NN may_MD determine_VB disease_NN presentation_NN (_( ie_NN , ulcer_NN disease_NN vs_IN gastric_JJ cancer_NN )_) 143_CD recent_JJ epidemiologic_JJ data_NNS suggest_VB that_CS the_ATI prevalence_NN of_IN H_ZZ pylori_NN infection_NN is_BEZ decreasing_VBG for_IN all_ABN ages_NNS , the_ATI prevalence_NN of_IN H_ZZ pylori_NN is_BEZ less_AP than_IN prevalence_JJ rates_NNS earlier_RBR in_IN the_ATI century_NN , and_CC seroconversion_NN rates_NNS (_( incidence_NN )_) in_IN adults_NNS are_BER low_JJ (_( {_( 1%_CD per_NNU year_NN )_) the_ATI mechanism_NN responsible_JJ for_IN the_ATI decreasing_VBG prevalence_NN is_BEZ not_XNOT known_VBN but_CC may_MD involve_VB changes_NNS in_IN health_NN , hygiene_NN , socioeconomic_JJ condition_NN , antibiotic_JJ usage_NN , and_CC cohort_NN effect_NN the_ATI impact_NN of_IN this_DT decreasing_JJ prevalence_NN on_IN gastrointestinal_JJ tract_NN diseases_NNS (_( ie_NN , ulcers_NNS , gastric_JJ cancer_NN )_) is_BEZ under_IN investigation_NN 144_CD NATURAL_NP COURSE_NP 145_CD inoculation_NN with_IN H_ZZ pylori_NN results_NNS in_IN acute_JJ symptomatic_JJ gastritis_NN with_IN hypochlorhydria_NN in_IN many_AP subjects_NNS although_CS spontaneous_JJ clearance_NN presumably_RB occurs_VBZ , many_AP , if_CS not_XNOT most_QL , of_IN these_DTS patients_NNS will_MD develop_VB chronic_JJ gastritis_NN (_( which_WDTR is_BEZ not_XNOT symptomatic_JJ )_) associated_VBN with_IN normal_JJ acid_NN production_NN the_ATI infection_NN appears_VBZ to_TO remain_VB stable_JJ , with_IN little_JJ change_NN in_IN the_ATI gastritis_NN or_CC antibody_NN titers_NNS over_IN time_NN , and_CC infection_NN probably_RB persists_VBZ for_IN decades_NNS , if_CS not_XNOT for_IN life_NN however_RB , eradication_NN of_IN the_ATI organism_NN does_DOZ result_NN in_IN improvement_NN or_CC healing_NN of_IN the_ATI gastritis_NN in_IN the_ATI majority_NN of_IN patients_NNS (_( see_VB below_IN )_) 146_CD GASTRITIS_NP 147_CD it_PP3 appears_VBZ that_CS H_ZZ pylori_NN is_BEZ the_ATI predominant_JJ cause_NN of_IN type_NN B_ZZ antral_JJ , or_CC environmental_JJ (_( vs_IN type_NN A_ZZ , or_CC autoimmune_NN )_) , gastritis_NN prevalence_NN of_IN H_ZZ pylori_NN in_IN subjects_NNS with_IN type_NN B_ZZ antral_JJ gastritis_NN approaches_NNS 100%_CD there_EX is_BEZ a_AT decreased_VBN prevalence_NN of_IN H_ZZ pylori_NN in_IN those_DTS with_IN a_AT specific_JJ gastritis_NN , such_ABL as_CS that_CS related_VBN to_TO alcohol_NN or_CC nonsteroidal_JJ anti-inflammatory_NN drug_NN ingestion_NN , lending_VBG credence_NN to_IN the_ATI association_NN of_IN H_ZZ pylori_NN and_CC type_NN B_ZZ gastritis_NN three_CD other_AP lines_NNS of_IN evidence_NN support_NN the_ATI hypothesis_NN that_CS H_ZZ pylori_NN causes_NNS gastritis_NN first_OD , acute_JJ inflammatory_JJ gastritis_NN developed_VBN in_IN volunteer_NN studies_NNS after_IN ingestion_NN of_IN H_ZZ pylori_NN However_NP , in_IN the_ATI case_NN of_IN one_CD1 volunteer_NN ingestion_NN , chronic_JJ active_JJ gastritis_NN persisted_VBD after_IN treatment_NN , so_QL future_NN human_JJ studies_NNS are_BER unlikely_JJ additionally_RB , accidental_JJ inoculation_NN during_IN the_ATI course_NN of_IN acid_NN secretory_NN studies_NNS resulted_VBD in_IN an_AT epidemic_NN of_IN gastritis_NN second_OD , animal_NN studies_NNS using_VBG a_AT gnotobiotic_JJ pig_NN model_NN resulted_VBD in_IN chronic_JJ inflammation_NN and_CC a_AT histologic_JJ picture_NN compatible_JJ with_IN human_JJ chronic_JJ active_JJ gastritis_NN 148_CD 24_CD finally_RB , it_PP3 appears_VBZ that_CS gastritis_NN resolves_VBZ after_IN treatment_NN and_CC subsequent_JJ eradication_NN of_IN H_ZZ pylori_NN studies_NNS with_IN bismuth_NN compounds_NNS showed_VBD improvement_NN or_CC disappearance_NN of_IN gastritis_NN after_IN eradication_NN of_IN the_ATI organism_NN however_RB , because_CS bismuth_NN may_MD have_HV effects_NNS on_IN the_ATI gastric_JJ mucosa_JJ independent_NN of_IN its_PP$ activity_NN against_IN H_ZZ pylori_NN , further_JJB studies_NNS using_VBG antibiotic_JJ combinations_NNS without_IN bismuth_NN were_BED performed_VBN , with_IN similar_JJ results_NNS thus_RB , it_PP3 appears_VBZ that_CS for_IN gastritis_NN , Koch's_NP$ postulates_NNS for_IN an_AT infecting_VBG organism_NN have_HV been_BEN fulfilled_VBN however_RB , chronic_JJ active_JJ gastritis_NN and_CC associated_VBN H_ZZ pylori_NN infection_NN are_BER common_JJ and_CC not_XNOT necessarily_RB associated_VBN with_IN symptoms_NNS 149_CD NONULCER_NP DYSPEPSIA_NP 150_CD there_EX are_BER conflicting_JJ data_NNS in_IN the_ATI literature_NN on_IN whether_CS nonulcer_NN dyspepsia_NN is_BEZ associated_VBN with_IN gastritis_NN or_CC H_ZZ pylori_NN infection_NN mechanisms_NNS by_IN which_WDTR gastritis_NN and_CC H_ZZ pylori_NN infection_NN could_MD result_VB in_IN symptoms_NNS of_IN dyspepsia_NN are_BER unclear_JJ however_RB , there_EX is_BEZ some_DTI evidence_NN that_CS inflammatory_JJ changes_NNS of_IN the_ATI gastric_JJ mucosa_NN result_NN in_IN a_AT motor_NN derangement_NN and_CC gastric_JJ emptying_VBG abnormalities_NNS , which_WDTR may_MD cause_VB upper_JJB gastrointestinal_JJ tract_NN symptoms_NNS the_ATI association_NN of_IN nonulcer_NN dyspepsia_NN and_CC chronic_JJ active_JJ gastritis_NN is_BEZ variable_JJ , occurring_VBG in_IN 30%_NP to_IN 70%_NP of_IN patients_NNS treatment_NN is_BEZ not_XNOT necessarily_RB associated_VBN with_IN clinical_JJ improvement_NN , and_CC many_AP investigators_NNS have_HV shown_VBN that_CS there_EX is_BEZ no_ATI association_NN between_IN either_DTX the_ATI finding_NN of_IN chronic_JJ gastritis_NN or_CC the_ATI symptoms_NNS of_IN dyspepsia.=20_CD 151_CD furthermore_RB , eradication_NN of_IN H_ZZ pylori_NN with_IN subsequent_JJ resolution_NN of_IN gastritis_NN does_DOZ not_XNOT alleviate_VB dyspeptic_JJ symptoms_NNS however_RB , efficacy_NN of_IN therapy_NN has_HVZ been_BEN variable_NN a_JJ few_AP studies_NNS have_HV shown_VBN that_CS dyspepsia_NN may_MD improve_VB after_IN the_ATI eradication_NN of_IN H_ZZ pylori_NN with_IN antimicrobial_JJ therapy_NN , but_CC the_ATI preponderance_NN of_IN evidence_NN does_DOZ not_XNOT support_VB the_ATI association_NN of_IN H_ZZ pylori_NN and_CC dyspeptic_JJ symptoms_NNS 152_CD DUODENAL_NP ULCER_NP 153_CD maintenance_NN of_IN gastric_JJ and_CC duodenal_JJ mucosal_JJ integrity_NN is_BEZ a_AT balance_NN between_IN mucosal_JJ defensive_JJ and_CC aggressive_JJ factors_NNS in_IN the_ATI past_NN we_PP1AS have_HV assumed_VBN that_CS aggressive_JJ factors_NNS consisted_VBD entirely_RB of_IN acid_NN and_CC pepsin_NN It_NP is_BEZ now_RN clear_JJ that_CS H_ZZ pylori_NN should_MD be_BE considered_VBN an_AT aggressive_JJ factor_NN and_CC may_MD also_RB affect_VB pathogenesis_NN via_IN alteration_NN of_IN mucosal_JJ defensive_JJ factors.=20_CD 154_CD the_ATI role_NN of_IN H_ZZ pylori_NN in_IN the_ATI causation_NN of_IN duodenal_JJ ulcer_NN is_BEZ supported_VBN by_IN the_ATI nearly_RB uni-_JJ versal_JJ finding_NN of_IN H_ZZ pylori_NN and_CC inflammation_JJ of_IN the_ATI gastric_JJ antrum_NN in_IN patients_NNS with_IN duodenal_JJ ulcer_NN (_( excluding_VBG those_DTS with_IN ulcers_NNS related_VBN to_IN nonsteroidal_JJ anti-inflammatory_NN drugs_NNS and_CC patients_NNS with_IN ulcers_NNS related_VBN to_TO gastrinoma_VB )_) this_DT association_NN among_IN H_ZZ pylori_NN , gastritis_NN , and_CC duodenal_JJ ulcer_NN disease_NN is_BEZ seen_VBN in_IN more_AP than_IN 90%_NP of_IN patients_NNS unfortunately_RB , no_ATI clinical_JJ clues_NNS are_BER reliable_JJ in_IN differentiating_VBG ulcers_NNS associated_VBN with_IN H._NP pylori_NN from_IN those_DTS secondary_JJ to_TO nonsteroidal_JJ anti-inflammatory_NN drugs_NNS or_CC gastrinoma_NN clearly_RB , concomitant_NN use_NN of_IN nonsteroidal_JJ anti-inflammatory_NN drugs_NNS or_CC lack_NN of_IN _** gastritis_NN _** on_IN a_AT biopsy_NN specimen_NN should_MD alert_JJ a_AT physician_NN that_CS another_DT cause_NN of_IN ulceration_NN is_BEZ likely_JJ 155_CD 31_CD one_CD1 pathogenic_JJ mechanism_NN that_WPR has_HVZ been_BEN hypothesized_VBN to_TO explain_VB duodenal_JJ ulceration_NN associated_VBN with_IN H_ZZ pylori_NN infection_NN is_BEZ an_AT increased_VBN postprandial_JJ gastrin_NN release_NN related_VBN to_IN the_ATI effect_NN of_IN H_ZZ pylori_NN on_IN antral_JJ endocrine_NN cells_NNS that_CS release_NN somatostatin_NN this_DT increase_NN in_IN gastrin_NN presumably_RB results_VBZ in_IN increased_JJ acid_NN delivery_NN to_IN the_ATI duodenal_JJ bulb_NN , resulting_JJ in_IN gastric_JJ metaplasia_NN , which_WDTR is_BEZ later_RBR colonized_VBN by_IN H_ZZ pylori_NN The_NP presence_NN of_IN H_ZZ pylori_NN in_IN this_DT metaplastic_JJ epithelium_NN causes_NNS a_AT secondary_JJ inflammatory_JJ process_NN and_CC subsequently_RB an_AT ulcer_NN 156_CD 32_CD however_RB , other_AP effects_NNS that_CS H_ZZ pylori_NN may_MD have_HV on_IN duodenal_JJ defensive_JJ factors_NNS , ie_NN , bicarbonate_NN secretion_NN , need_NN to_TO be_BE clarified_VBN , and_CC the_ATI exact_JJ pathogenic_JJ mechanism_NN of_IN H_ZZ pylori_NN remains_VBZ unknown_JJ 157_CD 33_CD further_JJB evidence_NN supporting_VBG the_ATI association_NN of_IN H_ZZ pylori_NN and_CC duodenal_JJ ulcer_NN is_BEZ that_CS eradication_NN of_IN the_ATI organism_NN results_NNS in_IN markedly_RB reduced_JJ rates_NNS of_IN ulcer_NN relapse_NN compared_VBN with_IN findings_NNS in_IN patients_NNS treated_VBN with_IN conventional_JJ antisecretory_NN therapy_NN (_( ie_NN , histamine_NN sub_NN 2_CD blockers_NNS )_) relapse_NN rates_NNS in_IN those_DTS in_IN whom_WPOR H_ZZ pylori_NN has_HVZ been_BEN eradicated_VBN range_NN between_IN 0%_NP and_CC 25%_NN , compared_VBD with_IN relapse_NN rates_NNS of_IN 70%_NP to_IN 90%_NP seen_VBN in_IN those_DTS treated_VBN with_IN more_QL conventional_JJ therapy_NN 158_CD 34_CD while_CS it_PP3 is_BEZ clear_JJ that_CS H_ZZ pylori_NN plays_NNS a_AT pivotal_JJ role_NN in_IN the_ATI pathogenesis_NN and_CC prevalence_NN of_IN duodenal_JJ ulcer_NN disease_NN , the_ATI exact_JJ mechanism_NN by_IN which_WDTR infection_NN of_IN the_ATI gastric_JJ antrum_NN contributes_VBZ to_TO duodenal_JJ ulceration_NN and_CC the_ATI ideal_JJ form_NN of_IN therapy_NN for_IN duodenal_JJ ulcers_NNS remains_VBZ problematic_JJ (_( see_VB the_ATI _** Treatment_NP _** section_NN )_) 159_CD 35_CD GASTRIC_NP ULCERS_NP 160_CD 36_CD as_IN with_IN duodenal_JJ ulcer_NN , nearly_RB 100%_CD of_IN patients_NNS with_IN gastric_JJ ulcers_NNS who_WPR are_BER not_XNOT taking_VBG nonsteroidal_JJ anti- inflammatory_NN drugs_NNS have_HV evidence_NN of_IN H_ZZ pylori_NN infection_NN although_CS gastric_JJ ulcer_NN has_HVZ not_XNOT been_BEN nearly_RB as_CS well_RB studied_VBN as_IN duodenal_JJ ulcer_NN disease_NN , it_PP3 appears_VBZ that_CS eradication_NN of_IN H_ZZ pylori_NN in_IN patients_NNS with_IN gastric_JJ ulcers_NNS also_RB markedly_RB diminishes_VBZ rates_NNS of_IN relapse_NN once_RB again_RB , the_ATI mechanism_NN by_IN which_WDTR H_ZZ pylori_NN produces_VBZ gastric_JJ ulceration_NN and_CC the_ATI ideal_JJ form_NN of_IN therapy_NN for_IN this_DT infection_NN is_BEZ unclear_JJ 161_CD 37_CD GASTRIC_NP CANCER_NP 162_CD 38_CD three_CD lines_NNS of_IN evidence_NN support_VB the_ATI association_NN of_IN gastric_JJ cancer_NN and_CC infection_NN with_IN H_ZZ pylori_NN first_OD , populations_NNS at_IN increased_JJ risk_NN of_IN developing_VBG gastric_JJ cancer_NN have_HV higher_JJR prevalence_JJ rates_NNS of_IN H_ZZ pylori_NN in_IN all_ABN age_NN groups_NNS second_OD , precursor_NN histologic_JJ lesions_NNS known_VBN to_TO be_BE present_JJ before_IN the_ATI development_NN of_IN gastric_JJ cancer_NN are_BER also_RB associated_VBN with_IN H_ZZ pylori_NN infection_NN third_OD , in_IN numerous_JJ epidemiologic_JJ studies_NNS gastric_JJ cancer_NN has_HVZ been_BEN shown_VBN to_TO be_BE strongly_RB associated_VBN with_IN H_ZZ pylori_NN infection_NN in_IN two_CD of_IN these_DTS studies_NNS , infection_NN with_IN H_ZZ pylori_NN was_BEDZ documented_VBN by_IN serologic_JJ analysis_NN more_AP than_IN a_AT decade_NN before_IN the_ATI development_NN of_IN cancer_NN 163_CD 39_CD the_ATI purported_VBN mechanism_NN of_IN H_ZZ pylori_NN in_IN gastric_JJ carcinogenesis_NN is_BEZ related_VBN to_IN the_ATI superficial_JJ and_CC chronic_JJ active_JJ gastritis_NN that_CS occurs_VBZ in_IN response_NN to_IN infection_NN some_DTI patients_NNS , in_IN response_NN to_IN this_DT chronic_JJ inflammatory_JJ process_NN , will_MD subsequently_RB develop_VB gastric_JJ atrophy_RB , a_AT process_NN that_WPR may_MD occur_VB over_IN many_AP decades_NNS gastric_JJ atrophy_RB is_BEZ known_VBN to_TO be_BE associated_VBN with_IN increased_VBN epithelial_JJ cell_NN proliferation_NN ; coupled_VBN with_IN dietary_JJ factors_NNS , environmental_JJ factors_NNS , and_or_CC mutational_JJ events_NNS , this_DT may_MD result_VB in_IN the_ATI _** fertile_JJ field_NN _** necessary_JJ for_IN the_ATI carcinogenesis_NN to_TO occur_VB 164_CD 40_CD further_JJB work_NN along_IN these_DTS lines_NNS documenting_VBG the_ATI epidemiologic_JJ association_NN and_CC the_ATI carcinogenic_JJ mechanism_NN involved_VBN may_MD lead_VB to_TO intervention_NN and_CC prevention_NN of_IN gastric_JJ cancer_NN at_IN the_ATI present_JJ time_NN there_EX is_BEZ no_ATI clinical_JJ role_NN for_IN eradication_NN of_IN H_ZZ pylori_NN in_IN cancer_NN prevention_NN , even_RB in_IN _** high-risk_NN _** subjects_NNS 165_CD 41_CD DIAGNOSIS_NP 166_CD 42_CD diagnosis_NN of_IN H_ZZ pylori_NN uses_VBZ a_AT variety_NN of_IN noninvasive_JJ and_CC invasive_JJ tests_NNS (_( Table_NP 1_CD1 )_) the_ATI carbon_NN 13_CD and_CC carbon_NN 14_CD urea_NN breath_NN tests_NNS take_VB advantage_NN of_IN the_ATI fact_NN that_CS the_ATI organism_NN possesses_VBZ a_AT potent_JJ urease_NN enzyme_NN the_ATI subject_NN ingests_NNS radiolabeled_JJ urea_NN , which_WDTR , in_IN the_ATI presence_NN of_IN this_DT bacterial_JJ urease_NN , results_VBZ in_IN the_ATI formation_NN of_IN ammonium_NN and_CC radiolabeled_JJ bicarbonate_NN this_DT bicarbonate_NN is_BEZ readily_RB absorbed_VBN into_IN the_ATI bloodstream_NN , and_CC the_ATI radiolabeled_JJ carbon_NN is_BEZ excreted_VBN in_IN the_ATI breath_NN in_IN the_ATI form_NN of_IN carbon_NN dioxide_NN in_IN the_ATI Carbon-14_CD-CD breath_NN test_NN , Carbon-14_CD-CD is_BEZ detected_VBN by_IN scintillation_NN counter_NN , whereas_CS in_IN the_ATI Carbon- 13_CD-CD breath_NN test_NN , mass_NN spectrography_NN is_BEZ used_VBN the_ATI sensitivity_NN and_CC specificity_NN of_IN these_DTS breath_NN tests_NNS is_BEZ 90%_NP to_TO 95%_VB .=20_CD 167_CD 43_CD advantages_NNS of_IN the_ATI breath_NN tests_NNS are_BER their_PP$ simplicity_NN and_CC noninvasiveness_NN as_QL well_RB as_IN the_ATI minimal_JJ radiation_NN exposure_NN that_CS occurs_VBZ with_IN Carbon-14_CD-CD however_RB , the_ATI test_NN does_DOZ require_VB fasting_NN , and_CC false- negative_JJ results_NNS may_MD occur_VB if_CS antibiotics_NNS have_HV been_BEN used_VBN within_IN the_ATI previous_JJ 4_CD weeks_NNS additionally_RB , false-positive_JJ results_NNS can_MD occur_VB from_IN urease_JJ present_NN in_IN the_ATI mouth_NN , but_CC this_DT can_MD be_BE diminished_VBN by_IN toothbrushing_VBG before_IN testing_NN although_CS this_DT test_NN is_BEZ currently_RB available_JJ only_RB as_IN a_AT research_NN tool_NN , its_PP$ availability_NN as_IN a_AT routine_JJ clinical_JJ test_NN is_BEZ expected_VBN in_IN the_ATI near_IN future_NN 168_CD 44_CD helicobacter_NN pylori_NN urease_NN activity_NN can_MD also_RB be_BE used_VBN to_TO diagnose_VB infection_NN by_IN measuring_VBG the_ATI gastric_JJ ammonia- urea_NN ratio_NN the_ATI presence_NN of_IN bacterial_JJ urease_NN results_NNS in_IN an_AT increased_JJ ratio_NN of_IN ammonia_NN (_( result_NN of_IN urease_NN activity_NN on_IN urea_NN )_) to_TO urea_VB with_IN eradication_NN of_IN H_ZZ pylori_NN , urease_NN activity_NN decreases_VBZ and_CC the_ATI ammonia-urea_NN ratio_NN falls_VBZ to_TO normal_JJ 169_CD 45_CD urease_NN activity_NN can_MD also_RB be_BE detected_VBN within_IN a_AT mucosal_JJ biopsy_NN specimen_NN obtained_VBN at_IN the_ATI time_NN of_IN endoscopy_NN the_ATI specimen_NN is_BEZ placed_VBN within_IN a_AT urea_NN gel_NN or_CC broth_NN that_CS contains_VBZ a_AT pH_NN detector_NN (_( most_QL commonly_RB phenol_JJ red_JJ )_) ; if_CS the_ATI specimen_NN contains_VBZ H_ZZ pylori_NN , its_PP$ urease_NN will_MD form_VB ammonia_NN , resulting_JJ in_IN an_AT increased_JJ pH_NN and_CC a_AT distinctive_JJ color_NN change_NN (_( Clotest_JJT , Trimed_NP Specialties_NP Inc_JNP , Lenexa_NP , Kan_NP )_) this_DT test_NN can_MD be_BE read_VB within_IN 2_CD to_IN 3_CD hours_NNS , and_CC two_CD thirds_NNS of_IN the_ATI tests_NNS will_MD become_VB positive_JJ within_IN 30_CD minutes_NNS the_ATI sensitivity_NN and_CC specificity_NN of_IN this_DT test_NN is_BEZ 90%_NP to_TO 98%_VB false-negative_JJ results_NNS can_MD occur_VB secondary_JJ to_TO sampling_NN artifact_NN or_CC a_AT low_JJ inoculum_NN of_IN bacteria_NNS in_IN the_ATI sample_NN 170_CD 46_CD mucosal_JJ biopsy_NN can_MD also_RB be_BE used_VBN to_TO detect_VB the_ATI infection_NN Originally_NP , the_ATI Warthin-Starry_NP silver_NN stain_NN was_BEDZ commonly_RB used_VBN ; however_RB , the_ATI Giemsa_NP stain_NN is_BEZ simpler_JJR to_TO perform_VB and_CC also_RB allows_VBZ the_ATI pathologist_NN to_TO determine_VB the_ATI histologic_JJ characteristics.=20_CD 171_CD 47_CD its_PP$ simplicity_NN and_CC ease_NN of_IN use_NN make_NN Giemsa_NP the_ATI stain_NN of_IN choice_NN for_IN detecting_JJ H_ZZ pylori_NN however_RB , with_IN experience_NN , H_ZZ pylori_NN can_MD be_BE readily_RB detected_VBN with_IN routine_NN hematoxylin-eosin_NN staining_NN biopsy_NN of_IN the_ATI antrum_NN of_IN the_ATI stomach_NN results_NNS in_IN the_ATI greatest_JJT yield_NN , and_CC the_ATI performance_NN of_IN two_CD endoscopic_JJ biopsies_NNS also_RB significantly_RB increases_VBZ detection_NN of_IN H_ZZ pylori_NN 172_CD 48_CD diagnosis_NN can_MD also_RB be_BE made_VBN by_IN culture_NN of_IN mucosal_JJ biopsy_NN specimens_NNS advantages_NNS of_IN culture_NN include_VB the_ATI establishment_NN of_IN antibiotic_JJ sensitivities_NNS if_CS treatment_NN is_BEZ indicated_VBN biopsy_NN specimens_NNS need_NN to_TO be_BE placed_VBN into_IN supplemented_VBN selected_JJ media_NNS , such_IN as_IN chocolate_NN agar_NN , to_TO which_WDTR antibiotics_NNS have_HV been_BEN added_VBN to_TO prevent_VB other_AP bacterial_JJ overgrowth_NN the_ATI organism_NN requires_VBZ a_AT warm_JJ , humid_JJ microaerophilic_JJ environment_NN for_IN optimal_JJ growth_NN sensitivities_NNS for_IN cultures_NNS are_BER 70%_NP to_TO 95%_VB , with_IN a_AT specificity_NN of_IN 100%_CD if_CS metronidazole_NN resistance_NN becomes_VBZ widespread_JJ , then_RN the_ATI use_NN of_IN culture_NN and_CC sensitivity_NN may_MD become_VB necessary_JJ in_IN routine_NN clinical_JJ practice_NN 173_CD 49_CD diagnosis_NN via_IN serologic_JJ studies_NNS is_BEZ possible_JJ through_IN the_ATI detection_NN of_IN antibodies_NNS produced_VBN against_IN high-molecular-weight_NN cell_NN proteins_NNS of_IN the_ATI outer_JJB membrane_NN of_IN the_ATI organism_NN initially_RB , antibodies_NNS were_BED detected_VBN by_IN enzyme-linked_JJ immunosorbent_NN assay_NN against_IN whole_JJ extracts_NNS of_IN the_ATI organism_NN ; however_RB , these_DTS serologic_JJ tests_NNS were_BED less_QL sensitive_JJ and_CC specific_JJ than_IN the_ATI newer_JJR antibodies_NNS against_IN high-molecular-weight_NN cell_NN proteins_NNS however_RB , positive_JJ tests_NNS indicate_VB both_ABX current_JJ infection_NN as_QL well_RB as_IN old_JJ infection_NN thus_RB , serologic_JJ tests_NNS are_BER valuable_JJ as_IN an_AT epidemiologic_JJ tool_NN but_CC are_BER suboptimal_VBN in_IN individual_JJ case_NN testing_NN serologic_JJ testing_NN may_MD be_BE used_VBN after_IN therapy_NN for_IN H_ZZ pylori_NN Successful_JJ eradication_NN of_IN the_ATI organism_NN results_NNS in_IN a_AT progressive_JJ fall_NN in_IN antibody_NN titer_NN , and_CC this_DT titration_NN of_IN the_ATI serum_NN antibody_NN response_NN can_MD be_BE useful_JJ in_IN assessing_VBG the_ATI efficacy_NN of_IN therapy_NN for_IN H_ZZ pylori_NN sensitivity_NN and_CC specificity_NN of_IN the_ATI newer_JJR antibody_NN tests_NNS is_BEZ greater_JJR than_IN 90%_NP 174_CD 50_CD TREATMENT_NP 175_CD 51_CD the_ATI treatment_NN of_IN H_ZZ pylori_NN and_CC associated_VBN gastrointestinal_JJ tract_NN disease_NN has_HVZ been_BEN an_AT extraordinarily_RB controversial_JJ subject_NN at_IN the_ATI present_JJ time_NN , it_PP3 is_BEZ appropriate_JJ to_TO treat_VB only_RB H_ZZ pylori_NN associated_VBN with_IN duodenal_JJ or_CC gastric_JJ ulcers_NNS ongoing_VBG randomized_VBN controlled_JJ studies_NNS looking_VBG at_IN the_ATI effect_NN of_IN H_ZZ pylori_NN treatment_NN and_CC eradication_NN on_IN the_ATI occurrence_NN of_IN gastric_JJ cancer_NN in_IN high-risk_NN populations_NNS will_MD eventually_RB answer_VB the_ATI question_NN of_IN whether_CS or_CC not_XNOT patients_NNS at_IN high_JJ risk_NN for_IN gastric_JJ cancer_NN also_RB should_MD be_BE treated_VBN 176_CD 52_CD the_ATI goal_NN of_IN therapy_NN in_IN treating_VBG patients_NNS with_IN peptic_JJ ulcer_NN disease_NN and_CC H_ZZ pylori_NN is_BEZ eradication_JJ of_IN the_ATI organism_NN because_CS of_IN the_ATI complexity_NN and_CC side_NN effects_NNS of_IN the_ATI regimens_NNS described_VBN below_IN and_CC the_ATI availability_NN of_IN other_AP effective_JJ therapies_NNS for_IN ulcer_NN disease_NN (_( eg_NN , histamine_NN sub_NN 2_CD blockers_NNS , sucralfate_NN , antacids_NNS , proton_NN pump_NN inhibitors_NNS )_) , the_ATI treatment_NN of_IN H_ZZ pylori_NN in_IN the_ATI setting_NN of_IN peptic_JJ ulcer_NN disease_NN remains_VBZ an_AT option_NN for_IN any_DTI patient_NN with_IN a_AT peptic_JJ ulcer_NN who_WPR has_HVZ H_ZZ pylori_NN although_CS most_AP studies_NNS have_HV focused_VBN on_IN patients_NNS with_IN duodenal_JJ ulcer_NN , those_DTS with_IN gastric_JJ ulcer_NN probably_RB respond_VB as_IN well_RB to_TO eradication_NN of_IN the_ATI organism_NN Recurrence_NP of_IN ulcer_NN disease_NN is_BEZ rare_JJ after_IN eradication_NN and_CC healing_NN of_IN the_ATI ulcer_NN (_( {_( 10%_CD per_NNU year_NN )_) , reflecting_VBG the_ATI low_JJ reinfection_NN rate_NN with_IN H_ZZ pylori_NN in_IN this_DT population_NN (_( 1%_CD to_TO 2%_VB per_NNU year_NN )_) in_IN patients_NNS with_IN recurrent_JJ , recalcitrant_JJ , or_CC complicated_JJ ulcer_NN disease_NN , H_ZZ pylori_NN eradication_NN therapy_NN may_MD be_BE the_ATI most_QL appropriate_JJ treatment.=20_CD 177_CD 53_CD there_EX is_BEZ recent_JJ evidence_NN that_CS in_IN patients_NNS presenting_VBG with_IN bleeding_JJ peptic_JJ ulcers_NNS , H_ZZ pylori_NN eradication_NN decreased_VBD rebleeding_VBG associated_VBN with_IN later_RBR ulcer_NN recurrence_NN , although_CS this_DT preliminary_JJ finding_VBG needs_NNS confirmation_NN in_IN large_JJ clinical_JJ trials_NNS as_CS safer_JJR and_CC simpler_JJR regimens_NNS become_VB available_JJ with_IN the_ATI development_NN of_IN novel_NN antimicrobial_JJ agents_NNS , it_PP3 may_MD be_BE appropriate_JJ to_TO treat_VB all_ABN presentations_NNS of_IN peptic_JJ ulcer_NN disease_NN as_IN infectious_JJ disease_NN whether_CS patients_NNS who_WPR are_BER positive_JJ for_IN H_ZZ pylori_NN and_CC taking_VBG nonsteroidal_JJ anti-inflammatory_NN drugs_NNS respond_VB to_TO H_ZZ pylori_NN therapy_NN is_BEZ unknown_JJ , and_CC this_DT cannot_NN be_BE recommended_VBN as_IN a_AT treatment_NN option_NN at_IN this_DT time_NN 178_CD 54_CD there_EX are_BER no_ATI data_NNS at_IN this_DT time_NN to_TO support_VB H_ZZ pylori_NN eradication_NN as_IN a_AT treatment_NN of_IN nonulcer_NN dyspepsia_NN or_CC gastritis_NN or_CC to_TO prevent_VB gastric_JJ cancer_NN 179_CD 55_CD although_CS H_ZZ pylori_NN shows_VBZ in_IN vitro_NN susceptibility_NN to_TO most_QL antibiotics_NNS , this_DT does_DOZ not_XNOT translate_VB into_IN in_RB vivo_RB effectiveness_NN this_DT dichotomy_NN may_MD result_VB from_IN a_AT variety_NN of_IN reasons_NNS , including_IN the_ATI fact_NN that_CS the_ATI bacteria_NNS reside_VB below_IN the_ATI mucous_JJ layer_NN and_CC thus_RB have_HV a_AT decreased_VBN exposure_NN to_IN luminal_JJ concentrations_NNS of_IN antibiotics_NNS in_IN addition_NN , resistance_NN to_IN single_JJ antibiotic_JJ agents_NNS develops_VBZ rapidly_RB , and_CC metronidazole_NN resistance_NN may_MD be_BE seen_VBN in_IN as_QL many_AP as_CS 30%_NP of_IN strains_NNS Probably_NP the_ATI most_QL common_JJ cause_NN of_IN failure_NN to_TO eradicate_VB H_ZZ pylori_NN is_BEZ noncompliance_NN with_IN these_DTS complex_JJ regimens_NNS additionally_RB , side_NN effects_NNS may_MD be_BE seen_VBN in_IN up_RP to_IN 30%_NP of_IN patients_NNS treated_VBN with_IN the_ATI regimens_NNS described_VBN below_RI 180_CD 56_CD the_ATI most_AP effective_JJ regimen_NNS for_IN eradicating_VBG H_ZZ pylori_NN has_HVZ been_BEN bismuth_NN and_CC two_CD antibiotics_NNS the_ATI regimen_NNS with_IN the_ATI greatest_JJT success_NN rate_NN is_BEZ tetracycline_NN (_( 2_CD g_d_NN )_) , metronidazole_NN (_( 750_CD mg_d_NN )_) , and_CC bismuth_NN (_( eight_CD tablets_NNS per_NNU day_NN )_) for_IN 2_CD weeks_NNS , which_WDTR results_VBZ in_IN an_AT eradication_JJ rate_NN of_IN 90%_NP in_IN those_DTS intolerant_JJ of_IN tetracycline_NN , amoxicillin_NN can_MD be_BE substituted_VBN with_IN nearly_RB equal_JJ efficacy_NN antibiotics_NNS without_IN bismuth_NN can_MD also_RB eradicate_VB H_ZZ pylori_NN in_IN 90%_NP of_IN patients_NNS .=20_CD 181_CD 57_CD newer_JJR regimens_NNS include_VB the_ATI use_NN of_IN omeprazole_NN and_CC such_ABL antibiotics_NNS as_IN amoxicillin_NN or_CC clarithromycin_NN ; these_DTS result_NN in_IN eradication_JJ rates_NNS of_IN 60%_NP to_IN 80%_NP and_CC appear_VB to_TO be_BE much_RB better_JJR tolerated_VBN Thus_JJ , these_DTS regimens_NNS are_BER currently_RB used_VBN by_IN many_AP physicians_NNS as_IN the_ATI treatment_NN regimens_NNS of_IN choice_NN reinfection_NN after_IN eradication_NN is_BEZ unusual_JJ , and_CC so_PN maintenance_NN therapy_NN is_BEZ unnecessary_JJ this_DT approach_NN to_TO therapy_NN should_MD be_BE more_QL cost-effective_JJ than_IN the_ATI standard_NN (_( antisecretory_NN agents_NNS )_) therapy_NN , which_WDTR requires_VBZ frequent_JJ retreatment_NN or_CC maintenance_NN therapy_NN as_CS well_RB as_IN continued_VBD use_NN of_IN medical_JJ resources_NNS 182_CD viral_JJ Imitations_NNS of_IN Host_NPT Defense_NP Proteins_NP : flattery_NN That_NP Turns_NNS to_IN Battery_NP 183_CD a_AT 40-year-old_JJB Indian_JNP woman_NN with_IN Takayasu's_NP$ arteritis_NN presented_VBN to_TO the_ATI National_NP Naval_NPT Medical_NP Center_NP with_IN chest_NN pain_NN of_IN 1_CD1 day's_NN$ duration_NN One_NP year_NN previously_RB , she_PP3A had_HVD presented_VBN with_IN malaise_NN , diminished_VBD left_VBN upper_JJB extremity_NN pulses_NNS , and_CC an_AT elevated_VBD erythrocyte_NN sedimentation_NN rate_NN A_ZZ diagnosis_NN of_IN Takayasu's_NP$ arteritis_NN had_HVD been_BEN made_VBN by_IN angiographic_JJ demonstration_NN of_IN stenosis_NN of_IN the_ATI left_NN subclavian_JJ artery_NN she_PP3A had_HVD been_BEN treated_VBN initially_RB with_IN 1_CD1 mg_kg_CD per_NNU day_NN of_IN prednisone_NN with_IN angiographically_RB evident_JJ improvement_NN , and_CC the_ATI drug_NN dosage_NN had_HVD been_BEN tapered_JJ over_IN the_ATI past_NN year_NN to_IN 10_CD mg_NNU of_IN prednisone_NN every_AT other_AP day_NN 184_CD on_IN the_ATI day_NN of_IN admission_NN she_PP3A noted_VBD constant_JJ , sharp_JJ left_JJ chest_NN pain_NN without_IN radiation_NN and_CC without_IN dyspnea_NN her_PP$ past_NN medical_JJ history_NN was_BEDZ otherwise_RB unremarkable_JJ the_ATI physical_JJ examination_NN revealed_VBN a_AT woman_NN who_WPR appeared_VBD well_RB nourished_VBN her_PP$ temperature_NN was_BEDZ 38.5_CD degrees_NNS C_ZZ orally_RB her_PP$ heart_NN rate_NN was_BEDZ 92_CD beats_VBZ per_NNU minute_NN , and_CC her_PP$ blood_NN pressure_NN was_BEDZ 126_78_CD mm_UH Hg_&FO the_ATI physical_JJ examination_NN produced_VBN entirely_RB normal_JJ results_NNS except_CS for_IN slightly_RB diminished_VBN left_VBN upper_JJB extremity_NN pulses_NNS that_CS were_BED unchanged_JJ from_IN the_ATI previous_JJ month_NN results_NNS of_IN blood_NN analysis_NN were_BED normal_JJ except_CS for_IN an_AT erythrocyte_NN sedimentation_JJ rate_NN of_IN 52_CD mm_h_NN and_CC a_AT white_JJ blood_NN cell_NN count_NN of_IN 11.3x10_CD sup_VB 9_L_NN with_IN a_AT normal_JJ differential_JJ the_ATI electrocardiogram_NN was_BEDZ normal.=20_CD 185_CD on_IN the_ATI second_OD hospital_NN day_NN , several_AP vesicles_NNS appeared_VBD in_IN the_ATI left_NN T-7_NP dermatomal_JJ distribution_NN the_ATI mucous_JJ membranes_NNS and_CC other_AP dermatomes_NNS remained_VBD normal_JJ the_ATI results_NNS of_IN a_AT Tzanck_NP test_NN were_BED positive_JJ , and_CC a_AT clinical_JJ diagnosis_NN of_IN localized_JJ varicella-zoster_NN virus_NN (_( VZV_NP )_) infection_NN was_BEDZ made_VBN since_IN the_ATI patient_NN was_BEDZ considered_VBN to_TO be_BE at_IN low_JJ risk_NN for_IN dissemination_NN , treatment_NN with_IN acyclovir_NN was_BEDZ withheld_VBN and_CC oral_JJ analgesics_NNS were_BED given_VBN for_IN pain_NN a_AT culture_NN of_IN the_ATI vesicular_NN fluid_NN confirmed_VBN the_ATI diagnosis_NN the_ATI vesicles_NNS healed_VBN during_IN the_ATI next_AP several_AP weeks_NNS 186_CD CASE_NP DISCUSSION_NP 187_CD in_IN an_AT article_NN entitled_VBN _** Viral_NP Quasispecies_NNS _** published_VBN in_IN Scientific_NP American_JNP in_IN 1993_CD , Nobel_NP laureate_NN Manfred_NP Eigen_NP wrote_VBD : _** according_IN to_TO Greek_JNP mythology_NN , when_WRB curious_JJ Pandora_NP opened_VBD a_AT forbidden_JJ box_NN she_PP3A set_VBD loose_JJ all_ABN the_ATI miseries_NNS and_CC evils_NNS known_VBN to_IN the_ATI world_NN one_CD1 of_IN them_PP3OS was_BEDZ undoubtedly_RB the_ATI virus-the_NN very_QL name_NN of_IN which_WDTR is_BEZ Latin_JNP for_IN slime_NN , poison_NN and_CC stench_NN _** later_RBR , somewhat_RB more_QL prosaically_RB , he_PP3A wrote_VBD , _** Essentially_NP , a_AT virus_NN is_BEZ a_AT genetic_JJ program_NN that_CS carries_VBZ the_ATI simple_JJ message_NN '_**' Reproduce_NP me_PP1O !_! '_**' from_IN one_CD1 cell_NN to_IN another.=20_CD 188_CD Eigen_NP has_HVZ captured_VBN the_ATI essential_JJ paradox_NN of_IN the_ATI virus_NN : how_WRB can_MD something_PN so_QL helpless_JJ and_CC dependent_JJ do_DO so_QL much_AP damage_NN to_IN its_PP$ host_NN ? the_ATI case_NN presented_VBN herein_RB illustrates_VBZ the_ATI complex_JJ relationship_NN that_CS certain_JJ viruses_NNS may_MD have_HV with_IN their_PP$ hosts_NNS varicella-zoster_NN virus_NN is_BEZ a_AT herpesvirus_VBN in_IN which_WDTR the_ATI first_OD disease_NN manifestation_NN on_IN invading_JJ the_ATI human_JJ host_NN is_BEZ varicella_JJ (_( chickenpox_NN )_) , usually_RB occurring_VBG in_IN childhood_NN The_NP virus_NN then_RN becomes_VBZ latent_JJ in_IN the_ATI ganglia_NNS , only_RB to_TO reemerge_VB most_QL commonly_RB in_IN a_AT dermatomal_JJ distribution_NN as_IN zoster_NN (_( shingles_NNS )_) later_RBR in_IN life_NN , or_CC sometimes_RB as_IN disseminated_VBN infection_NN when_WRB the_ATI immune_JJ system_NN is_BEZ severely_RB depressed_JJ how_WRB do_DO all_ABN viral_JJ pathogens_NNS elude_VB the_ATI immune_JJ system_NN initially_RB , and_CC how_WRB do_DO viruses_NNS like_IN VZV_NP survive_VB for_IN so_QL long_RB in_IN the_ATI host?=20_CD 189_CD although_CS specific_JJ mechanisms_NNS of_IN pathogenesis_NN are_BER poorly_RB understood_VBN for_IN most_QL viruses_NNS , one_CD1 particularly_RB interesting_JJ strategy_NN that_WPR may_MD have_HV general_JJ relevance_NN involves_VBZ the_ATI ability_NN of_IN viruses_NNS to_TO copy_VB key_NN host_NN genes_NNS to_TO subvert_VB host_NN functions_NNS this_DT strategy_NN , which_WDTR was_BEDZ first_OD identified_VBN for_IN the_ATI oncogenes_NNS of_IN acutely_RB transforming_VBG retroviruses_NNS by_IN J._NP Michael_NP Bishop_NPT , MD_NP , and_CC Harold_NP Varmus_JJ , MD_NP , 15_CD years_NNS ago_RB , is_BEZ now_RN known_VBN to_TO be_BE used_VBN by_IN DNA_NP viruses_NNS as_IN well_RB all_ABN of_IN the_ATI DNA_NP virus_NN examples_NNS have_HV been_BEN discovered_VBN within_IN the_ATI past_JJB 5_CD years_NNS , and_CC so_PN far_RB all_ABN of_IN them_PP3OS come_VB from_IN the_ATI poxviruses_NNS and_CC herpesviruses_NNS interestingly_RB , most_AP of_IN the_ATI products_NNS of_IN the_ATI pirated_NN genes_NNS of_IN DNA_NP viruses_NNS mimic_VB key_NN regulatory_JJ molecules_NNS of_IN the_ATI immune_JJ system_NN 190_CD among_IN all_ABN known_VBN viral_JJ protein_NN sequences_NNS , only_RB a_AT small_JJ number_NN have_HV significant_JJ sequence_NN similarity_NN to_IN cellular_JJ proteins_NNS (_( Table_NP 1_CD1 )_) of_IN these_DTS , the_ATI majority_NN are_BER proteins_NNS involved_VBN in_IN regulating_VBG cell_NN growth_NN or_CC in_IN host_NN defense_NN the_ATI former_AP are_BER found_VBN primarily_RB among_IN the_ATI oncogenic_JJ RNA_NP retroviruses_NNS , whereas_CS the_ATI latter_AP are_BER found_VBN primarily_RB among_IN the_ATI DNA_NP poxviruses_NNS and_CC herpesviruses_NNS the_ATI sequence_NN relationship_NN of_IN the_ATI host_NN and_CC viral_JJ homologues_NNS for_IN the_ATI RNA_NP viruses_NNS is_BEZ very_QL strong_JJ , generally_RB more_AP than_IN 80%_NP amino_NN acid_NN identity_NN , yet_RB for_IN the_ATI DNA_NP viruses_NNS it_PP3 is_BEZ usually_RB weak_JJ , generally_RB less_AP than_IN 40%_NP amino_NN acid_NN identity.=20_CD 191_CD in_IN most_AP cases_NNS , the_ATI protein_NN sequences_NNS discovered_VBN separately_RB by_IN virologists_NNS and_CC cell_NN biologists_NNS have_HV been_BEN connected_VBN by_IN homology_NN searches_NNS of_IN protein_NN sequence_NN databases_NNS in_IN this_DT way_NN , the_ATI databases_NNS and_CC the_ATI algorithms_NNS that_CS analyze_NN them_PP3OS have_HV served_VBN as_IN a_AT computerized_VBN dating_VBG service_NN for_IN modern_JJ biology_NN , matching_JJ fields_NNS with_IN distinct_JJ pasts_NNS to_IN the_ATI promise_NN of_IN shared_VBD discovery_NN in_IN the_ATI future_NN 192_CD BARRIERS_NPT TO_NPT VIRAL_NP REPLICATION_NP 193_CD a_AT successful_JJ virus_NN must_MD first_OD penetrate_VB the_ATI host's_NP$ defenses_NNS and_CC then_RN redirect_VB the_ATI host's_NP$ cell_NN functions_NNS to_IN its_PP$ own_AP replicative_JJ advantage_NN this_DT is_BEZ true_JJ whether_CS the_ATI virus_NN infects_NNS a_AT bacterium_NN or_CC a_AT human_JJ being_BEG in_IN the_ATI case_NN of_IN bacteria_NNS , restriction_NN enzymes_NNS are_BER a_AT primitive_JJ but_CC effective_JJ immune_JJ system_NN that_CS works_NNS by_IN chopping_JJ up_RP viral_JJ DNA_NP before_CS it_PP3 can_MD be_BE transcribed_VBN or_CC replicated_VBN however_RB , the_ATI barriers_NNS that_DT must_MD be_BE overcome_VB for_IN the_ATI reproductive_JJ success_NN of_IN an_AT animal_NN virus_NN are_BER by_IN far_RB more_QL daunting_JJ and_CC diverse_JJ the_ATI virus_NN must_MD first_OD survive_VB physical_JJ threats_NNS such_ABL as_IN heat_NN , ultraviolet_NN radiation_NN , and_CC gastric_JJ acidity_NN then_RN it_PP3 must_MD get_VB past_NN the_ATI integument_NN and_CC elude_VB extracellular_JJ immune_JJ defenses_NNS such_IN as_IN complement-mediated_JJ lysis_NN and_CC antibody_NN neutralization_NN if_CS the_ATI virus_NN is_BEZ still_RB viable_JJ at_IN this_DT point_NN , it_PP3 must_MD find_VB a_AT way_NN to_TO attach_VB to_IN a_AT suitable_JJ host_NN cell_NN , penetrate_VB the_ATI plasma_NN membrane_NN , and_CC finally_RB commandeer_VB the_ATI host's_NP$ replicative_JJ machinery.=20_CD 194_CD inside_IN the_ATI cell_NN , the_ATI virus_NN must_MD hide_VB from_IN antigen- specific_JJ cytotoxic_JJ T_ZZ lymphocytes_NNS , which_WDTR home_NR in_RP on_IN the_ATI viral_JJ peptides_NNS displayed_VBN by_IN class_NN I_PP1A major_JJ histocompatibility_JJ complex_JJ (_( MHC_NP )_) molecules_NNS on_IN the_ATI surfaces_NNS of_IN infected_JJ cells_NNS the_ATI virus_NN must_MD also_RB neutralize_VB the_ATI potent_JJ antiviral_JJ and_CC proinflammatory_JJ effects_NNS of_IN cytokines_NNS such_IN as_IN tumor_NN necrosis_NN factor_NN (_( TNF_NP )_) , interleukin_NN 1_CD1 (_( IL-1_CD-CD )_) , and_CC interferon_NN gamma_NN (_( IFN-gamma_NP )_) finally_RB , it_PP3 must_MD come_VB to_IN terms_NNS with_IN its_PP$ own_AP virulence_NN , since_IN the_ATI death_NN of_IN the_ATI host_NN before_CS its_PP$ reproduction_NN may_MD be_BE a_AT Pyrrhic_JNP victory_NN for_IN the_ATI virus_NN the_ATI host-virus_JJ relationship_NN , developed_VBD over_IN evolutionary_JJ time_NN , can_MD range_VB from_IN all-out_JJB biological_JJ warfare_NN (_( humans_NNS and_CC smallpox_NN )_) to_IN peaceful_JJ coexistence_NN (_( swine_NNS and_CC swinepox_NN )_) 195_CD VIRAL_NPT WEAPONS_NPT AGAINST_NPT IMMUNOLOGIC_NPT DEFENSESOF_NPT THE_NP HOST_NP 196_CD all_ABN prospective_JJ pathogens_NNS must_MD counteract_VB both_ABX the_ATI general_JJ and_CC antigen-specific_JJ effector_JJ mechanisms_NNS of_IN the_ATI immune_JJ system_NN (_( Table_NP 2_CD )_) Known_NP viral_JJ strategies_NNS for_IN eluding_VBG antigen-recognition_NN molecules_NNS (_( antibody_NN and_CC T-cell_NP antigen_NN receptors_NNS )_) include_VB antigenic_JJ drift_NN and_CC the_ATI sabotage_NN of_IN antigen_NN presentation_NN pathways_NNS the_ATI influenza_NN A_ZZ hemagglutinin_NN and_CC neuraminidase_NN and_CC the_ATI human_JJ immunodeficiency_NN virus_NN envelope_NN protein_NN are_BER the_ATI best-documented_JJ examples_NNS of_IN how_WRB antigenic_JJ drift_NN may_MD enable_VB a_AT virus_NN to_TO escape_VB detection_NN by_IN the_ATI immune_JJ system_NN this_DT countermeasure_NN does_DOZ not_XNOT involve_VB pirating_VBG host_NN genes_NNS , however_RB 197_CD in_IN contrast_NN , the_ATI open_JJ reading_NN frame_NN UL18_CD of_IN the_ATI human_JJ cytomegalovirus_JJ (_( HCMV_NP )_) , a_AT beta_NN herpesvirus_JJ , encodes_NNS a_AT protein_NN that_WPR is_BEZ approximately_RB 20%_NP identical_JJ in_IN amino_NN acid_NN sequence_NN to_IN the_ATI variable_NN chain_NN of_IN mammalian_NN class_NN I_PP1A MHC_NP molecules_NNS the_ATI UL18_CD product_NN binds_VBZ to_IN cellular_JJ beta_NN sub_NN 2_CD -microglobulin_NN , the_ATI invariant_JJ chain_NN of_IN the_ATI class_NN I_PP1A molecule_VB essential_JJ for_IN transporting_VBG normal_JJ class_NN I_PP1A heterodimers_NNS to_IN the_ATI plasma_NN membrane_NN in_IN this_DT way_NN , deployment_NN of_IN fully_RB assembled_JJ class_NN I_PP1A molecules_NNS on_IN the_ATI cell_NN surface_NN is_BEZ prevented_VBN in_IN cells_NNS infected_VBN with_IN HCMV_NP , thereby_RB possibly_RB resulting_JJ in_IN defective_JJ antigen_NN presentation_NN to_IN cytotoxic_JJ T_ZZ lymphocytes_NNS 198_CD as_CS for_IN antigen-nonspecific_JJ effectors_NNS of_IN the_ATI immune_JJ system_NN , various_JJ viral_JJ countermeasures_NNS that_WPR involve_VB the_ATI pirating_NN of_IN host_NN genes_NNS have_HV been_BEN identified_VBN examples_NNS for_IN cytokines_NNS , cytokine_NN receptors_NNS , chemoattractant_NN receptors_NNS , and_CC complement_NN control_NN proteins_NNS have_HV been_BEN demonstrated_VBN these_DTS viral_JJ imitators_NNS may_MD modulate_VB intracellular_VB communication_NN in_IN at_RB least_RB two_CD ways_NNS (_( Figure_NP 1_CD1 )_) the_ATI first_OD way_NN involves_VBZ the_ATI disruption_NN by_IN poxvirus_JJ products_NNS of_IN communication_NN pathways_NNS that_CS lead_NN to_TO cytolysis_VB and_CC inflammation_NN the_ATI net_JJB result_NN of_IN this_DT disruption_NN is_BEZ decreased_VBN inflammation_NN at_IN infected_JJ sites_NNS and_CC increased_JJ virulence_NN in_RB vivo_RB , as_CS shown_VBN by_IN experiments_NNS with_IN recombinant_NN poxviruses_NNS that_CS specifically_RB lack_VB the_ATI gene_NN in_IN question.=20_CD 199_CD examples_NNS of_IN this_DT type_NN of_IN disruption_NN include_VB the_ATI IL- 1_CD-CD receptor_NN homologue_NN of_IN the_ATI vaccinia_NN virus_NN , the_ATI TNF_NP receptor_JJ homologues_NNS of_IN the_ATI myxoma_NN and_CC Shope_NP fibroma_NN viruses_NNS , the_ATI IFN-gamma_NP receptor_JJ homologue_NN of_IN the_ATI myxoma_NN virus_NN , the_ATI complement_NN control_NN protein_NN homologue_NN of_IN the_ATI vaccinia_NN virus_NN , a_AT serpin_NN (_( serine_NN protease_NN inhibitor_NN )_) homologue_NN of_IN the_ATI cowpox_NN virus_NN , and_CC the_ATI eukaryotic_JJ initiation_NN factor-2alpha_JJ homologue_NN of_IN the_ATI vaccinia_NN virus_NN 200_CD the_ATI respective_JJ poxviruses_NNS have_HV redesigned_VBN all_ABN the_ATI cytokine_NN receptor_NN homologues_NNS so_CS that_CS they_PP3AS lack_NN a_AT membrane_NN anchor_NN and_CC the_ATI cytoplasmic_JJ signaling_VBG domain_NN the_ATI cytokine_NN receptor_NN homologues_NNS are_BER therefore_RB secreted_VBN , ligand-binding_NN proteins_NNS incapable_JJ of_IN transmembrane_NN signal_NN transduction_NN the_ATI homologues_NNS appear_VB to_TO act_VB by_IN binding_JJ the_ATI respective_JJ cytokine_NN before_CS it_PP3 can_MD dock_NN to_IN its_PP$ cellular_JJ receptor_NN and_CC unload_VB its_PP$ antiviral_JJ signal_NN the_ATI complement_NN control_NN protein_NN homologue_NN of_IN the_ATI vaccinia_NN virus_NN binds_VBZ to_IN C4b_NP , thereby_RB halting_VBG the_ATI complement_NN cascade_NN , whether_CS it_PP3 is_BEZ activated_VBN by_IN classical_JJ or_CC alternative_JJ pathways_NNS the_ATI serpin_JJ homologue_NN of_IN the_ATI cowpox_NN virus_NN blocks_VBZ the_ATI action_NN of_IN the_ATI IL-1beta-converting_CD-CD enzyme_NN , a_AT cysteine_NN protease_NN that_CS cleaves_NNS an_AT inactive_JJ precursor_NN into_IN mature_JJ IL-1beta_CD-CD in_IN this_DT way_NN , the_ATI convertase_NN inhibitor_NN reduces_VBZ the_ATI concentration_NN of_IN mature_JJ IL-1beta_CD-CD , a_AT key_NN immunoregulatory_NN molecule_NN 201_CD the_ATI second_OD way_NN by_IN which_WDTR DNA_NP virus_NN imitators_NNS may_MD modulate_VB intracellular_NN communication_NN is_BEZ by_IN expropriating_VBG a_AT normal_JJ cell_NN communication_NN pathway_NN the_ATI most_QL thoroughly_RB studied_JJ example_NN is_BEZ for_IN the_ATI open_JJ reading_NN frame_NN BCRF1_CD of_IN the_ATI Epstein-Barr_NP virus_NN (_( EBV_NP )_) , which_WDTR encodes_VBZ a_AT fully_RB functional_JJ homologue_NN of_IN interleukin_NN 10_CD (_( IL-10_CD-CD )_) .=20_CD 202_CD the_ATI reproductive_JJ potential_NN of_IN EBV_NP is_BEZ apparently_RB enhanced_VBN by_IN tapping_VBG into_IN the_ATI anti-inflammatory_JJ functions_NNS of_IN IL-10_CD-CD , which_WDTR are_BER mediated_VBN by_IN the_ATI cellular_JJ IL-10_CD-CD receptor_NN in_IN Herpesvirus_JJ saimiri_NN (_( HVS_NP )_) a_AT reciprocal_JJ situation_NN has_HVZ been_BEN discovered_VBN instead_RB of_IN pirating_VBG the_ATI gene_NN for_IN an_AT immunoregulatory_NN ligand_NN , HVS_NP copied_VBD the_ATI gene_NN for_IN an_AT interleukin_NN 8_CD (_( IL-8_NP )_) receptor_NN the_ATI viral_JJ IL-8_NP receptor_NN is_BEZ an_AT integral_JJ membrane_NN protein_NN that_CS , on_IN binding_JJ to_IN a_AT ligand_NN , transmits_NNS a_AT signal_NN to_IN the_ATI cytoplasm_NN this_DT property_NN distinguishes_VBZ it_PP3 from_IN the_ATI soluble_JJ cytokine_NN receptor_NN homologues_NNS of_IN poxviruses_NNS the_ATI precise_JJ biological_JJ actions_NNS of_IN IL-8_NP that_CS are_BER coveted_JJ by_IN the_ATI virus_NN are_BER not_XNOT yet_RB known_VBN , but_CC probably_RB involve_VB immune_JJ cell_NN activation_NN both_ABX EBV_NP and_CC HVS_NP are_BER closely_RB related_JJ gamma- herpesviruses_NNS with_IN highly_RB conserved_VBN genomes_NNS the_ATI HVS_NP IL-8_NP receptor_NN gene_NN and_CC the_ATI EBV_NP IL-10_CD- CD gene_NN are_BER two_CD genes_NNS not_XNOT conserved_VBN in_IN EBV_NP and_CC HVS_NP 203_CD subversion_NN of_IN the_ATI IL-1_CD-CD system_NN by_IN the_ATI vaccinia_NN virus_NN could_MD have_HV occurred_VBN either_DTX by_IN mimicking_VBG the_ATI ligands_NNS or_CC the_ATI receptors_NNS (_( Table_NP 3_CD )_) two_CD forms_NNS of_IN IL-1_CD-CD are_BER produced_VBN in_IN mammals-IL- 1alpha_CD-CD , which_WDTR is_BEZ cell_NN associated_VBN and_CC may_MD not_XNOT serve_VB a_AT signaling_VBG function_NN in_RB vivo_RB , and_CC IL- 1beta_CD-CD , the_ATI major_JJ circulating_JJ form_NN of_IN IL-1_CD-CD that_CS accounts_NNS for_IN the_ATI known_VBN biological_JJ actions_NNS of_IN IL-1_CD- CD a_AT third_OD isoform_NN , the_ATI IL-1_CD-CD receptor_NN antagonist_NN , blocks_VBZ the_ATI actions_NNS of_IN IL-1_CD-CD but_CC lacks_VBZ agonist_NN activity_NN all_ABN three_CD isoforms_NNS possess_VB about_IN 20%_NP amino_NN acid_NN sequence_NN identity_NN , which_WDTR indicates_VBZ that_CS they_PP3AS arose_VBD from_IN a_AT common_JJ ancestral_JJ gene_NN the_ATI IL-1_CD-CD receptor_NN is_BEZ also_RB complex.=20_CD 204_CD two_CD are_BER known_VBN the_ATI type_NN II_NP receptor_NN has_HVZ a_AT short_JJ cytoplasmic_JJ domain_NN and_CC has_HVZ not_XNOT been_BEN shown_VBN to_TO have_HV a_AT signaling_VBG function_NN it_PP3 may_MD reduce_VB concentrations_NNS of_IN soluble_JJ IL-1_CD-CD available_JJ to_IN the_ATI type_NN I_PP1A receptor_VB , which_WDTR in_IN contrast_NN has_HVZ a_AT long_JJ cytoplasmic_JJ domain_NN and_CC mediates_VBZ all_ABN the_ATI known_VBN signaling_VBG functions_NNS of_IN IL-1_CD-CD both_ABX receptors_NNS bind_VB all_ABN three_CD forms_NNS of_IN IL-1_CD-CD however_RB , the_ATI binding_JJ affinity_NN for_IN IL-1beta_CD-CD by_IN the_ATI type_NN II_NP receptor_NN is_BEZ about_RB 10_CD times_NNS greater_JJR than_IN that_DT of_IN the_ATI type_NN I_PP1A receptor_VB given_VBN these_DTS facts_NNS , natural_JJ selection_NN has_HVZ yielded_VBN what_WDT appears_VBZ to_TO be_BE the_ATI most_QL logical_JJ route_NN to_TO efficiently_RB subvert_VB the_ATI IL-1_CD-CD system_NN the_ATI viral_JJ IL-1_CD-CD receptor_NN corresponds_VBZ only_RB to_IN the_ATI soluble_JJ portion_NN of_IN the_ATI type_NN II_NP receptor_NN ; moreover_RB , it_PP3 binds_VBZ IL-1beta_CD-CD , the_ATI signaling_NN isoform_NN , but_CC ignores_VBZ IL-1alpha_CD-CD , the_ATI nonsignaling_NN isoform_NN 205_CD similarly_RB , natural_JJ selection_NN may_MD have_HV yielded_VBN what_WDT appears_VBZ to_TO be_BE the_ATI most_QL logical_JJ way_NN for_IN HVS_NP to_TO take_VB full_JJ advantage_NN of_IN the_ATI IL-8_NP signaling_VBG system_NN interleukin_NN 8_CD is_BEZ one_CD1 of_IN a_AT family_NN of_IN at_RB least_RB 18_CD structurally_RB and_CC functionally_RB related_VBN human_JJ molecules_NNS known_VBN as_IN chemokines-for_NN chemoattractants_NNS and_CC cytokines_NNS the_ATI chemokines_NNS possess_VB both_ABX broadly_RB overlapping_JJ and_CC distinct_JJ roles_NNS in_IN the_ATI regulation_NN of_IN phagocyte_NN and_CC lymphocyte_NN motility_NN and_CC activation_NN and_CC thus_RB may_MD play_VB important_JJ roles_NNS in_IN acute_JJ and_CC chronic_JJ inflammation.=20_CD 206_NP in_IN addition_NN , several_AP of_IN the_ATI chemokines_NNS may_MD play_VB a_AT broader_JJR role_NN in_IN cell_NN proliferation_NN the_ATI sequences_NNS for_IN a_AT receptor_JJ dedicated_JJ to_IN IL-8_NP (_( IL-8_NP receptor_NN A_ZZ or_CC IL8RA_NP )_) and_CC for_IN a_AT second_OD receptor_NN (_( IL-8_NP receptor_NN B_ZZ or_CC IL8RB_NP )_) shared_VBD among_IN IL-8_NP and_CC the_ATI closely_RB related_JJ chemokines_NNS called_VBN neutrophil- activating_NN peptide-2_NN (_( NAP-2_NP )_) and_CC the_ATI growth-related_JJ gene_NN product_NN GROalpha_NP have_HV been_BEN deduced_VBN by_IN molecular_JJ cloning_NN by_IN copying_VBG IL8RB_NP , the_ATI more_QL promiscuous_JJ IL-8_NP receptor_NN , HVS_NP may_MD be_BE able_JJ to_TO tap_VB into_IN a_AT richer_JJR variety_NN of_IN potential_JJ signaling_NN pathways_NNS than_IN if_CS it_PP3 had_HVD copied_VBN IL8RA_NP 207_CD when_WRB they_PP3AS are_BER expressed_VBN in_IN frog_NN oocytes_NNS , the_ATI viral_JJ IL-8_NP receptor_NN is_BEZ 200_CD times_NNS more_QL sensitive_JJ than_IN human_JJ IL8RB_NP to_IN GROalpha_NP , a_AT molecule_NN with_IN known_JJ growth-factor_NN activity_NN thus_RB , the_ATI viral_JJ receptor_NN may_MD sensitize_VB cells_NNS infected_VBN with_IN HVS_NP to_IN concentrations_NNS of_IN GROalpha_NP that_CS do_DO not_XNOT activate_VB the_ATI cellular_JJ receptor_NN the_ATI biochemical_JJ changes_NNS that_WPR occur_VB in_IN the_ATI cytoplasm_NN of_IN phagocytes_NNS stimulated_VBN with_IN IL-8_NP , GROalpha_NP , and_CC NAP- 2_NP are_BER similar_JJ to_IN those_DTS that_CS have_HV been_BEN measured_VBN during_IN the_ATI infection_NN of_IN fibroblasts_NNS by_IN HCMV_NP in_IN fact_NN , inhibition_NN of_IN these_DTS biochemical_JJ changes_NNS markedly_RB attenuates_VBZ HCMV_NP replication.=20_CD 208_NP by_IN analogy_NN with_IN HCMV_NP , these_DTS changes_NNS may_MD ensure_VB for_IN HVS_NP a_AT cytoplasmic_JJ milieu_NN that_WPR has_HVZ been_BEN optimally_RB conditioned_VBN for_IN replication_NN or_CC the_ATI establishment_NN of_IN latency_NN in_IN its_PP$ natural_JJ host_NN , the_ATI squirrel_NN monkey_NN , HVS_NP infects_NNS T_ZZ lymphocytes_NNS without_IN causing_VBG disease_NN when_WRB other_AP primates_NNS are_BER infected_VBN , however_RB , HVS_NP causes_NNS fatal_JJ leukemias_NNS and_CC lymphomas_NNS it_PP3 can_MD also_RB transform_VB human_JJ T_ZZ cells_NNS in_IN vitro_NN the_ATI relationship_NN of_IN the_ATI pirated_NN IL-8_NP receptor_NN of_IN HVS_NP to_IN malignant_JJ transformation_NN has_HVZ not_XNOT yet_RB been_BEN tested_VBN in_RB vivo_RB with_IN mutant_NN viruses_NNS 209_NP it_PP3 is_BEZ a_AT fascinating_JJ paradox_NN that_CS although_CS the_ATI HVS_NP homologue_NN of_IN IL8RB_NP is_BEZ only_RB 30%_NP identical_JJ to_IN IL8RB_NP , it_PP3 binds_VBZ the_ATI same_AP three_CD ligands_NNS as_CS IL8RB_NP , whereas_CS mammalian_NN IL8RA_NP is_BEZ 78%_JJ identical_JJ to_IN IL8RB_NP , but_CC it_PP3 has_HVZ a_AT more_QL restricted_JJ ligand_JJ profile_NN another_DT mammalian_NN chemokine_NN receptor_NN that_CS binds_VBZ closely_RB related_JJ molecules_NNS such_IN as_IN macrophage_JJ inflammatory_JJ protein- 1alpha_CD-CD (_( MIP-1alpha_CD-CD )_) and_CC RANTES_NP (_( an_AT acronym_NN for_IN reduced_VBN on_IN activation_JJ normal_JJ T_ZZ expressed_VBN and_CC secreted_VBN )_) has_HVZ also_RB been_BEN pirated_VBN , in_IN this_DT case_NN by_IN HCMV_NP although_CS the_ATI viral_JJ protein_NN binds_VBZ MIP-1alpha_CD-CD and_CC RANTES_NP , its_PP$ capacity_NN for_IN signal_NN transduction_NN has_HVZ not_XNOT yet_RB been_BEN reported_VBN 210_CD in_IN addition_NN to_IN these_DTS functionally_RB characterized_VBN viral_JJ proteins_NNS , several_AP open_JJ reading_NN frames_NNS have_HV been_BEN identified_VBN among_IN the_ATI poxviruses_NNS and_CC herpesviruses_NNS that_CS encode_JJ putative_JJ proteins_NNS with_IN clear-cut_JJ sequence_NN relationships_NNS to_IN families_NNS of_IN cellular_JJ proteins_NNS , but_CC where_WRB the_ATI specific_JJ function_NN of_IN the_ATI viral_JJ protein_NN or_CC its_PP$ closest_JJT cellular_JJ homologue_NN has_HVZ not_XNOT yet_RB been_BEN delineated_VBN several_AP of_IN these_DTS are_BER viral_JJ G_ZZ protein-coupled_JJ receptorlike_NN sequences_NNS the_ATI HVS_NP IL-8_NP receptor_NN and_CC the_ATI HCMV_NP MIP- 1alpha_RANTES_CD-CD binding_JJ protein_NN are_BER the_ATI only_AP functionally_RB characterized_VBN viral_JJ homologues_NNS of_IN mammalian_NN G_ZZ protein-coupled_JJ receptors_NNS there_EX are_BER other_AP examples_NNS of_IN herpesviruses_NNS that_CS have_HV pirated_JJ genes_NNS that_CS may_MD be_BE involved_VBN in_IN cell_NN cycle_NN regulation_NN and_CC programmed_VBN cell_NN death_NN (_( apoptosis_NN )_) 211_CD MOLECULAR_NPT MIMICRY_NPT BY_NPT CONVERGENT_NP EVOLUTION_NP 212_CD two_CD proteins_NNS may_MD have_HV no_ATI sequence_NN similarity_NN but_CC subserve_NN a_AT similar_JJ function_NN this_DT phenomenon_NN is_BEZ termed_VBN convergent_NN evolution_NN interestingly_RB , although_CS the_ATI herpesviruses_NNS have_HV acquired_JJ chemokine_NN receptor_NN genes_NNS to_TO mimic_VB their_PP$ primate_NN hosts_NNS , at_RB least_RB one_CD1 host_NN , Homo_NP sapiens_NNS , has_HVZ inactivated_VBN another_DT chemokine_NN receptor_NN gene_NN under_IN the_ATI pressure_NN of_IN convergent_JJ molecular_JJ mimicry_NN in_IN this_DT case_NN , however_RB , the_ATI pathogen_NN is_BEZ a_AT protozoan_NN the_ATI Duffy_NP blood_NN group_NN antigen_NN has_HVZ been_BEN known_VBN for_IN almost_RB 20_CD years_NNS to_TO be_BE the_ATI receptor_NN for_IN the_ATI malaria_NN parasite_NN Plasmodium_NP vivax_NN it_PP3 is_BEZ also_RB known_VBN that_CS the_ATI majority_NN of_IN inhabitants_NNS of_IN Africa_NP , where_WRB P_ZZ vivax_NN is_BEZ rare_JJ , lack_VB the_ATI Duffy_NP antigen_NN and_CC are_BER thus_RB protected_VBN from_IN vivax_NN malaria_NN it_PP3 has_HVZ recently_RB been_BEN shown_VBN that_CS the_ATI Duffy_NP blood_NN group_NN antigen_NN is_BEZ a_AT red_JJ blood_NN cell_NN chemokine- binding_NN protein_NN that_WPR is_BEZ more_QL promiscuous_JJ in_IN its_PP$ ligand_NN affiliations_NNS than_IN any_DTI of_IN the_ATI white_JJ blood_NN cell_NN chemokine_NN receptors.=20_CD 213_CD in_IN fact_NN , the_ATI Duffy_NP blood_NN group_NN antigen_NN is_BEZ able_JJ to_TO bind_VB all_ABN three_CD sets_NNS of_IN chemokines_NNS (_( IL-8_NP , NAP- 2_NP , GROalpha_NP ; RANTES_NP ; and_CC monocyte_NN chemoattractant_NN protein_NN 1_CD1 )_) that_CS target_NN three_CD distinct_JJ white_JJ blood_NN cell_NN chemokine_NN receptors_NNS recently_RB Chaudhuri_NP et_&FW al_APS succeeded_VBN in_IN cloning_VBG cDNAs_NP encoding_VBG the_ATI Duffy_NP antigen_NN the_ATI deduced_VBN protein_NN sequence_NN is_BEZ clearly_RB related_VBN to_TO that_CS of_IN the_ATI white_JJ cell_NN chemokine_NN receptors_NNS (_( almost_RB 26%_NN amino_NN acid_NN identity_NN )_) the_ATI parasite_NN molecule_NN that_CS binds_VBZ to_IN the_ATI Duffy_NP antigen_NN has_HVZ no_ATI sequence_NN relationship_NN to_IN chemokines_NNS and_CC thus_RB probably_RB targeted_VBN Duffy_NP by_IN a_AT convergent_JJ evolutionary_JJ pathway_NN the_ATI dynamic_JJ coevolution_NN of_IN hosts_NNS and_CC parasites_NNS may_MD be_BE graphically_RB illustrated_VBN by_IN the_ATI loss_NN of_IN the_ATI Duffy_NP antigen_NN in_IN malaria-exposed_JJ Africans_NNPS and_CC their_PP$ American_JNP descendants.=20_CD 214_CD although_CS the_ATI apparent_JJ good_JJ health_NN of_IN persons_NNS not_XNOT possessing_VBG the_ATI Duffy_NP antigen_NN may_MD argue_VB against_IN an_AT important_JJ role_NN in_IN homeostasis_NN for_IN Duffy_NP on_IN red_JJ blood_NN cells_NNS , the_ATI ability_NN of_IN chemokines_NNS to_TO block_VB infection_NN of_IN red_JJ cells_NNS by_IN the_ATI related_JJ parasite_NN Plasmodium_NP knowlesi_NN in_IN vitro_NN raises_VBZ the_ATI possibility_NN of_IN developing_VBG new_JJ chemokine-based_JJ therapeutics_NNS for_IN vivax_NN malaria_NN in_IN patients_NNS with_IN the_ATI Duffy_NP antigen_NN 215_CD several_AP examples_NNS of_IN viral_JJ interference_NN in_IN immunoregulatory_NN pathways_NNS involve_VB proteins_NNS without_IN clear-cut_JJ homology_NN to_IN host_NN proteins_NNS the_ATI p15E_CD protein_NN of_IN murine_NN retroviruses_NNS may_MD contribute_VB to_TO immunosuppression_VB by_IN inhibiting_JJ protein_NN kinase_NN C_ZZ adenoviruses_NNS encode_NN a_AT protein_NN dedicated_JJ to_TO the_ATI subversion_NN of_IN antigen_NN presentation_NN pathways_NNS however_RB , unlike_IN the_ATI UL18_CD gene_JJ product_NN of_IN HCMV_NP , this_DT adenovirus_JJ protein_NN (_( E3-gp19K_CD-CD )_) binds_VBZ to_TO the_ATI variable_JJ chain_NN of_IN the_ATI class_NN I_PP1A molecule_VB , thus_RB preventing_VBG its_PP$ assembly_NN and_CC transport_NN to_IN the_ATI plasma_NN membrane_NN .=20_CD 216_CD at_RB least_RB three_CD genes_NNS from_IN adenoviruses_NNS are_BER known_VBN to_TO disrupt_VB the_ATI TNF_NP cytolytic_JJ signal_NN transduction_NN pathway_NN at_IN the_ATI level_NN of_IN cytosolic_JJ second_OD messengers_NNS and_CC transcription_NN factor_NN activation_NN unlike_IN poxviruses_NNS , which_WDTR cause_NN acute_JJ , cytolytic_JJ infections_NNS in_IN which_WDTR the_ATI virus_NN drives_VBZ the_ATI pathology_NN , adenoviruses_NNS cause_NN persistent_JJ infections_NNS with_IN long- term_JJB viral_JJ shedding_VBG in_IN which_WDTR the_ATI immune_JJ system_NN drives_VBZ the_ATI pathology_NN thus_RB , in_IN contrast_NN to_IN the_ATI decreased_VBD virulence_NN of_IN poxviruses_NNS bearing_VBG inactivating_VBG mutations_NNS in_IN pirated_JJ immunoregulatory_NN genes_NNS , adenoviruses_NNS bearing_VBG inactivating_VBG mutations_NNS in_IN the_ATI genes_NNS that_WPR interfere_VB with_IN TNF_NP signaling_VBG cause_NN dramatically_RB increased_JJ pathology_NN in_IN rodent_NN models_NNS of_IN pneumonia_NN , despite_IN wild-type_JJ levels_NNS of_IN viral_JJ replication_NN 217_CD MOLECULAR_NPT MIMICRY_NPT AND_NPT THE_NPT GENERATION_NPT OF_NPT HOST_NPT DEFENSE_NP PROTEIN_NP DIVERSITY_NP 218_CD the_ATI virus_NN clearly_RB has_HVZ an_AT interest_NN in_IN copying_VBG and_CC improving_VBG what_WDT works_NNS well_RB in_IN the_ATI host_NN the_ATI host_NN , however_RB , has_HVZ an_AT interest_NN in_IN eluding_VBG imitation_NN by_IN the_ATI virus_NN a_AT natural_JJ competition_NN is_BEZ thus_RB established_VBN the_ATI score_NN of_IN this_DT competition_NN may_MD be_BE read_VB in_IN the_ATI sequence_NN differences_NNS between_IN homologous_JJ host_NN and_CC viral_JJ gene_NN products_NNS to_IN the_ATI extent_NN that_CS different_JJ host_NN species_NN may_MD be_BE infected_VBN by_IN different_JJ species-specific_JJ viruses_NNS that_DT may_MD or_CC may_MD not_XNOT target_NN the_ATI same_AP gene_NN for_IN copying_VBG , targeted_VBD genes_NNS might_MD be_BE subjected_VBN to_IN exaggerated_JJ sequence_NN variation_NN relative_JJ to_IN untargeted_JJ genes.=20_CD 219_CD it_PP3 has_HVZ recently_RB been_BEN shown_VBN that_CS human_JJ and_CC rodent_NN versions_NNS of_IN host_NN defense_NN proteins_NNS are_BER far_RB more_QL divergent_JJ in_IN sequence_NN than_IN human_JJ and_CC rodent_NN versions_NNS of_IN proteins_NNS from_IN any_DTI other_AP functional_JJ grouping_NN it_PP3 is_BEZ worth_IN considering_VBG that_CS molecular_JJ mimicry_NN by_IN species-specific_JJ pathogens_NNS may_MD be_BE a_AT potent_JJ selective_JJ force_NN behind_IN the_ATI generation_NN of_IN host_NN defense_NN protein_NN diversity_NN since_IN viruses_NNS can_MD mutate_VB much_AP more_QL quickly_RB than_IN their_PP$ hosts_NNS , the_ATI absolute_JJ dependence_NN of_IN the_ATI virus_NN on_IN the_ATI host_NN may_MD ultimately_RB be_BE the_ATI only_AP thing_NN that_CS constrains_VBZ the_ATI zest_NN with_IN which_WDTR it_PP3 redesigns_VBZ the_ATI cellular_JJ protein_NN to_TO subvert_VB the_ATI immune_JJ system_NN 220_CD CONCLUSION_NP 221_CD finally_RB , it_PP3 is_BEZ likely_JJ that_CS the_ATI pirating_NN of_IN immunoregulatory_NN genes_NNS may_MD not_XNOT be_BE restricted_JJ to_IN viruses_NNS , but_CC may_MD instead_RB be_BE a_AT general_JJ strategy_NN by_IN which_WDTR bacterial_JJ , protozoan_JJB , and_CC perhaps_RB metazoan_JJ parasites_NNS chisel_NN chinks_NNS in_IN the_ATI armor_NN of_IN the_ATI host_NN immune_JJ system_NN several_AP nonviral_JJ examples_NNS have_HV already_RB been_BEN identified_VBN there_EX are_BER probably_RB hundreds_CDS of_IN distinct_JJ cytokines_NNS and_CC dozens_CDS of_IN cytokine-activated_JJ second_OD messenger_NN systems_NNS that_CS regulate_VB immunity_NN and_CC inflammation_NN just_RB as_RB the_ATI retroviral_JJ oncogenes_NNS have_HV been_BEN useful_JJ for_IN identifying_VBG key_NN cellular_JJ proteins_NNS involved_VBN in_IN normal_JJ growth_NN and_CC differentiation_NN , the_ATI greatest_JJT value_NN of_IN the_ATI pirated_NN immunoregulatory_NN genes_NNS may_MD be_BE in_IN quickly_RB directing_VBG the_ATI therapeutic_JJ efforts_NNS of_IN immunologists_NNS , pharmacologists_NNS , and_CC clinicians_NNS to_TO key_NN molecules_NNS , such_ABL as_CS IL-1_CD-CD , TNF_NP , and_CC IL-8_NP , that_DT may_MD be_BE driving_VBG inflammatory_JJ reactions_NNS in_IN people_NNS 222_CD helicobacter_NN pylori_NN in_IN Peptic_NPT Ulcer_NP Disease_NP 223_CD NIH_NP Consensus_JJ Development_NP Panel_NP on_IN Helicobacter_NP pylori_NN in_IN Peptic_NP Ulcer_NP Disease_NP 224_NN peptic_JJ ulcer_NN disease_NN is_BEZ a_AT chronic_JJ inflammatory_JJ condition_NN of_IN the_ATI stomach_NN and_CC duodenum_NN that_QL affects_VBZ as_QL many_AP as_IN 10%_CD of_IN people_NNS in_IN the_ATI United_NP States_NP at_IN some_DTI time_NN in_IN their_PP$ lives_NNS the_ATI disease_NN has_HVZ relatively_RB low_JJ mortality_NN , but_CC it_PP3 results_NNS in_IN substantial_JJ human_JJ suffering_NN and_CC high_JJ economic_JJ costs_NNS 225_NN in_IN the_ATI early_JJ 20th_OD century_NN , the_ATI pathogenesis_NN of_IN the_ATI disorder_NN was_BEDZ believed_VBN to_TO be_BE related_VBN to_TO stress_VB and_CC dietary_JJ factors_NNS thus_RB , treatment_NN focused_VBD on_IN hospitalization_NN with_IN bed_NN rest_NN and_CC prescription_NN of_IN special_JJ bland_JJ foods_NNS later_RBR , the_ATI concept_NN arose_VBD that_CS peptic_JJ ulcer_NN disease_NN was_BEDZ caused_VBN by_IN the_ATI injurious_JJ effects_NNS of_IN digestive_JJ secretions_NNS such_IN as_IN gastric_JJ acid_NN ; hence_RB , antacids_NNS became_VBD the_ATI standard_NN of_IN therapy.=20_CD 226_CD in_IN 1971_CD , Sir_NPT James_NP Black_NP identified_VBD a_AT subtype_NN of_IN the_ATI histamine_NN receptor_NN (_( the_ATI H_ZZ sub_NN 2_CD receptor_NN )_) that_WPR appeared_VBD to_TO be_BE the_ATI principal_JJB mediator_NN of_IN gastric_JJ acid_NN secretion_NN antagonists_NNS of_IN this_DT receptor_NN proved_VBN to_TO be_BE safe_JJ and_CC effective_JJ therapy_NN for_IN peptic_JJ ulcer_NN disease_NN more_AP recently_RB , inhibitors_NNS of_IN the_ATI proton_NN pump_NN (_( H_ZZ sup_VB +_IN ,K_NN sup_VB +_IN -adenosinetriphosphatase_NN )_) in_IN gastric_JJ parietal_JJ cells_NNS have_HV proved_VBN to_TO be_BE rapidly_RB effective_JJ and_CC extremely_RB potent_JJ antiulcerative_JJ drugs_NNS other_AP drugs_NNS that_WPR appear_VB to_TO enhance_VB mucosal_JJ defense_NN such_IN as_IN bismuth_NN compounds_NNS , sucralfate_NN , and_CC prostaglandins_NNS have_HV also_RB been_BEN applied_VBN to_IN the_ATI treatment_NN of_IN peptic_JJ ulcers_NNS despite_IN these_DTS sophisticated_JJ therapeutic_JJ agents_NNS , the_ATI disturbing_JJ problem_NN of_IN the_ATI high_JJ recurrence_NN rate_NN of_IN peptic_JJ ulcer_NN , even_RB after_IN complete_JJ healing_NN , remains_VBZ 227_NN in_IN 1982_CD , Warren_NP and_CC Marshall_NP provided_VBD the_ATI first_OD insight_NN into_IN another_DT important_JJ pathogenic_JJ factor_NN in_IN peptic_JJ ulcer_NN disease_NN they_PP3AS isolated_JJ a_AT spiral_NN urease-producing_NN organism_NN (_( later_RBR identified_VBN as_IN Helicobacter_NP pylori_NN )_) nestled_VBD in_IN the_ATI narrow_JJ interface_NN between_IN the_ATI gastric_JJ epithelial_JJ cell_NN surface_NN and_CC the_ATI overlying_JJ mucus_NN gel_NN in_IN their_PP$ early_JJ studies_NNS , the_ATI presence_NN of_IN this_DT organism_NN was_BEDZ shown_VBN to_TO be_BE highly_RB correlated_VBN with_IN antral_JJ gastritis_NN as_QL well_RB as_CS with_IN gastric_JJ and_CC duodenal_JJ ulcers_NNS , and_CC eradication_NN of_IN this_DT organism_NN effectively_RB eliminated_VBN ulcer_NN recurrences_NNS Furthermore_NP , a_AT disturbing_JJ epidemiologic_JJ relationship_NN between_IN H_ZZ pylori_NN infection_NN and_CC gastric_JJ malignancies_NNS was_BEDZ reported.=20_CD 228_NN such_ABL studies_NNS have_HV given_JJ rise_NN to_IN the_ATI hypothesis_NN that_CS H_ZZ pylori_NN is_BEZ a_AT major_JJ etiologic_JJ factor_NN in_IN peptic_JJ ulcer_NN disease_NN , and_CC that_CS diagnosis_NN and_CC eradication_NN of_IN the_ATI organism_NN are_BER necessary_JJ for_IN optimal_JJ therapy_NN of_IN the_ATI disorder_NN 229_NN to_TO address_VB these_DTS issues_NNS , the_ATI National_NP Institute_NPL of_IN Diabetes_NP and_CC Digestive_NP and_CC Kidney_NP Diseases_NP and_CC the_ATI Office_NP of_IN Medical_NP Applications_NNS of_IN Research_NP of_IN the_ATI National_NP Institutes_NNS of_IN Health_NP convened_VBN a_AT Consensus_JJ Development_NP Conference_NP on_IN Helicobacter_NP pylori_NN in_IN Peptic_NPT Ulcer_NP Disease_NP The_NP conference_NN was_BEDZ cosponsored_VBN by_IN the_ATI National_NP Institute_NPL of_IN Allergy_NP and_CC Infectious_JJ Diseases.=20_CD 230_CD WHAT_NPT IS_NPT THE_NPT CAUSAL_NPT RELATIONSHIP_NP OF_NP H_ZZ PYLORI_NPT TO_NP UPPER_NP GASTROINTESTINAL_NP DISEASE_NP ? 231_CD a_AT strong_JJ association_NN between_IN H_ZZ pylori_NN and_CC upper_JJB gastrointestinal_JJ disease_NN has_HVZ been_BEN reported_VBN the_ATI causal_JJ relationship_NN between_IN H_ZZ pylori_NN and_CC chronic_JJ superficial_JJ gastritis_NN is_BEZ well_RB established_VBN the_ATI evidence_NN for_IN this_DT statement_NN is_BEZ as_IN follows_VBZ : 232_CD virtually_RB all_ABN H_ZZ pylori-positive_JJ patients_NNS demonstrate_VB antral_JJ gastritis_NN 233_CD eradication_NN of_IN H_ZZ pylori_NN infection_NN results_NNS in_IN resolution_NN of_IN gastritis_NN 234_CD the_ATI lesion_NN of_IN chronic_JJ superficial_JJ gastritis_NN has_HVZ been_BEN reproduced_VBN following_JJ intragastric_JJ administration_NN of_IN the_ATI isolated_JJ organism_NN in_IN some_DTI animal_NN models_NNS and_CC oral_JJ administration_NN in_IN two_CD humans_NNS 235_CD a_AT causal_JJ relationship_NN between_IN H_ZZ pylori_NN and_CC peptic_JJ ulcer_NN disease_NN is_BEZ more_QL difficult_JJ to_TO establish_VB from_IN the_ATI available_JJ data_NNS , in_IN part_NN because_IN of_IN the_ATI lack_NN of_IN an_AT animal_NN model_NN , and_CC because_CS only_RB a_AT small_JJ proportion_NN of_IN individuals_NNS harboring_VBG the_ATI organism_NN develop_VB ulceration_NN however_RB , nearly_RB all_ABN patients_NNS with_IN duodenal_JJ ulcer_NN have_HV H_ZZ pylori_NN gastritis_NN thus_RB , infection_NN with_IN the_ATI organism_NN may_MD be_BE a_AT prerequisite_NN for_IN the_ATI occurrence_NN of_IN almost_RB all_ABN duodenal_JJ ulcers_NNS in_IN the_ATI absence_NN of_IN other_AP precipitating_VBG factors_NNS such_IN as_IN nonsteroidal_JJ anti-inflammatory_NN drug_NN (_( NSAID_NP )_) use_NN or_CC Zollinger-Ellison_NP syndrome.=20_CD 236_CD the_ATI association_NN between_IN H_ZZ pylori_NN infection_NN and_CC gastric_JJ ulcer_NN is_BEZ only_RB slightly_RB less_QL strong_JJ , in_IN that_DT 80%_NP of_IN patients_NNS with_IN non-NSAID-induced_JJ gastric_JJ ulcers_NNS are_BER infected_VBN nevertheless_RB , it_PP3 is_BEZ important_JJ to_TO note_VB that_CS the_ATI majority_NN of_IN H_ZZ pylori-infected_JJ individuals_NNS do_DO not_XNOT develop_VB duodenal_JJ or_CC gastric_JJ ulcers_NNS these_DTS facts_NNS imply_VB that_CS host_NN characteristics_NNS , strain_NN variability_NN , or_CC other_AP factors_NNS play_VB a_AT role_NN in_IN the_ATI pathogenesis_NN of_IN peptic_JJ ulcer_NN disease_NN 237_CD the_ATI strongest_JJT evidence_NN for_IN the_ATI pathogenic_JJ role_NN of_IN H_ZZ pylori_NN in_IN peptic_JJ ulcer_NN disease_NN is_BEZ the_ATI marked_JJ decrease_NN in_IN recurrence_NN rate_NN of_IN ulcers_NNS following_JJ the_ATI eradication_NN of_IN infection_NN the_ATI prevention_NN of_IN recurrence_NN following_JJ H_ZZ pylori_NN eradication_NN is_BEZ less_QL well_RB documented_VBN for_IN gastric_JJ ulcer_NN than_CS for_IN duodenal_JJ ulcer_NN , but_CC the_ATI available_JJ data_NNS suggest_VB similar_JJ efficacy_NN 238_CD in_IN the_ATI case_NN of_IN duodenal_JJ ulcer_NN , it_PP3 is_BEZ curious_JJ that_CS in_IN some_DTI studies_NNS the_ATI organism_NN is_BEZ more_QL often_RB present_JJ in_IN the_ATI antrum_NN than_CS in_IN the_ATI duodenum_NN , where_WRB the_ATI ulcer_NN is_BEZ found_VBN suggested_JJ mechanisms_NNS by_IN which_WDTR an_AT antral_JJ organism_NN causes_NNS a_AT duodenal_JJ lesion_NN include_VB bacterial_JJ colonization_NN of_IN gastric_JJ metaplasia_NN in_IN the_ATI duodenum_NN , secondary_JJ changes_NNS in_IN gastric_JJ acid_NN or_CC duodenal_JJ bicarbonate_NN secretion_NN , or_CC changes_NNS caused_VBN by_IN products_NNS of_IN the_ATI infecting_NN organism_NN and_or_CC the_ATI inflammatory_JJ response_NN of_IN the_ATI host_NN further_JJB studies_NNS are_BER needed_VBN to_TO clarify_VB the_ATI mechanisms_NNS of_IN bacterial_JJ pathogenesis_NN and_CC host_NN responses_NNS leading_JJ to_IN duodenal_JJ ulceration_NN 239_CD to_TO date_VB , there_EX is_BEZ no_ATI convincing_JJ evidence_NN for_IN an_AT association_NN of_IN H_ZZ pylori_NN infection_NN with_IN nonulcerative_JJ dyspepsia_NN the_ATI prevalence_NN of_IN H_ZZ pylori_NN infection_NN is_BEZ no_ATI higher_JJR in_IN patients_NNS with_IN nonulcerative_JJ dyspepsia_NN than_CS in_IN the_ATI general_JJ population_NN although_CS some_DTI patients_NNS with_IN nonulcerative_JJ dyspepsia_NN may_MD have_HV symptoms_NNS that_CS are_BER related_VBN to_IN the_ATI presence_NN of_IN H_ZZ pylori_NN , there_EX are_BER no_ATI data_NNS to_TO demonstrate_VB how_WRB to_TO identify_VB such_ABL a_AT subject_NN studies_NNS are_BER needed_VBN to_TO determine_VB whether_CS H_ZZ pylori- infected_JJ patients_NNS with_IN nonulcerative_JJ dyspepsia_NN would_MD benefit_VB from_IN treatment_NN of_IN the_ATI infection_NN 240_CD HOW_NPT DOES_NPT ONE_NPT DIAGNOSE_NPT AND_NP ERADICATE_NP H_ZZ PYLORI_NP INFECTION_NP ? 241_CD a_AT fundamental_JJ principle_NN of_IN specific_JJ antimicrobial_JJ therapy_NN is_BEZ accurate_JJ diagnosis_NN numerous_JJ validated_JJ methods_NNS to_TO diagnose_VB patients_NNS with_IN H_ZZ pylori_NN infection_NN are_BER in_IN use_NN these_DTS methods_NNS can_MD be_BE divided_VBN into_IN invasive_JJ and_CC noninvasive_JJ diagnostic_JJ tests_NNS 242_CD 21_CD the_ATI invasive_JJ tests_NNS include_VB endoscopy_NN followed_VBN by_IN gastric_JJ biopsy_NN and_CC histologic_JJ demonstration_NN of_IN organisms_NNS , biopsy_NN with_IN direct_JJ detection_NN of_IN urease_NN activity_NN in_IN the_ATI tissue_NN specimen_NN , and_CC biopsy_NN with_IN culture_NN of_IN the_ATI H_ZZ pylori_NN organism_NN although_CS culturing_VBG the_ATI organism_NN is_BEZ traditionally_RB considered_VBN the_ATI criterion_NN (_( _** gold_NN _** )_) standard_NN for_IN diagnosis_NN of_IN many_AP infectious_JJ agents_NNS , it_PP3 is_BEZ the_ATI least_RB sensitive_JJ diagnostic_JJ test_NN (_( approximately_RB 70%_NP to_IN 80%_NP positivity_NN )_) both_ABX histologic_JJ demonstration_NN of_IN the_ATI organism_NN by_IN Giemsa_NP or_CC Warthin-Starry_NP stains_NNS and_CC urease_NN testing_NN have_HV sensitivities_NNS and_CC specificities_NNS greater_JJR than_IN 90%_NP 243_CD excellent_JJ diagnostic_JJ sensitivities_NNS and_CC specificities_NNS (_( }95%_NN )_) are_BER also_RB obtained_VBN with_IN noninvasive_JJ tests_NNS for_IN the_ATI initial_JJ diagnosis_NN of_IN H_ZZ pylori_NN infection_NN these_DTS include_VB serological_JJ tests_NNS for_IN IgG_NP antibodies_NNS to_TO H_ZZ pylori_NN antigens_NNS and_CC breath_NN tests_NNS of_IN urease_NN activity_NN using_VBG orally_RB administered_VBN urea_NN labeled_VBN with_IN carbon_NN 14_CD or_CC carbon_NN 13_CD a_AT number_NN of_IN highly_RB accurate_JJ serological_JJ kits_NNS for_IN diagnosis_NN of_IN H_ZZ pylori_NN infection_NN are_BER available_JJ labeled_JJ urea_NN breath_NN tests_NNS have_HV had_HVD restricted_JJ availability_NN as_IN research_NN tools_NNS in_IN the_ATI past_NN , but_CC commercial_JJ assays_NNS will_MD be_BE available_JJ in_IN the_ATI near_IN future_NN 244_CD it_PP3 is_BEZ important_JJ to_TO note_VB that_CS , with_IN the_ATI exception_NN of_IN the_ATI serological_JJ assays_NNS , all_ABN of_IN the_ATI tests_NNS for_IN diagnosis_NN of_IN H_ZZ pylori_NN infection_NN may_MD be_BE falsely_RB negative_JJ in_IN patients_NNS who_WPR have_HV taken_VBN antibiotics_NNS , bismuth_NN compounds_NNS , or_CC omeprazole_NN in_IN the_ATI recent_JJ past_NN 245_CD currently_RB , there_EX is_BEZ no_ATI readily_RB available_JJ , inexpensive_JJ , and_CC accurate_JJ noninvasive_JJ method_NN to_TO monitor_NN eradication_NN of_IN H_ZZ pylori_NN without_IN such_ABL an_AT assay_NN , routine_NN monitoring_VBG for_IN relapse_NN , reinfection_NN , or_CC treatment_NN failure_NN cannot_NN be_BE recommended_VBN even_CS if_CS such_ABL a_AT test_NN were_BED available_JJ , testing_NN all_ABN patients_NNS treated_VBN for_IN H_ZZ pylori_NN infection_NN probably_RB would_MD not_XNOT be_BE necessary_JJ in_IN view_NN of_IN the_ATI high_JJ efficacy_NN of_IN treatment_NN and_CC the_ATI low_JJ reinfection_NN rate_NN Important_NP exceptions_NNS would_MD be_BE patients_NNS with_IN complicated_JJ , recurrent_JJ , or_CC refractory_JJ peptic_JJ ulcers_NNS who_WPR should_MD be_BE evaluated_VBN for_IN successful_JJ eradication_NN of_IN infection_NN before_CS cessation_NN of_IN antiulcer_NN therapy_NN antibody_NN levels_NNS decrease_NN slowly_RB following_JJ successful_JJ eradication_NN of_IN H_ZZ pylori_NN infection.=20_CD 246_CD if_CS the_ATI same_AP well-standardized_JJ assay_NN is_BEZ used_VBN , a_AT dramatic_JJ decrease_NN in_IN antibody_NN titer_NN 6_CD to_IN 12_CD months_NNS following_JJ antimicrobial_JJ treatment_NN indicates_VBZ successful_JJ eradication_NN however_RB , variability_NN among_IN serological_JJ tests_NNS applied_VBN in_IN commercial_JJ laboratories_NNS may_MD limit_VB their_PP$ usefulness_NN in_IN confirming_VBG H_ZZ pylori_NN eradication_NN although_CS breath_NN testing_NN is_BEZ the_ATI best_JJT noninvasive_JJ assay_NN for_IN evaluating_JJ success_NN of_IN eradication_NN , there_EX are_BER unresolved_JJ issues_NNS of_IN availability_NN , cost_NN , and_CC ease_NN of_IN use_NN in_IN the_ATI practical_JJ application_NN of_IN this_DT method_NN invasive_JJ tests_NNS can_MD also_RB be_BE used_VBN for_IN documenting_VBG cure_NN , but_CC these_DTS incur_VB the_ATI cost_NN and_CC morbidity_NN associated_VBN with_IN endoscopy_NN 247_CD therapy_NN for_IN H_ZZ pylori_NN poses_VBZ several_AP unique_JJ challenges_VBZ the_ATI organism_NN resides_NNS under_IN a_AT mucus_NN gel_NN layer_NN in_IN the_ATI highly_RB acidic_JJ milieu_NN of_IN the_ATI stomach_NN , where_WRB rapid_JJ removal_NN of_IN ingested_VBN antimicrobials_NNS may_MD occur_VB these_DTS and_CC other_AP factors_NNS may_MD contribute_VB to_IN the_ATI variable_NN correlation_NN between_IN in_IN vitro_NN and_CC in_RB vivo_RB antimicrobial_JJ activity_NN a_AT problem_NN in_IN selection_NN of_IN a_AT therapeutic_JJ regimen_NNS has_HVZ been_BEN the_ATI lack_NN of_IN a_AT suitable_JJ animal_NN model_NN for_IN these_DTS reasons_NNS , much_AP of_IN the_ATI available_JJ information_NN concerning_IN choice_NN of_IN antimicrobial_JJ agents_NNS is_BEZ based_VBN on_IN small_JJ empiric_JJ trials_NNS in_IN humans_NNS Multiple_NP agents_NNS that_CS have_HV been_BEN studied_VBN in_IN various_JJ combinations_NNS include_VB metronidazole_NN , tetracycline_NN , amoxicillin_NN , clarithromycin_NN , bismuth_NN compounds_NNS , H_ZZ sub_NN 2_CD -receptor_NN antagonists_NNS , and_CC proton-pump_NN inhibitors_NNS The_NP choice_NN of_IN a_AT particular_JJ regimen_NNS must_MD be_BE tempered_VBN by_IN the_ATI rapidly_RB developing_VBG data_NNS on_IN optimal_JJ therapy_NN 248_CD consideration_NN of_IN the_ATI therapeutic_JJ options_NNS should_MD take_VB into_IN account_NN efficacy_NN , compliance_NN , side_NN effects_NNS , and_CC cost_NN a_AT triple_JJ antimicrobial_JJ regimen_NNS consisting_VBG of_IN bismuth_NN subsalicylate_NN , tetracycline_NN , and_CC metronidazole_NN has_HVZ been_BEN studied_VBN extensively_RB and_CC can_MD yield_VB eradication_VB rates_NNS of_IN approximately_RB 90%_NP substitution_NN of_IN amoxicillin_NN for_IN tetracycline_NN or_CC metronidazole_NN lowers_NNS efficacy_NN only_RB slightly_RB (_( }80%_NP )_) one_CD1 promising_JJ study_NN reported_VBN efficacy_NN of_IN approximately_RB 90%_NP with_IN the_ATI combination_NN of_IN ranitidine_NN , metronidazole_NN , and_CC amoxicillin_NN although_CS variable_NN , eradication_JJ rates_NNS of_IN more_AP than_IN 80%_NP have_HV also_RB been_BEN reported_VBN with_IN the_ATI combination_NN of_IN omeprazole_NN (_( a_AT proton-pump_NN inhibitor_NN )_) and_CC amoxicillin_NN Omeprazole_NP should_MD be_BE given_VBN at_RB least_RB twice_RB daily_JJ and_CC the_ATI two_CD agents_NNS begun_VBN at_IN the_ATI same_AP time_NN because_CS immediate_JJ pretreatment_NN with_IN omeprazole_NN lowers_NNS efficacy_NN of_IN the_ATI combination_NN of_IN omeprazole_NN and_CC amoxicillin_NN two-drug_NN or_CC three-drug_NN regimens_NNS should_MD last_AP 2_CD weeks_NNS if_CS therapy_NN is_BEZ begun_VBN at_IN the_ATI time_NN of_IN active_JJ peptic_JJ disease_NN , treatment_NN with_IN antisecretory_NN agents_NNS in_IN addition_NN to_IN antimicrobials_NNS is_BEZ recommended.=20_CD 249_CD when_WRB multiple_JJ drugs_NNS are_BER administered_VBN at_IN various_JJ times_NNS in_IN the_ATI day_NN , patient_NN compliance_NN may_MD become_VB an_AT important_JJ factor_NN affecting_VBG efficacy_NN if_CS symptoms_NNS persist_VB or_CC recur_NN after_IN initial_JJ treatment_NN , diagnostic_JJ reevaluation_NN should_MD be_BE undertaken_VBN and_CC a_AT second_OD course_RB of_IN therapy_NN considered_VBN side_NN effects_NNS are_BER more_QL frequent_JJ with_IN the_ATI three-drug_NN regimen_NNS than_CS with_IN the_ATI two-drug_NN regimen_NNS , but_CC have_HV been_BEN mild_JJ in_IN either_DTX case_NN and_CC infrequently_RB have_HV prevented_VBN completion_NN of_IN therapy_NN serious_JJ but_CC rare_JJ events_NNS such_IN as_IN anaphylaxis_NN , Stevens- Johnson_NP syndrome_NN , and_CC pseudomembranous_JJ colitis_NN should_MD be_BE expected_VBN as_CS antimicrobial_JJ regimens_NNS are_BER used_VBN more_QL widely_RB safety_NN and_CC efficacy_NN of_IN antimicrobial_JJ therapy_NN in_IN H_ZZ pylori- infected_JJ children_NNS and_CC adolescents_NNS have_HV not_XNOT been_BEN studied_VBN in_IN detail_NN 250_CD resistance_NN to_IN antimicrobials_NNS , in_IN particular_JJ to_IN nitroimidazoles_NNS such_ABL as_IN metronidazole_NN , is_BEZ an_AT important_JJ problem_NN and_CC a_AT cause_NN for_IN treatment_NN failure_NN in_IN some_DTI studies_NNS resistance_NN to_TO metronidazole_VB varies_VBZ worldwide_NN , with_IN the_ATI highest_JJT rates_NNS (_( 40%_NP to_IN 50%_NP )_) in_IN developing_VBG countries_NNS application_NN of_IN currently_RB available_JJ one-drug_NN regimens_NNS has_HVZ led_VBN to_TO enhanced_VBN antimicrobial_JJ resistance_NN and_CC , thus_RB , is_BEZ strongly_RB discouraged_VBN the_ATI widespread_JJ application_NN of_IN antimicrobial_JJ regimens_NNS to_TO treat_VB H_ZZ pylori_NN infection_NN may_MD magnify_VB the_ATI problem_NN of_IN drug_NN resistance_NN thus_RB , alternative_NN treatment_NN or_CC prevention_NN strategies_NNS such_IN as_IN vaccines_NNS or_CC immunotherapy_NN may_MD deserve_VB attention_NN in_IN the_ATI future_NN 251_CD DOES_NPT ERADICATION_NP OF_NP H_ZZ PYLORI_NPT INFECTION_NPT BENEFIT_NPT THE_NPT PATIENT_NP WITH_NP PEPTIC_NPT ULCER_NP DISEASE_NP ? 252_CD helicobacter_NN pylori_NN infection_NN is_BEZ strongly_RB associated_VBN with_IN the_ATI predominant_JJ forms_NNS of_IN peptic_JJ ulcer_NN disease_NN and_CC appears_VBZ to_TO play_VB an_AT important_JJ contributory_JJ role_NN in_IN their_PP$ pathogenesis_NN ; thus_RB , it_PP3 is_BEZ reasonable_JJ to_TO suggest_VB that_CS eradication_NN of_IN H_ZZ pylori_NN infection_NN may_MD benefit_VB patients_NNS with_IN peptic_JJ ulcer_NN disease_NN although_CS further_JJB studies_NNS are_BER needed_VBN to_TO delineate_VB fully_RB the_ATI role_NN of_IN H_ZZ pylori_NN eradication_NN in_IN many_AP other_AP patient_NN populations_NNS , available_JJ studies_NNS have_HV demonstrated_VBN clearly_RB the_ATI principal_JJB benefit_NN of_IN eradication_NN in_IN patients_NNS with_IN peptic_JJ ulcers_NNS , a_AT substantial_JJ reduction_NN in_IN the_ATI risk_NN of_IN ulcer_NN recurrence_NN (_( to_IN {_( 10%_CD in_IN 1_CD1 year_NN )_) the_ATI evidence_NN is_BEZ more_QL complete_JJ for_IN patients_NNS with_IN duodenal_JJ ulcers_NNS than_CS for_IN those_DTS with_IN gastric_JJ ulcers_NNS , although_CS the_ATI benefits_NNS to_IN the_ATI two_CD sets_NNS of_IN patients_NNS appear_VB to_IN be_BE comparable.=20_CD 253_CD the_ATI side_NN effects_NNS of_IN current_JJ regimens_NNS for_IN eradication_NN of_IN H_ZZ pylori_NN infection_NN are_BER generally_RB minor_JJ and_CC are_BER outweighed_VBN by_IN the_ATI benefit_NN of_IN reduced_JJ ulcer_NN recurrence_NN when_WRB combined_VBN with_IN standard_NN antisecretory_NN therapy_NN , H_ZZ pylori_NN eradication_NN may_MD contribute_VB to_IN a_AT modest_JJ reduction_NN in_IN time_NN to_TO ulcer_NN healing_NN moreover_RB , eradication_NN of_IN H_ZZ pylori_NN infection_NN may_MD enhance_VB healing_NN of_IN ulcers_NNS refractory_JJ to_IN conventional_JJ therapy_NN 254_CD a_AT separate_JJ question_NN is_BEZ whether_CS H_ZZ pylori_NN eradication_NN prevents_VBZ future_NN problems_NNS in_IN peptic_JJ ulcer_NN patients_NNS with_IN a_AT history_NN of_IN bleeding_NN or_CC other_AP complications_NNS although_CS preliminary_JJ data_NNS indicate_VB such_ABL efficacy_NN , more_QL definitive_JJ data_NNS are_BER needed_VBN 255_CD the_ATI benefits_NNS of_IN eradicating_VBG H_ZZ pylori_NN infection_NN in_IN patients_NNS with_IN peptic_JJ ulcer_NN disease_NN may_MD vary_VB depending_VBG on_IN a_AT variety_NN of_IN factors_NNS including_IN those_DTS related_VBN to_IN the_ATI host_NN , the_ATI organism_NN , and_CC the_ATI environment_NN Such_NP factors_NNS include_VB patient_NN demographics_NNS (_( age_NN , socioeconomic_JJ status_NN , concurrent_JJ illness_NN , and_CC behavioral_JJ factors_NNS )_) , frequency_NN of_IN reinfection_NN , mode_NN of_IN transmission_NN , and_CC strain_NN variation_NN 256_CD the_ATI potential_JJ cost_NN savings_NNS associated_VBN with_IN treating_VBG H_ZZ pylori_NN infection_NN have_HV not_XNOT been_BEN established_VBN , but_CC may_MD be_BE substantial_JJ carefully_RB designed_VBN economic_JJ analyses_NNS are_BER needed_VBN to_TO assess_VB more_QL completely_RB the_ATI cost-effectiveness_NN of_IN H_ZZ pylori_NN eradication_NN in_IN patients_NNS with_IN peptic_JJ ulcer_NN disease_NN 257_CD WHAT_NPT IS_NPT THE_NPT RELATIONSHIP_NP BETWEEN_NP H_ZZ PYLORI_NPT INFECTION_NPT AND_NP GASTRIC_NP MALIGNANCY_NP ? 258_CD 37_CD adenocarcinoma_NN of_IN the_ATI stomach_NN is_BEZ one_CD1 of_IN the_ATI most_QL common_JJ malignancies_NNS in_IN the_ATI world_NN , although_CS it_PP3 is_BEZ relatively_RB uncommon_JJ in_IN the_ATI United_NP States_NP (_( 24_CD 000_CD new_JJ cases_NNS and_CC 14_CD 000_CD deaths_NNS per_NNU year_NN )_) there_EX is_BEZ evidence_NN that_CS H_ZZ pylori_NN infection_NN is_BEZ associated_VBN with_IN adenocarcinoma_NN of_IN the_ATI body_NN and_CC antrum_NN of_IN the_ATI stomach_NN however_RB , gastric_JJ cancer_NN occurs_VBZ in_IN some_DTI individuals_NNS with_IN no_ATI evidence_NN of_IN H_ZZ pylori_NN infection_NN , and_CC in_IN the_ATI United_NP States_NP fewer_AP than_IN 1%_CD of_IN H_ZZ pylori-infected_JJ individuals_NNS will_MD ever_RB develop_VB gastric_JJ cancer_NN the_ATI effect_NN of_IN prevention_NN or_CC treatment_NN of_IN H_ZZ pylori_NN infection_NN on_IN gastric_JJ cancer_NN risk_NN has_HVZ not_XNOT been_BEN studied_VBN adequately_RB 259_CD 38_CD descriptive_JJ epidemiologic_JJ data_NNS indicate_VB that_CS gastric_JJ cancer_NN occurs_VBZ more_QL frequently_RB in_IN some_DTI populations_NNS that_CS have_HV higher_JJR rates_NNS of_IN H_ZZ pylori_NN infection_NN rates_NNS both_ABX of_IN H_ZZ pylori_NN infection_NN and_CC of_IN gastric_JJ cancer_NN correlate_VB inversely_RB with_IN socioeconomic_JJ status_NN , increase_NN as_IN a_AT function_NN of_IN age_NN , have_HV declined_VBN in_IN successive_JJ birth_NN cohorts_NNS in_IN developed_JJ countries_NNS , and_CC occur_VB less_QL commonly_RB in_IN whites_NNS than_IN in_IN African_JNP Americans_NNPS and_CC Hispanics_NP in_IN the_ATI United_NP States_NP a_AT geographic_JJ correlation_NN has_HVZ been_BEN found_VBN between_IN H_ZZ pylori_NN infection_NN and_CC gastric_JJ cancer_NN death_NN rates_NNS however_RB , some_DTI clear_JJ examples_NNS exist_VB of_IN disparity_NN in_IN the_ATI epidemiology_NN of_IN the_ATI two_CD diseases_NNS gastric_JJ cancer_NN is_BEZ more_QL common_NN in_IN men_NNS than_IN in_IN women_NNS , whereas_CS the_ATI rates_NNS of_IN H_ZZ pylori_NN infection_NN are_BER not_XNOT different_JJ between_IN the_ATI sexes_NNS Some_NP populations_NNS are_BER reported_VBN to_TO have_HV a_AT high_JJ rate_NN of_IN H_ZZ pylori_NN infection_NN but_CC low_JJ rates_NNS of_IN gastric_JJ cancer_NN these_DTS disparities_NNS indicate_VB that_CS factors_NNS other_AP than_IN H_ZZ pylori_NN infection_NN are_BER also_RB important_JJ in_IN gastric_JJ cancer_NN risk_NN 260_CD 39_CD some_DTI but_CC not_XNOT all_ABN of_IN the_ATI retrospective_JJ serological_JJ studies_NNS have_HV shown_VBN that_CS patients_NNS with_IN gastric_JJ cancer_NN more_QL frequently_RB have_HV H_ZZ pylori_NN infection_NN than_IN do_DO controls_NNS the_ATI strongest_JJT evidence_NN that_CS H_ZZ pylori_NN infection_NN is_BEZ associated_VBN with_IN gastric_JJ cancer_NN comes_VBZ from_IN three_CD prospective_JJ cohort_NN serological_JJ studies_NNS that_WPR indicate_VB that_CS H_ZZ pylori-infected_JJ individuals_NNS have_HV a_AT significantly_RB increased_JJ rate_NN of_IN gastric_JJ cancer_NN there_EX is_BEZ no_ATI association_NN in_IN any_DTI of_IN these_DTS studies_NNS between_IN H_ZZ pylori_NN infection_NN and_CC cancer_NN in_IN the_ATI gastric_JJ cardia_NN and_CC gastroesophageal_JJ junction_NN , which_WDTR is_BEZ increasing_JJ in_IN incidence_NN in_IN the_ATI United_NP States_NP 261_CD Non-Hodgkin's_NP$ lymphoma_NN of_IN the_ATI stomach_NN is_BEZ a_AT rare_JJ disorder_NN that_CS accounts_NNS for_IN only_RB 3%_CD of_IN gastric_JJ malignancies_NNS mucosa-associated_JJ lymphoid_NN tissue_NN lymphomas_NNS , which_WDTR constitute_VB a_AT subset_NN of_IN non-Hodgkin's_NP$ lymphoma_NN , are_BER low- grade_JJ clonal_JJ neoplasms_NNS that_CS are_BER thought_VBN to_TO arise_VB from_IN lymphoid_NN aggregates_NNS in_IN the_ATI lamina_NN propria_NN preliminary_JJ epidemiologic_JJ data_NNS suggest_VB that_CS H_ZZ pylori_NN infection_NN is_BEZ associated_VBN both_ABX with_IN non-Hodgkin's_NP$ lymphoma_NN and_CC with_IN mucosa-associated_JJ lymphoid_NN tissue_NN lymphomas_NNS of_IN the_ATI stomach_NN Further_NP study_NN of_IN the_ATI relationship_NN between_IN H_ZZ pylori_NN infection_NN and_CC gastric_JJ lymphomas_NNS is_BEZ warranted_VBD 262_CD in_IN summary_NN , if_CS there_EX is_BEZ any_DTI causal_JJ relationship_NN between_IN H_ZZ pylori_NN infection_NN and_CC gastric_JJ cancer_NN , clearly_RB other_AP factors_NNS are_BER also_RB important_JJ in_IN gastric_JJ carcinogenesis_NN helicobacter_NN pylori_NN eradication_NN for_IN the_ATI purpose_NN of_IN preventing_VBG gastric_JJ cancer_NN cannot_NN be_BE recommended_VBN at_IN this_DT time_NN 263_CD WHICH_NP H_ZZ PYLORI-INFECTED_NPT PATIENTS_NPT SHOULD_NPT BE_NP TREATED_NP ? 264_CD there_EX are_BER ample_JJ data_NNS to_TO support_VB the_ATI antimicrobial_JJ eradication_NN of_IN H_ZZ pylori_NN infection_NN in_IN patients_NNS with_IN peptic_JJ ulcer_NN disease_NN all_ABN patients_NNS with_IN gastric_JJ or_CC duodenal_JJ ulcers_NNS who_WPR are_BER infected_VBN with_IN H_ZZ pylori_NN should_MD be_BE treated_VBN with_IN antimicrobials_NNS regardless_RB of_IN whether_CS they_PP3AS are_BER suffering_VBG from_IN the_ATI initial_JJ presentation_NN of_IN the_ATI disease_NN or_CC from_IN a_AT recurrence_NN Helicobacter_NP pylori-infected_JJ patients_NNS with_IN peptic_JJ ulcer_NN disease_NN who_WPR are_BER receiving_VBG maintenance_NN treatment_NN with_IN antisecretory_NN agents_NNS or_CC who_WPR have_HV a_AT history_NN of_IN complicated_JJ or_CC refractory_JJ disease_NN should_MD also_RB be_BE treated_VBN for_IN the_ATI infection_NN the_ATI presence_NN of_IN NSAIDs_NP , including_IN aspirin_NN , as_IN a_AT contributing_VBG factor_NN should_MD not_XNOT alter_VB the_ATI antimicrobial_JJ regimen_NNS , but_CC these_DTS drugs_NNS should_MD be_BE discontinued_VBN whenever_WRB possible_JJ however_RB , in_IN asymptomatic_JJ H_ZZ pylori-infected_JJ patients_NNS without_IN ulcers_NNS , the_ATI data_NNS are_BER not_XNOT sufficient_JJ to_TO support_VB prophylactic_JJ antimicrobial_JJ therapy_NN to_TO prevent_VB ulcer_NN disease_NN in_IN the_ATI future_NN or_CC to_TO reduce_VB the_ATI likelihood_NN of_IN developing_VBG gastric_JJ neoplasia_NN also_RB , no_ATI convincing_JJ data_NNS exist_VB to_TO support_VB routine_NN treatment_NN of_IN patients_NNS with_IN nonulcerative_JJ dyspepsia_NN who_WPR are_BER H_ZZ pylori-infected.=20_CD-CD 265_NN thus_RB , at_IN the_ATI present_JJ time_NN there_EX is_BEZ no_ATI reason_NN to_TO consider_VB routine_NN detection_NN or_CC treatment_NN of_IN H_ZZ pylori_NN infection_NN in_IN the_ATI absence_NN of_IN ulcers_NNS Carefully_NP controlled_VBD prospective_JJ studies_NNS are_BER needed_VBN to_TO assess_VB the_ATI benefits_NNS of_IN treating_VBG nonulcer_NN dyspepsia_NN patients_NNS with_IN H_ZZ pylori_NN infection_NN obviously_RB , no_ATI patient_NN should_MD be_BE treated_VBN for_IN H_ZZ pylori_NN unless_CS one_CD1 of_IN the_ATI sensitive_JJ and_CC specific_JJ tests_NNS previously_RB discussed_VBN demonstrates_VBZ infection_NN 266_NN bleeding_NN is_BEZ the_ATI complication_NN of_IN peptic_JJ ulcer_NN disease_NN associated_VBN with_IN the_ATI highest_JJT mortality_NN rate_NN and_CC , therefore_RB , demands_NNS aggressive_JJ therapy_NN the_ATI available_JJ data_NNS suggest_VB that_CS after_IN these_DTS ulcers_NNS heal_JJ , the_ATI likelihood_NN of_IN recurrence_NN with_IN bleeding_NN is_BEZ significantly_RB reduced_VBN by_IN maintenance_NN antisecretory_NN therapy_NN preliminary_JJ studies_NNS indicate_VB that_CS eradication_NN of_IN H_ZZ pylori_NN infection_NN may_MD be_BE equally_RB efficient_JJ in_IN preventing_VBG the_ATI recurrence_NN of_IN ulcerative_JJ bleeding_NN until_CS these_DTS studies_NNS can_MD be_BE confirmed_VBN , maintenance_NN antisecretory_NN therapy_NN may_MD be_BE prudent_JJ in_IN such_ABL patients_NNS even_RB after_IN H_ZZ pylori_NN eradication_NN in_IN view_NN of_IN the_ATI high_JJ risks_NNS associated_VBN with_IN rebleeding_NN 267_CD WHAT_NPT ARE_NPT THE_NPT MOST_NPT IMPORTANT_NPT QUESTIONS_NPT THAT_NPT MUST_NPT BE_NPT ADDRESSED_NP BY_NP FUTURE_NPT RESEARCH_NP IN_NP H_ZZ PYLORI_NP INFECTIONS_NP ? 268_NN although_CS much_AP is_BEZ known_VBN about_IN the_ATI role_NN of_IN H_ZZ pylori_NN in_IN gastrointestinal_JJ disease_NN , many_AP issues_NNS are_BER still_RB unresolved_JJ 269_NN further_JJB , well-designed_JJ studies_NNS on_IN the_ATI role_NN of_IN H_ZZ pylori_NN eradication_NN in_IN the_ATI management_NN of_IN peptic_JJ ulcer_NN disease_NN are_BER needed_VBN , particularly_RB in_IN populations_NNS not_XNOT well_RB studied_VBN to_TO date_VB , including_IN children_NNS , patients_NNS with_IN gastric_JJ ulcers_NNS , and_CC patients_NNS with_IN duodenal_JJ or_CC gastric_JJ ulcers_NNS with_IN complications_NNS these_DTS studies_NNS should_MD use_VB standard_NN definitions_NNS , be_BE randomized_VBN , be_BE analyzed_VBN on_IN an_AT intent-to-treat_NN basis_NN , have_HV sample_NN size_NN adequate_JJ to_TO detect_VB clinically_RB meaningful_JJ differences_NNS between_IN treatment_NN arms_NNS , and_CC be_BE double-blinded_JJ whenever_WRB possible_JJ 270_CD fundamental_JJ questions_NNS remain_VB concerning_IN the_ATI initial_JJ evaluation_NN of_IN a_AT patient_NN who_WPR presents_VBZ with_IN dyspepsia_NN should_MD that_CS patient_NN be_BE tested_VBN for_IN H._NP pylori_NN infection_NN ? should_MD that_CS patient_NN be_BE treated_VBN empirically_RB for_IN H._NP pylori_NN infection_NN if_CS it_PP3 is_BEZ present_JJ ? the_ATI answers_NNS to_IN these_DTS questions_NNS depend_VB in_IN part_NN on_IN whether_CS antimicrobial_JJ therapy_NN relieves_NNS symptoms_NNS in_IN some_DTI or_CC all_ABN symptomatic_JJ patients_NNS with_IN H_ZZ pylori_NN infection_NN and_CC gastritis_NN , but_CC without_IN ulcers_NNS if_CS the_ATI answer_NN is_BEZ yes_UH , patients_NNS presenting_VBG to_IN the_ATI physician_NN with_IN dyspepsia_NN should_MD be_BE tested_VBN for_IN H_ZZ pylori_NN infection_NN and_CC , if_CS the_ATI results_NNS are_BER positive_JJ , be_BE treated_VBN with_IN antimicrobial_JJ therapy.=20_CD 271_CD however_RB , if_CS symptomatic_JJ H_ZZ pylori-infected_JJ patients_NNS without_IN ulcers_NNS do_DO not_XNOT respond_VB to_IN antimicrobial_JJ therapy_NN , it_PP3 will_MD continue_VB to_TO be_BE imperative_JJ to_TO confirm_VB the_ATI diagnosis_NN of_IN peptic_JJ ulcer_NN disease_NN in_IN order_NN to_TO identify_VB the_ATI patients_NNS who_WPR will_MD benefit_VB from_IN treatment_NN of_IN their_PP$ infection_NN under_IN these_DTS circumstances_NNS , the_ATI question_NN arises_VBZ as_CS to_TO whether_CS it_PP3 is_BEZ necessary_JJ , appropriate_JJ , and_CC cost-effective_JJ to_TO perform_VB endoscopy_NN in_IN dyspeptic_JJ patients_NNS at_IN initial_JJ presentation_NN 272_NN another_DT major_JJ question_NN that_CS remains_VBZ to_TO be_BE answered_VBN is_BEZ whether_CS eradication_NN of_IN H_ZZ pylori_NN infection_NN prevents_VBZ gastric_JJ cancer_NN such_ABL a_AT question_NN cannot_NN be_BE answered_VBN directly_RB without_IN a_AT long_JJ and_CC costly_JJ study_NN Thus_JJ , an_AT alternative_NN approach_NN might_MD be_BE to_TO conduct_VB studies_NNS looking_VBG at_IN intermediate_JJ end_NN points_NNS that_CS are_BER thought_VBN to_TO predict_VB the_ATI evolution_NN of_IN malignancy_NN and_CC their_PP$ response_NN to_TO H_ZZ pylori_NN eradication_NN epidemiologic_JJ studies_NNS are_BER also_RB needed_VBN to_TO define_VB more_QL precisely_RB the_ATI subset_NN of_IN H_ZZ pylori-infected_JJ individuals_NNS who_WPR will_MD develop_VB gastric_JJ cancer_NN 273_CD a_AT major_JJ opportunity_NN for_IN additional_JJ studies_NNS is_BEZ in_IN the_ATI area_NN of_IN mechanisms_NNS by_IN which_WDTR H_ZZ pylori_NN infection_NN leads_VBZ to_IN gastrointestinal_JJ disease_NN virulence_NN factors_NNS , bacterial_JJ genetics_NNS , mechanisms_NNS of_IN immunity_NN , animal_NN models_NNS , antibiotic_JJ resistance_NN , and_CC modes_NNS of_IN transmission_NN are_BER all_ABN issues_NNS that_DT should_MD be_BE examined_VBN in_IN future_NN studies_NNS furthermore_RB , the_ATI natural_JJ history_NN of_IN H_ZZ pylori_NN infections_NNS and_CC the_ATI nature_NN of_IN the_ATI interaction_NN between_IN host_NN and_CC organism_NN require_VB further_JJB study_NN the_ATI pathogenic_JJ consequences_NNS of_IN H_ZZ pylori_NN infection_NN in_IN childhood_NN and_CC adolescence_NN and_CC the_ATI optimal_JJ management_NN of_IN infection_NN are_BER additional_JJ important_JJ questions_NNS more_AP information_NN is_BEZ needed_VBN on_IN the_ATI value_NN of_IN testing_NN to_TO confirm_VB eradication_NN after_IN antimicrobial_JJ therapy_NN , and_CC antimicrobial_JJ regimens_NNS need_NN to_TO be_BE optimized_VBN to_TO improve_VB treatment_NN efficacy_NN a_AT comprehensive_JJ economic_JJ analysis_NN should_MD be_BE conducted_VBN to_TO examine_VB the_ATI cost-effectiveness_NN of_IN treating_VBG H_ZZ pylori_NN infection_NN 274_CD CONCLUSIONS_NP 275_CD the_ATI discovery_NN of_IN H_ZZ pylori_NN as_IN a_AT gastrointestinal_JJ pathogen_NN has_HVZ had_HVN a_AT profound_JJ effect_NN on_IN current_JJ concepts_NNS of_IN the_ATI pathogenesis_NN of_IN peptic_JJ ulcer_NN disease_NN evidence_NN presented_VBN at_IN this_DT Consensus_JJ Development_NP Conference_NP has_HVZ led_VBN to_IN the_ATI following_JJ conclusions_NNS : 276_CD ulcer_NN patients_NNS with_IN H_ZZ pylori_NN infection_NN require_VB treatment_NN with_IN antimicrobial_JJ agents_NNS in_IN addition_NN to_TO antisecretory_VB drugs_NNS whether_CS on_IN first_OD presentation_NN with_IN the_ATI illness_NN or_CC on_IN recurrence_NN 277_NN the_ATI value_NN of_IN treatment_NN of_IN patients_NNS with_IN nonulcerative_JJ dyspepsia_NN and_CC H._NP pylori_NN infection_NN remains_VBZ to_TO be_BE determined_JJ 278_NN the_ATI interesting_JJ relationship_NN between_IN H_ZZ pylori_NN infection_NN and_CC gastric_JJ cancers_NNS requires_VBZ further_JJB exploration_NN 279_CD chronic_JJ Hepatitis_NP C_ZZ : advances_NNS in_IN Diagnostic_NP Testing_NP and_CC Therapy_NP 280_CD the_ATI methods_NNS for_IN diagnosing_VBG hepatitis_NN C_ZZ virus_NN infection_NN have_HV been_BEN evolving_VBG since_IN the_ATI first-generation_JJ enzyme-linked_JJ immunosorbent_NN assay_NN antibody_NN test_NN was_BEDZ devised_VBN in_IN 1989_CD in_IN addition_NN to_IN assaying_VBG for_IN serum_NN antibodies_NNS against_IN viral_JJ proteins_NNS , serum_NN and_CC liver_NN tissue_NN can_MD be_BE tested_VBN for_IN viral_JJ RNA_NP , evidence_NN of_IN ongoing_VBG viral_JJ replication_NN the_ATI improving_VBG ability_NN to_TO diagnose_VB hepatitis_NN C_ZZ has_HVZ furthered_VBD the_ATI understanding_NN of_IN the_ATI natural_JJ history_NN of_IN this_DT infection_NN acute_JJ hepatitis_NN C_ZZ results_NNS in_IN chronic_JJ elevations_NNS of_IN serum_NN transaminase_NN levels_NNS following_JJ nearly_RB one_CD1 half_ABN of_IN cases_NNS cirrhosis_NN complicates_VBZ approximately_RB 20%_NP of_IN chronic_JJ infections_NNS Long-standing_NP chronic_JJ hepatitis_NN C_ZZ may_MD play_VB a_AT role_NN in_IN the_ATI pathogenesis_NN of_IN hepatocellular_NN carcinoma_NN sustained_JJ normalization_NN of_IN serum_NN transaminase_NN levels_NNS , often_RB accompanied_VBN by_IN a_AT decrease_NN in_IN or_CC disappearance_NN of_IN viral_JJ RNA_NP , occurs_VBZ in_IN approximately_RB 25%_JJ of_IN patients_NNS with_IN chronic_JJ hepatitis_NN C_ZZ who_WPR are_BER treated_VBN with_IN a_AT 6- month_JJ course_RB of_IN recombinant_NN interferon_NN alfa_NN This_NN treatment_NN can_MD occasionally_RB be_BE complicated_VBN by_IN hematologic_JJ , endocrinologic_JJ , and_CC psychiatric_JJ adverse_JJ effects_NNS but_CC is_BEZ usually_RB fairly_RB well_RB tolerated_VBN whether_CS interferon_NN therapy_NN will_MD diminish_VB the_ATI risk_NN of_IN cirrhosis_NN or_CC carcinoma_NN is_BEZ not_XNOT yet_RB known_VBN this_DT article_NN reviews_NNS the_ATI diagnosis_NN of_IN chronic_JJ hepatitis_NN C_ZZ infection_NN as_QL well_RB as_IN the_ATI mechanisms_NNS of_IN action_NN , efficacy_NN , and_CC adverse_JJ effects_NNS associated_VBN with_IN interferon_NN alfa_NN therapy_NN 281_CD it_PP3 has_HVZ only_RB been_BEN 4_CD years_NNS since_IN the_ATI first_OD immunoassay_NN to_TO detect_VB human_JJ serum_NN antibodies_NNS directed_VBN against_IN hepatitis_NN C_ZZ virus_NN (_( HCV_NP )_) antigens_NNS was_BEDZ developed_VBN subsequent_JJ improvements_NNS in_IN diagnosing_VBG hepatitis_NN C_ZZ and_CC the_ATI rapidly_RB evolving_VBG description_NN of_IN the_ATI hepatitis_NN C_ZZ genome_NN have_HV contributed_VBN to_IN the_ATI expanding_JJ understanding_NN of_IN the_ATI epidemiologic_JJ characteristics_NNS , natural_JJ history_NN , and_CC response_NN to_IN treatment_NN of_IN chronic_JJ hepatitis_NN C_ZZ infection_NN 282_NN while_CS approximately_RB 90%_NP of_IN cases_NNS of_IN posttransfusional_JJ hepatitis_NN are_BER now_RN known_VBN to_TO be_BE caused_VBN by_IN HCV_NP , transfusions_NNS account_VB for_IN only_RB 5%_JJ to_IN 10%_CD of_IN new_JJ cases_NNS of_IN hepatitis_NN C_ZZ other_AP percutaneous_JJ exposures_NNS , mostly_RB from_IN intravenous_JJ drug_NN use_NN but_CC also_RB related_VBN to_TO hemodialysis_VB , organ_NN transplantation_NN , and_CC occupational_JJ exposures_NNS , account_NN for_IN a_AT significant_JJ number_NN of_IN cases_NNS vertical_JJ (_( from_IN mother_NN to_TO neonate_VB at_IN birth_NN )_) and_CC sexual_JJ transmission_NN have_HV also_RB been_BEN implicated_VBN as_IN risk_NN factors_NNS for_IN hepatitis_NN C_ZZ infection_NN in_IN many_AP epidemiologic_JJ series_NN , however_RB , known_JJ risk_NN factors_NNS have_HV still_RB not_XNOT been_BEN identified_VBN in_IN up_RP to_IN 40%_NP of_IN cases_NNS of_IN hepatitis_NN C_ZZ 283_CD various_JJ studies_NNS of_IN both_ABX posttransfusion_NN and_CC community- acquired_JJ hepatitis_NN C_ZZ have_HV demonstrated_VBN that_CS chronic_JJ elevations_NNS of_IN serum_NN transaminase_NN levels_NNS develop_VB following_JJ nearly_RB 50%_NP of_IN cases_NNS of_IN acute_JJ hepatitis_NN C_ZZ it_PP3 has_HVZ been_BEN reported_VBN that_CS approximately_RB 20%_NP of_IN these_DTS chronic_JJ infections_NNS progress_NN to_TO cirrhosis_VB epidemiologic_JJ evidence_NN also_RB implicates_NNS hepatitis_NN C_ZZ as_CS having_HVG a_AT possible_JJ causal_JJ role_NN in_IN the_ATI development_NN of_IN some_DTI cases_NNS of_IN hepatocellular_NN carcinoma_NN 284_NN prior_RB to_IN the_ATI demonstration_NN of_IN the_ATI efficacy_NN of_IN interferon_NN alfa_NN therapy_NN , there_EX were_BED no_ATI successful_JJ therapies_NNS for_IN eradicating_VBG hepatitis_NN C._NP While_NP not_XNOT universally_RB effective_JJ , treatment_NN with_IN interferon_NN represents_VBZ a_AT major_JJ advance_NN in_IN the_ATI management_NN of_IN this_DT chronic_JJ disorder_NN not_XNOT every_AT patient_NN with_IN chronic_JJ hepatitis_NN C_ZZ , however_RB , is_BEZ an_AT appropriate_JJ candidate_NN for_IN interferon_NN therapy_NN the_ATI choice_NN of_IN which_WDTR patients_NNS to_TO treat_VB involves_VBZ both_ABX objective_JJ and_CC subjective_JJ criteria_NNS , guided_VBN by_IN clinical_JJ judgment_NN 285_NN this_DT article_NN will_MD concentrate_VB on_IN the_ATI advances_NNS made_VBN in_IN the_ATI diagnostic_JJ testing_NN for_IN chronic_JJ hepatitis_NN C_ZZ as_QL well_RB as_IN the_ATI results_NNS achieved_VBN with_IN interferon_NN therapy_NN specifically_RB , the_ATI indications_NNS for_IN interferon_NN treatment_NN , the_ATI expected_JJ response_NN rates_NNS , and_CC the_ATI anticipated_VBN adverse_JJ effects_NNS will_MD be_BE reviewed_VBN 286_NN DIFFERENTIAL_NPT DIAGNOSIS_NPT OF_NPT CHRONIC_NP HEPATITIS_NP 287_CD the_ATI term_NN hepatitis_NN indicates_VBZ a_AT liver_NN disease_NN that_CS primarily_RB involves_VBZ ongoing_VBG hepatocellular_NN necrosis_NN hepatitis_NN is_BEZ typically_RB characterized_VBN by_IN a_AT disproportionate_JJ elevation_NN of_IN the_ATI serum_NN transaminase_NN levels_NNS compared_VBN with_IN serum_NN alkaline_JJ phosphatase_NN and_CC bilirubin_NN levels_NNS in_IN contrast_NN , cholestatic_JJ liver_NN diseases_NNS , such_IN as_IN primary_JJ biliary_NN cirrhosis_NN or_CC sclerosing_VBG cholangitis_NN , typically_RB exhibit_VB the_ATI opposite_JJ pattern_NN , with_IN predominant_JJ elevations_NNS of_IN serum_NN alkaline_JJ phosphatase_NN and_CC , possibly_RB , bilirubin_NN levels_NNS there_EX are_BER clearly_RB instances_NNS in_IN which_WDTR it_PP3 is_BEZ difficult_JJ to_TO categorize_VB a_AT liver_NN disease_NN as_IN either_DTX hepatocellular_NN or_CC cholestatic_JJ based_VBN solely_RB on_IN the_ATI liver_NN enzyme_NN levels_NNS while_CS not_XNOT universally_RB indicated_VBN in_IN the_ATI assessment_NN of_IN chronic_JJ liver_NN diseases_NNS , liver_NN biopsy_NN may_MD clarify_VB which_WDTR general_JJ pathophysiologic_JJ pattern_NN predominates_VBZ 288_CD all_ABN cases_NNS of_IN hepatitis_NN A_ZZ , most_QL cases_NNS of_IN viral_JJ hepatitis_NN B_ZZ , about_IN half_ABN the_ATI cases_NNS of_IN hepatitis_NN C_ZZ , and_CC many_AP other_AP causes_NNS of_IN abnormal_JJ liver_NN enzyme_JJ levels_NNS of_IN varying_JJ causes_NNS remit_VB without_IN long-term_JJB sequelae_NN most_AP authorities_NNS designate_VB liver_NN disease_NN as_CS chronic_JJ if_CS elevations_NNS in_IN serum_NN liver_NN enzyme_NN levels_NNS persist_VB for_IN more_AP than_IN 6_CD months_NNS there_EX are_BER a_AT number_NN of_IN nonviral_JJ causes_NNS of_IN chronic_JJ elevations_NNS in_IN serum_NN transaminase_NN levels_NNS , including_IN alcohol- related_JJ liver_NN disease_NN , autoimmune_NN hepatitis_NN , medication-induced_JJ liver_NN disease_NN , Wilson's_NP$ disease_NN , hemochromatosis_NN , alpha_NN sub_NN 1_CD1 -antitrypsin_NN deficiency_NN , and_CC nonalcoholic_JJ steatohepatitis_NN Since_NP several_AP of_IN these_DTS diseases_NNS are_BER treatable_VBN in_IN their_PP$ early_JJ stages_NNS , they_PP3AS need_NN to_TO be_BE considered_VBN in_IN the_ATI differential_JJ diagnosis_NN of_IN patients_NNS with_IN persistently_RB elevated_VBD serum_NN transaminase_NN levels_NNS 289_NN the_ATI two_CD major_JJ causes_NNS of_IN chronic_JJ viral_JJ hepatitis_NN in_IN the_ATI United_NP States_NP are_BER hepatitis_NN B_ZZ and_CC C._NP prior_RB to_IN 1989_CD , the_ATI term_NN non-A_NN , non-B_NN (_( NANB_NP )_) hepatitis_NN was_BEDZ used_VBN to_TO connote_VB those_DTS cases_NNS of_IN chronic_JJ hepatitis_NN thought_VBD to_TO be_BE virally_RB mediated_VBN but_CC without_IN specific_JJ positive_JJ serologic_JJ findings_NNS since_IN the_ATI discovery_NN of_IN the_ATI hepatitis_NN C_ZZ genome_NN in_IN 1989_CD , it_PP3 has_HVZ been_BEN recognized_VBN that_CS hepatitis_NN C_ZZ accounts_NNS for_IN 60%_NP to_IN 90%_NP of_IN what_WDT was_BEDZ formerly_RB designated_VBN NANB_NP hepatitis_NN 290_CD there_EX are_BER clearly_RB other_AP non-A_NN , non-B_NN , non-C_NN (_( NANBNC_NP )_) hepatitis_NN viruses_NNS hepatitis_NN E_ZZ is_BEZ a_AT recently_RB discovered_VBN RNA_NP virus_NN transmitted_VBN via_IN the_ATI fecal-oral_JJ route_NN that_WPR has_HVZ been_BEN documented_VBN primarily_RB in_IN Southeast_NP Asia_NP , India_NP , and_CC South_NP America_NP similar_JJ to_TO hepatitis_VB A_ZZ , hepatitis_NN E_ZZ does_DOZ not_XNOT appear_VB to_TO eventuate_VB in_IN chronic_JJ hepatitis_NN Epstein-Barr_NP virus_NN (_( mononucleosis_NN )_) , herpes_NNS simplex_NN virus_NN , cytomegalovirus_JJ , and_CC adenovirus_JJ may_MD all_ABN cause_VB acute_JJ hepatitis_NN but_CC do_DO not_XNOT result_VB in_IN chronic_JJ liver_NN disease_NN in_IN immunocompetent_NN hosts_NNS still_RB , some_DTI of_IN these_DTS infections_NNS may_MD take_VB several_AP months_NNS to_TO resolve_VB (_( although_CS nearly_RB always_RB fewer_AP than_IN 6_CD months_NNS )_) It_NP is_BEZ probable_JJ , however_RB , that_CS there_EX are_BER other_AP , yet_RB unrecognized_JJ NANBNC_NP hepatitis_NN viruses_NNS that_CS result_NN in_IN chronic_JJ liver_NN disease_NN 291_CD DIAGNOSIS_NPT OF_NP HEPATITIS_NP C_ZZ 292_NN the_ATI methods_NNS available_JJ for_IN diagnosing_VBG hepatitis_NN C_ZZ infection_NN have_HV been_BEN continually_RB evolving_VBG since_IN 1989_CD prior_RB to_TO that_CS , indirect_JJ surrogate_NN markers_NNS were_BED used_VBN in_IN an_AT attempt_NN to_TO identify_VB potential_JJ blood_NN donors_NNS who_WPR might_MD transmit_VB posttransfusional_JJ NANB_NP hepatitis_NN in_IN 1986_CD , for_IN example_NN , it_PP3 was_BEDZ recognized_VBN that_CS NANB_NP hepatitis_NN (_( most_AP of_IN which_WDTR , we_PP1AS now_RN recognize_VB , was_BEDZ hepatitis_NN C_ZZ )_) shared_VBD several_AP epidemiologic_JJ risk_NN factors_NNS with_IN hepatitis_NN B._NP therefore_RB , donated_VBN blood_NN was_BEDZ screened_VBN for_IN antibody_NN to_TO hepatitis_NN B_ZZ core_NN antigen_NN as_QL well_RB as_IN for_IN elevated_VBD serum_NN alanine_NN aminotransferase_NN levels_NNS while_CS screening_NN with_IN these_DTS surrogate_NN markers_NNS may_MD have_HV successfully_RB decreased_VBN the_ATI rate_NN of_IN posttransfusion_NN NANB_NP hepatitis_NN , this_DT indirect_JJ method_NN did_DOD not_XNOT eliminate_VB it_PP3 altogether_RB 293_CD First-Generation_NN Assays_NNS for_IN Hepatitis_NP C_ZZ Antibodies_NNS in_IN Serum_NP 294_CD Choo_NP et_&FW al_APS first_OD cloned_VBN HCV_NP from_IN highly_RB infectious_JJ chimpanzee_NN plasma_NN in_IN 1989_CD after_IN inserting_VBG complementary_JJ DNA_NP fragments_NNS from_IN this_DT serum_NN into_IN a_AT cloning_VBG vector_NN , viral_JJ proteins_NNS were_BED expressed_VBN by_IN Escherichia_NP coli_&FW organisms_NNS when_WRB the_ATI resultant_JJ proteins_NNS were_BED screened_VBN with_IN serum_NN from_IN a_AT patient_NN with_IN NANB_NP hepatitis_NN , a_AT single_JJ clone_NN (_( termed_VBD 5-1-1_CD-CD )_) reacted_VBN a_AT larger_JJR antigen_NN , c100-3_CD-CD , was_BEDZ assembled_VBN from_IN several_AP clones_NNS and_CC expressed_VBN in_IN yeast_NN as_IN a_AT fusion_NN protein_NN using_VBG human_JJ superoxide_NN dismutase_NN (_( SOD_NP )_) to_TO facilitate_VB expression_NN the_ATI 5-1-1_CD-CD and_CC c100-3_CD-CD antigens_NNS comprise_VB amino_NN acid_NN sequences_NNS derived_VBN from_IN nonstructural_JJ regions_NNS of_IN the_ATI hepatitis_NN C_ZZ genome_NN 295_NN in_IN the_ATI first-generation_JJ enzyme-linked_JJ immunosorbent_NN assay_NN (_( ELISA-1_CD-CD )_) , the_ATI patient's_NN$ serum_NN is_BEZ tested_VBN for_IN the_ATI presence_NN of_IN IgG_NP antibody_NN against_IN the_ATI c100-3_CD-CD antigen_NN the_ATI patient's_NN$ serum_NN is_BEZ added_VBN to_IN a_AT plate_NN coated_VBN with_IN recombinant_NN c100-3_CD-CD antigen_NN and_CC then_RN washed_VBN with_IN monoclonal_JJ antibody_NN against_IN human_JJ IgG_NP _** linked_VBN _** to_IN the_ATI enzyme_NN , horseradish_NN peroxidase_NN if_CS human_JJ antibody_NN against_IN c100-3_CD-CD is_BEZ present_JJ , when_WRB additional_JJ reagents_NNS are_BER added_VBN , they_PP3AS react_VB with_IN the_ATI horseradish_NN peroxidase_NN , emitting_VBG an_AT optical_JJ density_NN greater_JJR than_IN the_ATI predetermined_JJ threshold_NN (_( when_WRB read_VB at_IN a_AT specific_JJ wavelength_NN )_) 296_NN the_ATI ELISA-1_CD-CD test_NN was_BEDZ initially_RB confirmed_VBN in_IN human_JJ sera_NNS that_CS had_HVD transmitted_VBN NANB_NP hepatitis_NN to_IN chimpanzees_NNS and_CC in_IN a_AT retrospective_JJ analysis_NN of_IN human_JJ donor_NN blood_NN that_WPR resulted_VBD in_IN posttransfusion_NN NANB_NP hepatitis_NN unfortunately_RB , shortly_RB thereafter_RB , reports_NNS suggested_VBN that_CS false- positive_JJ ELISA-1_CD-CD results_NNS may_MD arise_VB in_IN the_ATI setting_NN of_IN hypergammaglobulinemia_NN , where_WRB low_JJ optical_JJ density_NN readings_NNS were_BED attributed_VBN to_IN binding_NN of_IN nonspecific_JJ antibodies_NNS to_IN the_ATI SOD_NP carrier_NN moiety_NN 297_NN the_ATI first-generation_NN recombinant_NN immunoblot_NN assay_NN (_( RIBA-1_CD- CD )_) incorporates_VBZ nitrocellulose_JJ strips_NNS of_IN purified_VBN c100_CD recombinant_NN antigen_NN from_IN yeast_NN , 5-1-1_CD-CD recombinant_NN antigen_NN from_IN E_ZZ coli_&FW organisms_NNS , and_CC SOD_NP These_NP strips_NNS are_BER bathed_VBN in_IN the_ATI serum_NN to_TO be_BE tested_VBN , and_CC goat_NN antibody_NN directed_VBN against_IN human_JJ IgG_NP is_BEZ added_VBN the_ATI antigen_NN band_NN response_NN is_BEZ compared_VBN with_IN that_DT of_IN positive_JJ controls_NNS for_IN the_ATI test_NN to_TO be_BE rated_VBN positive_JJ , there_EX must_MD be_BE at_RB least_RB a_AT weakly_RB positive_JJ response_NN to_TO both_ABX the_ATI c100_CD and_CC 5-1-1_CD-CD bands_NNS the_ATI inclusion_NN of_IN the_ATI SOD_NP strip_NN is_BEZ an_AT attempt_NN to_TO minimize_JJ possible_JJ false-positive_JJ results_NNS confounding_VBG ELISA- 1_CD-CD a_AT number_NN of_IN reports_NNS have_HV suggested_VBN improved_JJ specificity_NN of_IN RIBA-1_CD-CD compared_VBN with_IN ELISA-1_CD-CD 298_CD with_IN first-generation_NN testing_NN , HCV_NP antibodies_NNS are_BER usually_RB detectable_JJ a_AT mean_NN of_IN 15_CD weeks_NNS (_( range_NN , 10_CD to_IN 52_CD weeks_NNS )_) following_JJ acute_JJ infection_NN 299_NN this_DT implies_VBZ that_CS there_EX is_BEZ a_AT seronegative_JJ _** window_NN _** during_IN which_WDTR patients_NNS with_IN acute_JJ hepatitis_NN C_ZZ may_MD have_HV a_AT negative_JJ test_NN result_NN using_VBG first-generation_NN assays_NNS moreover_RB , not_XNOT all_ABN patients_NNS with_IN consistent_JJ clinical_JJ histories_NNS ultimately_RB seroconvert_JJ using_VBG first-generation_NN testing_NN this_DT may_MD relate_VB to_TO either_DTX low_JJ titers_NNS of_IN antibodies_NNS directed_VBN against_IN the_ATI specific_JJ antigens_NNS tested_VBN for_IN by_IN these_DTS assays_NNS or_CC to_TO more_QL global_JJ impairments_NNS in_IN the_ATI particular_JJ host's_NP$ immune_JJ response_NN 300_CD Second-Generation_NN Assays_NNS for_IN Hepatitis_NP C_ZZ Antibodies_NNS in_IN Serum_NP 301_CD the_ATI concerns_NNS regarding_IN suboptimal_JJ sensitivity_NN and_CC specificity_NN , as_CS well_RB as_IN the_ATI protracted_JJ seronegative_JJ window_NN , underscored_JJ the_ATI need_NN for_IN improved_JJ diagnostic_JJ testing_NN beyond_IN the_ATI capacity_NN of_IN first-generation_NN testing_NN the_ATI second-generation_NN assays_NNS incorporate_VB additional_JJ recombinant_NN antigens_NNS from_IN the_ATI viral_JJ genome_NN the_ATI ELISA-2_NP test_NN is_BEZ based_VBN on_IN antigens_NNS from_IN both_ABX the_ATI core_NN region_NN (_( c22-3_CD )_) and_CC a_AT nonstructural_JJ protein_NN consisting_VBG of_IN c100-3_CD-CD and_CC c33c_CD proteins_NNS (_( c200_CD )_) in_IN the_ATI second-generation_NN RIBA-2_NP assay_NN , the_ATI c33c_CD and_CC c22-3_CD HCV_NP recombinant_NN antigens_NNS expressed_VBN in_IN yeast_NN were_BED added_VBN to_IN the_ATI 5-1-1_CD-CD , c100-3_CD-CD , and_CC SOD_NP antigens_NNS already_RB present_JJ in_IN RIBA-1_CD-CD the_ATI RIBA-2_NP assay_NN result_NN is_BEZ considered_VBN positive_JJ when_WRB there_EX is_BEZ at_IN least_RB weak_JJ positivity_NN in_IN response_NN to_IN any_DTI two_CD or_CC more_QL HCV_NP antigens_NNS 302_NP the_ATI RIBA-2_NP test_NN has_HVZ been_BEN especially_RB helpful_JJ in_IN resolving_JJ the_ATI true_JJ status_NN of_IN samples_NNS found_VBN to_TO be_BE indeterminate_JJ by_IN RIBA-1_CD-CD several_AP studies_NNS have_HV shown_VBN not_XNOT only_RB increased_JJ sensitivity_NN and_CC specificity_NN of_IN second-generation_NN assays_NNS compared_VBN with_IN their_PP$ first-generation_NN counterparts_NNS but_CC also_RB earlier_RBR seroconversion_NN against_IN the_ATI c22-3_CD and_CC c33c_CD antigens_NNS than_CS against_IN the_ATI c100-3_CD-CD antigen_NN 303_NP polymerase_NN Chain_NP Reaction_NN Assay_NP for_IN HCV_NPT RNA_NP 304_NP the_ATI ELISA_NP and_CC RIBA_NP tests_NNS detect_VB only_RB the_ATI presence_NN of_IN antibodies_NNS to_TO HCV_NP antigens_NNS they_PP3AS do_DO not_XNOT provide_VB insight_NN into_IN the_ATI replication_NN of_IN HCV_NP and_CC are_BER flawed_JJ because_CS of_IN prolonged_JJ seronegative_JJ windows_NNS the_ATI detection_NN of_IN serum_NN and_or_CC liver_NN HCV_NP RNA_NP using_VBG polymerase_NN chain_NN reaction_NN (_( PCR_NP )_) techniques_NNS offers_VBZ advantages_NNS on_IN both_ABX fronts_NNS 305_CD the_ATI PCR_NP techniques_NNS are_BER currently_RB the_ATI most_QL sensitive_JJ methods_NNS of_IN detecting_JJ HCV_NP RNA_NP the_ATI PCR_NP technique_NN amplifies_NNS reverse-transcribed_JJ complementary_JJ DNA_NP , permitting_VBG detection_NN of_IN minute_JJ quantities_NNS of_IN viral_JJ RNA_NP it_PP3 appears_VBZ that_CS primers_NNS from_IN the_ATI highly_RB conserved_VBN 5'_NNS$ noncoding_VBG region_NN are_BER the_ATI most_QL helpful_JJ for_IN identifying_VBG hepatitis_NN C_ZZ infection_NN Rather_NP than_IN merely_RB determining_VBG the_ATI presence_NN or_CC absence_NN of_IN viral_JJ RNA_NP , quantifying_VBG the_ATI amount_NN of_IN HCV_NP RNA_NP has_HVZ been_BEN refined_VBN with_IN a_AT competitive_JJ reverse_JJ transcriptase_NN PCR_NP assay_NN 306_NP the_ATI PCR_NP assays_NNS can_MD detect_VB viral_JJ RNA_NP within_IN 1_CD1 to_IN 2_CD weeks_NNS of_IN exposure_NN to_IN HCV_NP , shortening_VBG the_ATI _** window_NN _** period_NN viral_JJ RNA_NP has_HVZ been_BEN accepted_VBN as_CS the_ATI current_JJ _** gold_NN standard_NN _** by_IN which_WDTR to_TO make_VB the_ATI diagnosis_NN of_IN hepatitis_NN C_ZZ infection_NN ; however_RB , the_ATI false-positive_JJ and_CC false-negative_JJ rates_NNS for_IN PCR_NP have_HV yet_RB to_TO be_BE determined_JJ more_AP work_NN is_BEZ clearly_RB needed_VBN to_TO appraise_VB the_ATI clinical_JJ impact_NN and_CC cost-effectiveness_NN of_IN this_DT technique_NN while_CS primarily_RB still_RB a_AT research_NN tool_NN , PCR_NP for_IN HCV_NP RNA_NP will_MD probably_RB become_VB routinely_RB available_JJ for_IN clinical_JJ use_NN in_IN the_ATI near_IN future_NN 307_NP there_EX have_HV been_BEN reports_NNS of_IN patients_NNS in_IN whom_WPOR HCV_NP RNA_NP was_BEDZ documented_VBN by_IN PCR_NP despite_IN negative_JJ ELISA-2_NP test_NN results_NNS and_CC of_IN patients_NNS who_WPR tested_VBD negative_JJ for_IN viral_JJ RNA_NP by_IN PCR_NP but_CC positive_JJ for_IN HCV_NP antibody_NN by_IN ELISA-2_NP While_NP the_ATI latter_AP may_MD represent_VB false-positive_JJ results_NNS , it_PP3 is_BEZ also_RB possible_JJ that_CS HCV_NP may_MD only_RB intermittently_RB replicate_JJ at_IN levels_NNS sufficient_JJ for_IN viral_JJ RNA_NP to_TO be_BE detected_VBN in_IN the_ATI serum_NN 308_NP it_PP3 is_BEZ fairly_RB straightforward_JJ to_TO diagnose_VB chronic_JJ hepatitis_NN C_ZZ in_IN a_AT patient_NN with_IN a_AT history_NN of_IN blood_NN transfusions_NNS , chronic_JJ elevations_NNS of_IN serum_NN transaminase_NN levels_NNS , a_AT positive_JJ ELISA-2_NP assay_NN result_NN , and_CC chronic_JJ active_JJ hepatitis_NN on_IN liver_NN biopsy_NN in_IN other_AP patients_NNS , however_RB , the_ATI diagnosis_NN of_IN chronic_JJ hepatitis_NN C_ZZ can_MD be_BE more_QL clinically_RB challenging_JJ Especially_NP in_IN patients_NNS without_IN risk_NN factors_NNS for_IN hepatitis_NN C_ZZ , it_PP3 is_BEZ imperative_JJ to_TO exclude_VB other_AP potential_JJ causes_NNS of_IN chronic_JJ elevations_NNS of_IN serum_NN transaminase_NN levels_NNS , even_CS if_CS a_AT second-generation_NN assay_NN result_NN is_BEZ positive_JJ while_CS serum_NN or_CC hepatic_JJ viral_JJ RNA_NP implies_VBZ ongoing_VBG viral_JJ replication_NN and_CC therefore_RB persistent_JJ infection_NN , a_AT positive_JJ ELISA-2_NP or_CC RIBA-2_NP result_NN may_MD merely_RB reflect_VB past_NN exposure_NN to_IN the_ATI virus_NN 309_NP liver_NN biopsy_NN often_RB plays_VBZ a_AT key_NN role_NN in_IN the_ATI management_NN of_IN patients_NNS with_IN suspected_VBD chronic_JJ hepatitis_NN C._NP although_CS there_EX are_BER no_ATI pathognomonic_JJ histologic_JJ features_NNS of_IN hepatitis_NN C_ZZ , liver_NN biopsy_NN can_MD help_VB to_TO exclude_VB other_AP pathologic_JJ conditions_NNS although_CS not_XNOT unique_JJ to_IN chronic_JJ hepatitis_NN C_ZZ infection_NN , prominent_JJ portal_NN lymphoid_NN follicles_NNS provide_VB a_AT suggestive_JJ diagnostic_JJ clue_NN other_AP characteristic_JJ histologic_JJ features_NNS appreciated_VBN in_IN chronic_JJ HCV_NP infection_NN include_VB damage_NN to_IN the_ATI intrahepatic_JJ bile_NN ducts_NNS and_CC steatosis_NN since_IN a_AT patient's_NN$ serum_NN transaminase_NN levels_NNS are_BER correlated_VBN poorly_RB with_IN the_ATI histologic_JJ extent_NN of_IN disease_NN , liver_NN biopsy_NN often_RB provides_VBZ the_ATI clinician_NN with_IN important_JJ _** staging_NN _** information_NN 310_CD TREATMENT_NPT OF_NPT CHRONIC_NP HEPATITIS_NP C_ZZ INFECTION_NP 311_CD once_RB the_ATI diagnosis_NN of_IN chronic_JJ hepatitis_NN C_ZZ is_BEZ made_VBN , the_ATI decision_NN of_IN whether_CS to_TO treat_VB with_IN interferon_NN is_BEZ typically_RB complex_JJ it_PP3 incorporates_VBZ laboratory_NN and_CC histologic_JJ criteria_NNS as_QL well_RB as_IN an_AT assessment_NN of_IN the_ATI patient's_NN$ overall_JJB clinical_JJ status_NN it_PP3 is_BEZ useful_JJ to_TO describe_VB the_ATI proposed_VBN mechanism_NN of_IN action_NN of_IN interferon_NN before_CS reviewing_VBG the_ATI results_NNS of_IN interferon's_NP$ efficacy_NN in_IN the_ATI treatment_NN of_IN chronic_JJ hepatitis_NN C._NP 312_CD interferons_NNS are_BER not_XNOT a_AT single_JJ molecular_JJ species_NN ; they_PP3AS comprise_VB three_CD (_( alfa_NN , beta_NN , and_CC gamma_NN )_) families_NNS of_IN proteins_NNS lymphocytes_NNS , macrophages_NNS , and_CC fibroblasts_NNS normally_RB produce_VB interferons_NNS in_IN response_NN to_IN viral_JJ antigenic_JJ stimulation_NN interferons_NNS can_MD induce_VB cytokine_VB gene_NN expression_NN and_CC enhance_VB the_ATI function_NN of_IN natural_JJ killer_NN cells_NNS , cytotoxic_JJ T_ZZ cells_NNS , and_CC macrophages_NNS rather_RB than_IN directly_RB inactivating_VBG viruses_NNS , interferons_NNS stimulate_VB target_NN cells_NNS by_IN binding_JJ to_IN specific_JJ cell_NN surface_NN receptors_NNS , inducing_VBG the_ATI synthesis_NN of_IN intracellular_NN effector_NN proteins_NNS 313_CD the_ATI antiviral_JJ effect_NN of_IN the_ATI interferons_NNS is_BEZ due_JJ to_IN the_ATI modulation_NN of_IN different_JJ steps_NNS of_IN the_ATI viral_JJ replication_NN cycle_NN for_IN example_NN , the_ATI induction_NN of_IN intracellular_NN 2_CD '-5'_NNS$ oligoadenylate_NN synthetase_NN results_NNS in_IN the_ATI formation_NN of_IN oligonucleotides_NNS , which_WDTR , in_IN the_ATI presence_NN of_IN double- stranded_JJ RNA_NP , activate_VB endoribonucleases_NNS that_CS degrade_JJ viral_JJ messenger_NN RNA_NP interferon_NN also_RB induces_VBZ the_ATI synthesis_NN of_IN a_AT double- stranded_JJ RNA-dependent_NP protein_NN kinase_NN that_CS interferes_VBZ with_IN the_ATI elongation_NN step_NN in_IN viral_JJ protein_NN synthesis_NN in_IN addition_NN to_IN its_PP$ multiple_JJ effects_NNS on_IN viral_JJ replication_NN , interferon_NN also_RB has_HVZ significant_JJ immunomodulatory_NN actions_NNS these_DTS complex_JJ effects_NNS include_VB increased_VBN HLA_NP class_NN I_PP1A expression_NN and_CC enhanced_VBN natural_JJ killer_NN cell_NN activity_NN exactly_RB which_WDTR of_IN the_ATI multiple_JJ actions_NNS of_IN interferon_NN alfa_NN account_NN for_IN its_PP$ effectiveness_NN in_IN treating_VBG chronic_JJ hepatitis_NN C_ZZ infection_NN is_BEZ incompletely_RB understood_VBN 314_CD selection_NN of_IN Patients_NP for_IN Treatment_NP 315_CD candidates_NNS for_IN interferon_NN therapy_NN should_MD have_HV a_AT clinical_JJ presentation_NN consistent_JJ with_IN chronic_JJ hepatitis_NN C_ZZ infection_NN and_CC (_( usually_RB )_) a_AT positive_JJ second-generation_NN test_NN or_CC PCR_NP result_NN there_EX is_BEZ disagreement_NN concerning_IN which_WDTR pretreatment_JJ clinical_JJ characteristics_NNS identify_VB patients_NNS most_QL likely_JJ to_TO benefit_VB from_IN antiviral_JJ therapy_NN 316_CD although_CS it_PP3 is_BEZ not_XNOT clear_JJ whether_CS patients_NNS with_IN only_RB mild_JJ elevations_NNS of_IN serum_NN transaminase_NN levels_NNS benefit_NN less_AP from_IN interferon_JJ therapy_NN , most_QL research_NN studies_NNS have_HV focused_VBN on_IN patients_NNS whose_WP$R serum_NN transaminase_NN levels_NNS have_HV exceeded_VBN the_ATI upper_JJB limits_NNS of_IN normal_JJ by_IN two_CD to_IN three_CD times_NNS for_IN at_RB least_RB 6_CD months_NNS younger_JJR patients_NNS with_IN infection_NN of_IN more_QL recent_JJ onset_NN and_CC patients_NNS with_IN biopsy_JJ evidence_NN of_IN ongoing_VBG inflammation_NN but_CC minimal_JJ cirrhosis_NN appear_VB to_TO respond_VB more_QL effectively_RB to_TO interferon_VB treatment_NN than_IN patients_NNS with_IN minimal_JJ inflammation_NN or_CC with_IN established_VBN cirrhosis_NN the_ATI pretreatment_JJ titer_NN of_IN viral_JJ RNA_NP and_CC the_ATI degree_NN of_IN variability_NN in_IN the_ATI viral_JJ genome_NN as_CS determined_VBN by_IN sequencing_VBG of_IN complementary_JJ DNA_NP are_BER among_IN the_ATI other_AP determinants_NNS that_DT may_MD predict_VB a_AT sustained_JJ response_NN to_TO interferon_VB therapy_NN 317_CD the_ATI decision_NN to_TO treat_VB a_AT patient_NN with_IN interferon_NN is_BEZ influenced_VBN in_IN a_AT complex_JJ manner_NN by_IN the_ATI patient's_NN$ age_NN there_EX is_BEZ certainly_RB no_ATI rigid_JJ cutoff_NN in_IN terms_NNS of_IN years_NNS ; however_RB , the_ATI patient's_NN$ chronological_JJ age_NN may_MD be_BE less_QL important_JJ than_IN overall_JJB medical_JJ health_NN an_AT otherwise_RB healthy_JJ 65-year-old_JJB woman_NN who_WPR has_HVZ moderate_JJ elevations_NNS of_IN serum_NN transaminase_NN levels_NNS and_CC active_JJ inflammation_NN on_IN biopsy_NN without_IN evidence_NN of_IN cirrhosis_NN would_MD seem_VB to_TO be_BE a_AT suitable_JJ candidate_NN for_IN therapy_NN still_RB , at_IN our_PP$ current_JJ level_NN of_IN understanding_NN , the_ATI progression_NN from_IN acute_JJ hepatitis_NN C_ZZ infection_NN to_TO cirrhosis_NN and_CC , possibly_RB , to_TO hepatocellular_VB carcinoma_NN may_MD span_VB decades_NNS Before_NP interferon_NN treatment_NN can_MD be_BE widely_RB advocated_VBN for_IN older_JJR patients_NNS , the_ATI possible_JJ risks_NNS and_CC benefits_NNS of_IN therapy_NN have_HV to_TO be_BE measured_VBN , in_IN terms_NNS of_IN how_WRB the_ATI morbidity_NN and_CC mortality_NN associated_VBN with_IN hepatitis_NN C_ZZ can_MD be_BE modified_VBN by_IN this_DT treatment_NN , and_CC weighed_VBN against_IN realistic_JJ predictors_NNS of_IN a_AT patient_NN 's_BEZ expected_JJ survival_NN 318_CD 40_CD interferon_NN therapy_NN is_BEZ contraindicated_VBN in_IN patients_NNS in_IN whom_WPOR , despite_IN the_ATI advances_NNS described_VBN in_IN diagnostic_JJ testing_NN , a_AT distinction_NN between_IN autoimmune_NN hepatitis_NN and_CC hepatitis_NN C_ZZ infection_NN cannot_NN be_BE made_VBN confidently_RB there_EX have_HV been_BEN several_AP reports_NNS of_IN patients_NNS with_IN autoimmune_NN hepatitis_NN whose_WP$R condition_NN deteriorated_VBD dramatically_RB when_WRB treated_VBN with_IN interferon_NN if_CS there_EX are_BER doubts_NNS about_IN the_ATI correct_JJ ultimate_JJ diagnosis_NN , an_AT initial_JJ trial_NN of_IN corticosteroid_NN therapy_NN is_BEZ prudent_JJ while_CS corticosteroid_NN therapy_NN will_MD not_XNOT eradicate_VB hepatitis_NN C_ZZ infection_NN , it_PP3 is_BEZ less_QL potentially_RB harmful_JJ in_IN this_DT setting_VBG than_IN is_BEZ mistreating_VBG a_AT patient_NN with_IN interferon_NN if_CS interferon_NN therapy_NN is_BEZ attempted_VBN after_IN an_AT unsuccessful_JJ trial_NN of_IN corticosteroid_NN therapy_NN , most_QL clinicians_NNS would_MD suggest_VB initiating_JJ treatment_NN with_IN a_AT lower-than-usual_JJ dose_NN to_TO minimize_VB potential_JJ adverse_JJ effects_NNS 319_CD patients_NNS with_IN decompensated_JJ liver_NN disease_NN , manifested_VBN by_IN variceal_JJ bleeding_NN , ascites_NNS , jaundice_NN , encephalopathy_NN , or_CC profound_JJ synthetic_JJ dysfunction_NN , are_BER poor_JJ candidates_NNS for_IN interferon_NN therapy_NN unfortunately_RB , medical_JJ therapy_NN will_MD not_XNOT reverse_JJ their_PP$ established_JJ cirrhosis_NN and_CC end-stage_NN liver_NN disease_NN 320_CD efficacy_NN of_IN Interferon_NP for_IN Chronic_NP Hepatitis_NP C_ZZ 321_CD the_ATI first_OD large_JJ , multicenter_JJB , randomized_VBD , controlled_JJ trial_NN of_IN the_ATI treatment_NN of_IN chronic_JJ hepatitis_NN C_ZZ with_IN recombinant_NN interferon_NN alfa_NN demonstrated_VBN that_CS the_ATI probability_NN of_IN normalization_NN or_CC near_IN normalization_JJ of_IN the_ATI serum_NN alanine_NN aminotransferase_NN level_NN after_IN the_ATI subcutaneous_JJ administration_NN of_IN 3_CD million_CD units_NNS of_IN interferon_NN thrice_RB weekly_JJ for_IN 6_CD months_NNS was_BEDZ just_RB under_RB 50%_NP it_PP3 has_HVZ also_RB been_BEN shown_VBN that_CS in_IN patients_NNS who_WPR respond_VB to_TO interferon_VB therapy_NN , serum_NN levels_NNS of_IN HCV_NP RNA_NP decrease_NN or_CC disappear_VB , usually_RB preceding_JJ improvements_NNS in_IN serum_NN aminotransferase_NN levels_NNS while_CS histologic_JJ improvement_NN , manifested_VBD as_IN regression_NN of_IN lobular_NN and_CC periportal_JJ inflammation_NN , is_BEZ observed_VBN in_IN approximately_RB 50%_NP of_IN liver_NN biopsies_NNS of_IN patients_NNS treated_VBN with_IN this_DT regimen_NN of_IN interferon_NN , histologic_JJ improvement_NN is_BEZ not_XNOT necessarily_RB restricted_JJ to_IN the_ATI patients_NNS who_WPR exhibit_VB a_AT biochemical_JJ response_NN 322_CD transient_JJ flares_VBZ of_IN serum_NN alanine_NN aminotransferase_NN levels_NNS may_MD be_BE seen_VBN during_IN the_ATI posttreatment_NN follow-up_NN period_NN in_IN patients_NNS who_WPR sustain_VB remissions_NNS unfortunately_RB , in_IN the_ATI first_OD 6_CD months_NNS after_IN therapy_NN , about_IN 50%_NP of_IN patients_NNS who_WPR initially_RB respond_VB successfully_RB demonstrate_VB sustained_VBN relapses_NNS of_IN elevated_VBD transaminase_NN levels_NNS accompanied_VBN by_IN increases_NNS in_IN serum_NN viral_JJ RNA_NP alternative_NN dosing_NN schedules_NNS and_CC treatment_NN periods_NNS have_HV not_XNOT reliably_RB been_BEN shown_VBN to_TO alter_VB the_ATI initial_JJ and_CC sustained_JJ response_NN rates_NNS , but_CC studies_NNS using_VBG higher_JJR doses_NNS and_CC longer_RBR treatment_NN periods_NNS are_BER under_IN way.=20_CD 323_CD it_PP3 is_BEZ important_JJ to_TO keep_VB in_IN mind_NN that_CS normalizing_VBG transaminase_NN levels_NNS and_CC even_RB successfully_RB clearing_VBG serum_NN viral_JJ RNA_NP may_MD not_XNOT provide_VB evidence_NN of_IN a_AT _** cure_NN _** use_NN of_IN more_AP sensitive_JJ assays_NNS for_IN serum_NN or_CC liver_NN tissue_NN HCV_NP RNA_NP may_MD be_BE necessary_JJ to_TO document_NN eradication_NN of_IN the_ATI virus_NN to_TO date_NN , there_EX are_BER no_ATI studies_NNS with_IN sufficient_JJ longitudinal_JJ follow-up_NN to_TO assess_VB whether_CS _** successful_JJ _** treatment_NN with_IN interferon_NN decreases_VBZ the_ATI progression_NN of_IN chronic_JJ hepatitis_NN C_ZZ infection_NN to_TO cirrhosis_VB or_CC to_TO hepatocellular_NN carcinoma_NN 324_CD adverse_JJ Effects_NNS of_IN Interferon_NP 325_CD symptoms_NNS of_IN fatigue_NN and_CC malaise_NN are_BER common_NN in_IN patients_NNS with_IN chronic_JJ hepatitis_NN and_CC may_MD be_BE exacerbated_VBN by_IN interferon_NN therapy_NN transient_JJ minor_JJ flulike_JJ adverse_JJ effects_NNS , such_IN as_IN fever_NN , myalgias_NNS , arthralgias_NNS , and_CC headache_NN , often_RB follow_VB the_ATI injections_NNS for_IN several_AP hours_NNS these_DTS symptoms_NNS can_MD usually_RB be_BE ameliorated_VBN by_IN acetaminophen_NN or_CC nonsteroidal_JJ anti-inflammatory_NN drugs_NNS and_CC may_MD be_BE minimized_VBN if_CS the_ATI patient_NN self-administers_VBZ the_ATI medication_NN at_IN bedtime_NN many_AP of_IN these_DTS symptoms_NNS are_BER better_JJR tolerated_VBN the_RB longer_RBR therapy_NN continues_VBZ 326_CD other_AP , uncommonly_RB reported_VBN adverse_JJ effects_NNS of_IN interferon_NN therapy_NN include_VB diarrhea_NN , anorexia_NN , and_CC mild_JJ alopecia_NN while_CS many_AP patients_NNS describe_VB anxiety_NN or_CC increased_JJ irritability_NN while_CS taking_VBG interferon_NN , special_JJ caution_NN should_MD be_BE exercised_VBN in_IN treating_VBG patients_NNS who_WPR have_HV a_AT preexisting_VBG psychiatric_JJ history_NN there_EX have_HV been_BEN case_NN reports_NNS of_IN frank_JJ delirium_NN and_CC suicidal_JJ ideation_NN attributed_VBN to_TO interferon_VB therapy_NN 327_CD laboratory_NN abnormalities_NNS seen_VBN with_IN interferon_NN therapy_NN are_BER usually_RB restricted_JJ to_IN reversible_JJ mild_JJ thrombocytopenia_NN or_CC leukopenia_NN these_DTS may_MD occasionally_RB necessitate_VB dosage_NN reduction_NN mild_JJ asymptomatic_JJ thyroid_JJ function_NN test_NN abnormalities_NNS may_MD be_BE noted_VBN in_IN a_AT minority_NN of_IN patients_NNS receiving_VBG interferon_NN , but_CC clinically_RB significant_JJ thyroid_JJ dysfunction_NN (_( usually_RB hypothyroidism_JJ )_) is_BEZ very_QL uncommon_JJ 328_CD depending_VBG on_IN the_ATI preparation_NN used_VBN , neutralizing_VBG antibodies_NNS directed_VBN against_IN interferon_NN alfa_NN develop_VB during_IN treatment_NN in_IN a_AT small_JJ percentage_NN of_IN patients_NNS recombinant_NN interferon_NN alfa-2a_NN appears_VBZ to_TO induce_VB neutralizing_VBG antibodies_NNS more_QL frequently_RB than_IN interferon_NN alfa- 2b_NN or_CC lymphoblastoid-derived_JJ interferon_NN alfa_NN whether_CS these_DTS neutralizing_VBG antibodies_NNS alter_VB response_NN to_TO treatment_NN remains_VBZ controversial_JJ Additionally_NP , anti-smooth_NN muscle_NN , anti-nuclear_JJ , or_CC anti-thyroid_NN microsomal_JJ antibodies_NNS may_MD develop_VB during_IN interferon_NN therapy_NN for_IN hepatitis_NN B_ZZ infection_NN these_DTS autoantibodies_NNS do_DO not_XNOT appear_VB to_TO influence_VB response_NN to_IN treatment_NN 329_CD it_PP3 is_BEZ recommended_VBN that_CS patients_NNS have_HV complete_JJ blood_NN cell_NN counts_VBZ in_IN the_ATI first_OD couple_NN of_IN weeks_NNS after_IN interferon_NN therapy_NN is_BEZ initiated_VBN and_CC monthly_JJ thereafter_RB liver_NN function_NN tests_NNS are_BER usually_RB performed_VBN at_IN monthly_JJ intervals_NNS thrombocytopenia_NN or_CC leukopenia_NN , significant_JJ mood_NN disturbances_NNS , or_CC other_AP intractable_JJ adverse_JJ effects_NNS may_MD necessitate_VB either_DTX reduction_NN of_IN the_ATI dosage_NN or_CC cessation_NN of_IN interferon_NN therapy_NN Marked_NP elevations_NNS of_IN serum_NN transaminase_NN levels_NNS during_IN interferon_NN treatment_NN would_MD raise_VB questions_NNS concerning_IN other_AP causes_NNS for_IN the_ATI patient's_NN$ liver_NN disease_NN , and_CC therapy_NN should_MD be_BE stopped_VBN 330_CD although_CS there_EX are_BER ongoing_VBG clinical_JJ trials_NNS assessing_VBG the_ATI potential_JJ efficacy_NN of_IN alternative_JJ antiviral_JJ medications_NNS , the_ATI current_JJ treatment_NN of_IN chronic_JJ hepatitis_NN C_ZZ centers_NNS on_IN the_ATI use_NN of_IN interferon_NN alfa_NN at_IN our_PP$ current_JJ level_NN of_IN understanding_NN , the_ATI ideal_JJ candidate_NN for_IN therapy_NN might_MD be_BE an_AT otherwise_RB healthy_JJ patient_NN who_WPR acquired_JJ hepatitis_NN C_ZZ relatively_RB recently_RB and_CC has_HVZ moderate_JJ elevations_NNS of_IN serum_NN transaminase_NN levels_NNS , low_JJ pretreatment_JJ levels_NNS of_IN HCV_NP RNA_NP , and_CC active_JJ inflammation_NN without_IN cirrhosis_NN on_IN biopsy_NN as_CS described_VBN , only_RB approximately_RB 25%_JJ of_IN patients_NNS will_MD have_HV a_AT sustained_JJ response_NN to_TO interferon_VB therapy_NN after_IN a_AT 6-month_NN course_RB these_DTS data_NNS , coupled_VBN with_IN interferon_NN 's_BEZ known_VBN adverse_JJ effect_NN profile_NN , underscore_VB the_ATI need_NN to_TO use_VB this_DT medication_NN judiciously_RB and_CC to_TO continue_VB the_ATI search_NN for_IN a_AT more_QL effective_JJ medical_JJ treatment_NN of_IN chronic_JJ hepatitis_NN C._NP 331_CD how_WRB Is_NNS Anaphylaxis_NN Recognized_NP ? 332_CD prompt_JJ recognition_NN of_IN anaphylaxis_NN may_MD be_BE lifesaving_VBN although_CS its_PP$ presentation_NN has_HVZ been_BEN described_VBN , there_EX are_BER no_ATI criteria_NNS for_IN making_VBG a_AT rapid_JJ diagnosis_NN a_AT systematic_JJ review_NN of_IN the_ATI literature_NN was_BEDZ performed_VBN to_TO develop_VB objective_JJ clinical_JJ criteria_NNS aimed_VBN at_IN improving_VBG the_ATI recognition_NN of_IN anaphylaxis_NN a_AT MEDLINE_NP search_NN of_IN the_ATI word_NN anaphylaxis_NN over_IN a_AT 1-year_CD-CD period_NN identified_VBN all_ABN of_IN the_ATI reports_NNS describing_VBG the_ATI initial_JJ manifestations_NNS of_IN 160_CD reviewed_VBN articles_NNS , 116_CD contained_VBD a_AT clinical_JJ description_NN of_IN anaphylaxis_NN eighty-nine_CD (_( 77%_JJ )_) of_IN these_DTS 116_CD articles_NNS were_BED case_NN reports_NNS hypotension_NN (_( 84_NN reports_NNS (_( 72%_NN )_) )_) and_CC urticaria_NN and_or_CC angioedema_NN (_( 70_CD reports_NNS (_( 60%_NP )_) )_) were_BED the_ATI most_QL frequently_RB described_VBN signs_NNS Of_NP the_ATI identified_JJ allergens_NNS , 73%_CD were_BED diagnostic_JJ or_CC therapeutic_JJ agents_NNS In_NP 72_CD of_IN the_ATI 80_CD articles_NNS in_IN which_WDTR a_AT reaction_NN time_NN could_MD be_BE identified_VBN , the_ATI reaction_NN occurred_VBD within_IN 60_CD minutes_NNS as_IN a_AT result_NN of_IN this_DT analysis_NN , we_PP1AS conclude_VB that_CS anaphylaxis_NN recognition_NN may_MD be_BE improved_VBN by_IN the_ATI identification_NN of_IN one_CD1 of_IN the_ATI following_JJ criteria_NNS , which_WDTR describe_VB the_ATI presentation_NN in_IN 82%_NN of_IN the_ATI analyzed_JJ reports_NNS : (_( 1_CD1 )_) exposure_NN to_IN an_AT allergen_NN within_IN 1_CD1 hour_NN produces_VBZ one_CD1 or_CC more_QL systemic_JJ signs_NNS (_( hypotension_NN , upper_JJB or_CC lower_JJR respiratory_JJ tract_NN compromise_NN , or_CC increased_VBN gastrointestinal_JJ tract_NN motility_NN )_) , or_CC (_( 2_CD )_) urticaria_NN or_CC angioedema_NN accompanies_VBZ at_RB least_RB one_CD1 of_IN these_DTS systemic_JJ signs_NNS 333_CD anaphylaxis_NN is_BEZ a_AT fulminant_NN , multisystem_NN , and_CC sometimes_RB fatal_JJ syndrome_NN associated_VBN with_IN immediate_JJ hypersensitivity_NN in_IN the_ATI United_NP States_NP , it_PP3 has_HVZ been_BEN estimated_VBN to_TO occur_VB as_QL frequently_RB as_CS once_RB in_IN every_AT 3000_CD inpatients_NNS and_CC may_MD be_BE the_ATI cause_NN of_IN more_AP than_IN 500_CD deaths_NNS annually_RB .=20_CD 334_CD fatalities_NNS occur_VB in_IN approximately_RB 3%_CD to_TO 9%_NN of_IN the_ATI reported_VBN cases_NNS Immediate_NP diagnosis_NN is_BEZ imperative_JJ because_CS the_ATI more_QL rapid_JJ the_ATI onset_NN , the_ATI more_QL likely_JJ the_ATI reaction_NN will_MD be_BE severe_JJ , and_CC prompt_JJ treatment_NN may_MD be_BE lifesaving_NN in_IN addition_NN , recognition_NN is_BEZ important_JJ for_IN the_ATI prevention_NN of_IN further_JJB episodes.=20_CD 335_CD although_CS there_EX are_BER many_AP descriptions_NNS of_IN characteristic_JJ presentations_NNS , its_PP$ unanticipated_JJ nature_NN and_CC the_ATI lack_NN of_IN specific_JJ standard_JJ clinical_JJ criteria_NNS sometimes_RB make_VB anaphylaxis_NN a_AT difficult_JJ diagnostic_JJ problem_NN 336_CD the_ATI history_NN and_CC physical_JJ examination_NN are_BER the_ATI most_QL important_JJ elements_NNS of_IN patient_NN evaluation_NN , especially_RB when_WRB the_ATI process_NN must_MD be_BE rapid_JJ the_ATI goal_NN of_IN this_DT study_NN was_BEDZ to_TO construct_VB diagnostic_JJ criteria_NNS aimed_VBN at_IN improving_VBG the_ATI recognition_NN of_IN anaphylaxis_NN through_IN a_AT systematic_JJ review_NN of_IN the_ATI literature_NN 337_CD METHODS_NP 338_CD a_AT MEDLINE_NP search_NN for_IN citations_NNS of_IN anaphylaxis_NN over_IN a_AT 1-year_CD-CD period_NN identified_VBN all_ABN English_JNP language_NN reports_NNS pertaining_VBG to_IN humans_NNS because_CS this_DT investigation_NN was_BEDZ purely_RB clinical_JJ , a_AT distinction_NN between_IN IgE-mediated_NP hypersensitivity_NN reactions_NNS (_( anaphylactic_JJ )_) and_CC reactions_NNS with_IN identical_JJ clinical_JJ manifestations_NNS and_CC treatment_NN choices_NNS but_CC without_IN a_AT documented_VBN IgE-mediated_NP cause_NN (_( anaphylactoid_NN )_) was_BEDZ not_XNOT made.=20_CD 339_CD the_ATI articles_NNS were_BED reviewed_VBN independently_RB by_IN us_PP1OS , and_CC the_ATI information_NN was_BEDZ summarized_VBN in_IN spreadsheet_NN form_NN , and_CC four_CD article_NN categories_NNS were_BED defined_VBN : case_NN report_NN , investigative_JJ case_NN report_NN , investigation_NN , and_CC editorial_JJ an_AT investigative_JJ case_NN report_NN consisted_VBD of_IN a_AT case_NN report_NN and_CC an_AT investigation_NN of_IN some_DTI aspect_NN of_IN the_ATI case_NN , such_IN as_IN the_ATI performance_NN of_IN immunoassays_NNS to_TO confirm_VB the_ATI diagnosis_NN of_IN anaphylaxis_NN or_CC to_TO determine_VB the_ATI precipitating_VBG allergen_NN the_ATI editorial_JJ group_NN contained_VBD letters_NNS that_CS were_BED not_XNOT case_NN reports_NNS as_QL well_RB as_CS reviews_NNS and_CC commentaries_NNS it_PP3 was_BEDZ hypothesized_VBN that_CS clinical_JJ descriptions_NNS such_ABL as_CS those_DTS described_VBN in_IN the_ATI first_OD three_CD categories_NNS would_MD be_BE the_ATI most_QL useful_JJ in_IN determining_VBG the_ATI critical_JJ clinical_JJ characteristics_NNS of_IN anaphylaxis_NN thus_RB , the_ATI editorial_JJ articles_NNS were_BED not_XNOT used_VBN in_IN extracting_VBG the_ATI diagnostic_JJ components_NNS of_IN this_DT syndrome_NN we_PP1AS recorded_VBN whether_CS a_AT control_NN population_NN was_BEDZ used_VBN in_IN the_ATI analyzed_JJ studies_NNS for_IN evaluating_VBG the_ATI risk_NN factors_NNS , the_ATI initial_JJ clinical_JJ presentation_NN , or_CC the_ATI initial_JJ treatment_NN these_DTS were_BED called_VBN controlled_VBN studies_NNS immunologic_JJ investigations_NNS were_BED those_DTS in_IN which_WDTR skin_NN testing_NN , radioallergosorbent_NN tests_NNS , enzyme-linked_JJ immunosorbent_NN assays_NNS , or_CC other_AP immunologic_JJ laboratory_NN investigations_NNS were_BED used_VBN to_TO identify_VB the_ATI allergen_NN also_RB included_VBN in_IN this_DT category_NN were_BED studies_NNS that_CS examined_VBN markers_NNS of_IN immunologic_JJ activation_NN such_IN as_IN serum_NN or_CC urine_NN histamine_NN or_CC serum_NN tryptase_NN levels_NNS 340_CD the_ATI signs_NNS and_CC symptoms_NNS attributed_VBN to_TO anaphylaxis_VB were_BED recognized_VBN and_CC combined_VBN into_IN system-related_JJ groups_NNS the_ATI frequency_NN with_IN which_WDTR these_DTS manifestations_NNS occurred_VBD was_BEDZ obtained_VBN 341_CD whether_CS a_AT relevant_JJ exposure_NN to_IN a_AT precipitating_VBG allergen_NN could_MD be_BE identified_VBN was_BEDZ determined_JJ the_ATI identified_JJ allergens_NNS were_BED then_RN organized_VBN into_IN groups_NNS the_ATI reaction_NN time_NN , defined_VBD as_IN the_ATI time_NN between_IN the_ATI exposure_NN to_IN an_AT allergen_NN and_CC the_ATI actual_JJ onset_NN of_IN anaphylactic_JJ manifestations_NNS , was_BEDZ recorded_VBN 342_CD because_CS it_PP3 is_BEZ most_QL difficult_JJ to_TO establish_VB a_AT diagnosis_NN when_WRB there_EX are_BER no_ATI typical_JJ dermatologic_JJ manifestations_NNS such_IN as_IN urticaria_NN , angioedema_NN , flushing_VBG , and_CC pruritus_NN or_CC when_WRB there_EX is_BEZ no_ATI identifiable_JJ antigen_NN exposure_NN , these_DTS articles_NNS were_BED reviewed_VBN separately_RB 343_CD from_IN this_DT information_NN , criteria_NNS were_BED developed_VBN that_CS were_BED defined_VBN as_CS satisfactory_JJ if_CS they_PP3AS identified_VBD at_RB least_RB 80%_NP of_IN the_ATI reviewed_VBN anaphylactic_JJ events_NNS 344_CD the_ATI signs_NNS and_CC symptoms_NNS described_VBN in_IN the_ATI 116_CD articles_NNS that_CS we_PP1AS reviewed_VBN and_CC the_ATI frequency_NN with_IN which_WDTR they_PP3AS were_BED reported_VBN are_BER presented_VBN in_IN Table_NP 1_CD1 the_ATI most_QL frequently_RB described_VBN dermatologic_JJ manifestations_NNS included_VBN urticaria_NN , angioedema_NN , erythema_NN or_CC flushing_VBG , and_CC pruritus_NN Urticaria_NP and_or_CC angioedema_NN were_BED described_VBN in_IN 70_CD (_( 80%_NP )_) of_IN the_ATI 88_CD dermatologic_JJ reports_NNS (_( 60%_NP of_IN the_ATI entire_JJB group_NN of_IN 116_CD )_) thus_RB , these_DTS two_CD signs_NNS were_BED selected_VBN for_IN use_NN in_IN the_ATI criteria_NNS flushing_VBG or_CC erythema_NN were_BED noted_VBN in_IN 10_CD additional_JJ reports_NNS in_IN which_WDTR neither_DTX angioedema_NN nor_CC urticaria_NN were_BED described_VBN pruritus_NN was_BEDZ described_VBN in_IN 16_CD articles_NNS , but_CC 11_CD of_IN these_DTS also_RB reported_VBN urticaria_NN or_CC angioedema_NN 345_CD the_ATI most_AP frequent_JJ cardiovascular_NN sign_NN was_BEDZ hypotension_NN , appearing_VBG either_DTX as_IN hypotension_NN itself_PPL or_CC as_IN shock_NN , collapse_NN , or_CC syncope_NN associated_VBN with_IN hypotension_NN in_IN 84_NN (_( 97%_JJ )_) of_IN the_ATI 87_CD cardiovascular_NN reports_NNS (_( 72%_NN of_IN the_ATI entire_JJB group_NN of_IN analyzed_JJ articles_NNS )_) thus_RB , hypotension_NN was_BEDZ the_ATI most_QL commonly_RB reported_VBN manifestation_NN of_IN anaphylaxis_NN tachycardia_RB , a_AT relatively_RB nonspecific_JJ sign_NN , was_BEDZ described_VBN in_IN 10_CD articles_NNS , but_CC eight_CD of_IN these_DTS also_RB noted_JJ hypotension_NN hypotension_NN was_BEDZ used_VBN in_IN the_ATI criteria_NNS 346_CD the_ATI most_AP frequent_JJ respiratory_JJ tract_NN description_NN involved_JJ words_NNS associated_VBN with_IN obstruction_NN (_( wheeze_NN , bronchospasm_NN , asthma_NN , status_NN asthmaticus_JJ , and_CC rhonchi_NN )_) and_CC synonyms_NNS for_IN dyspnea_NN there_EX were_BED 41_CD reports_NNS of_IN bronchospasm_NN , and_CC 73_CD (_( 90%_NP )_) of_IN the_ATI 81_CD articles_NNS suggested_VBN either_DTX bronchospasm_NN or_CC dyspnea_NN thus_RB , bronchospasm_NN or_CC dyspnea_NN were_BED used_VBN for_IN respiratory_JJ tract_NN criteria_NNS although_CS not_XNOT mentioned_VBN as_CS frequently_RB , cough_NN was_BEDZ cited_VBN in_IN at_RB least_RB five_CD reports_NNS , and_CC in_IN three_CD , it_PP3 was_BEDZ the_ATI only_AP respiratory_JJ tract_NN manifestation_NN 347_CD emesis_RB , diarrhea_NN , and_CC abdominal_JJ cramps_NNS or_CC discomfort_NN were_BED the_ATI most_QL common_JJ gastrointestinal_JJ tract_NN signs_NNS and_CC symptoms_NNS because_CS these_DTS terms_NNS could_MD be_BE grouped_VBN most_QL easily_RB as_IN increased_VBN gastrointestinal_JJ tract_NN motility_NN , this_DT expression_NN was_BEDZ used_VBN in_IN the_ATI criteria_NNS nausea_NN was_BEDZ avoided_VBN because_CS it_PP3 could_MD not_XNOT be_BE measured_VBN objectively_RB and_CC because_CS of_IN its_PP$ relative_JJ nonspecificity_NN in_IN seven_CD articles_NNS , nausea_NN was_BEDZ mentioned_VBN ; three_CD of_IN these_DTS also_RB reported_VBN vomiting_NN ; and_CC the_ATI remaining_JJ four_CD reports_NNS also_RB described_VBN hypotension_NN reports_NNS of_IN genitourinary_NN peristalsis_NN appeared_VBD in_IN only_RB two_CD reports_NNS : one_CD1 describing_VBG uterine_NN contractions_NNS and_CC another_DT , urinary_NN incontinence_NN because_CS these_DTS reports_NNS were_BED so_QL few_AP in_IN number_NN and_CC because_CS one_CD1 of_IN the_ATI articles_NNS also_RB described_VBN increased_VBN gastrointestinal_JJ tract_NN motility_NN , genitourinary_NN signs_NNS were_BED not_XNOT included_VBN in_IN the_ATI criteria_NNS 348_CD laryngeal_JJ and_or_CC pharyngeal_JJ manifestations_NNS were_BED reported_VBN as_IN stridor_NN , laryngeal_JJ and_or_CC pharyngeal_JJ edema_NN , choking_VBG , throat_NN tightness_NN , dysphonia_NN , and_CC dysphagia_NN of_IN these_DTS , hoarseness_NN was_BEDZ described_VBN most_QL frequently_RB hoarseness_NN or_CC other_AP types_NNS of_IN dysphonia_NN were_BED noted_VBN in_IN 13_CD reports_NNS edema_NN of_IN portions_NNS of_IN the_ATI larynx_NN or_CC pharynx_NN , including_IN the_ATI tongue_NN , was_BEDZ reported_VBN in_IN nine_CD papers_NNS although_CS stridor_NN was_BEDZ described_VBN less_QL frequently_RB than_IN dysphonia_NN or_CC edema_NN , it_PP3 is_BEZ perhaps_RB the_ATI most_QL striking_JJ and_CC severe_JJ form_NN of_IN laryngeal_JJ involvement_NN thus_RB , dysphonia_NN , edema_NN , and_CC stridor_NN were_BED included_VBN in_IN the_ATI criteria_NNS in_IN the_ATI laryngeal_JJ and_or_CC pharyngeal_JJ category_NN 349_CD rhinoconjunctivitis_RB , including_IN rhinorrhea_NN , nasal_JJ congestion_NN , conjunctivitis_NN , sneezing_VBG , and_CC lacrimation_NN , was_BEDZ described_VBN in_IN 17_CD articles_NNS These_NP signs_NNS were_BED not_XNOT used_VBN in_IN the_ATI criteria_NNS because_CS they_PP3AS were_BED reported_VBN less_QL frequently_RB 350_CD ALLERGEN_NP IDENTIFICATION_NP 351_CD an_AT inciting_VBG allergen_NN was_BEDZ reported_VBN in_IN all_ABN but_CC six_CD (_( 5%_JJ )_) of_IN the_ATI 116_CD articles_NNS in_IN three_CD of_IN the_ATI six_CD , no_ATI allergen_NN could_MD be_BE identified_VBN despite_IN an_AT extensive_JJ evaluation_NN in_IN the_ATI other_AP three_CD , the_ATI main_JJB thrust_VBD of_IN the_ATI article_NN did_DOD not_XNOT involve_VB the_ATI identification_NN of_IN an_AT allergen_NN 352_CD to_TO facilitate_VB description_NN , the_ATI allergens_NNS were_BED organized_VBN into_IN large_JJ groups_NNS and_CC are_BER displayed_VBN in_IN Table_NP 2_CD exposures_NNS to_IN diagnostic_JJ or_CC therapeutic_JJ agents_NNS were_BED mentioned_VBN most_QL frequently_RB (_( 85_CD (_( 73%_CD )_) of_IN the_ATI 116_CD analyzed_JJ papers_NNS )_) and_CC are_BER characterized_VBN further_JJB in_IN Table_NP 3_CD of_IN these_DTS , sensitivity_NN to_TO latex_NN was_BEDZ discussed_VBN most_QL frequently_RB 353_CD REACTION_NP TIME_NP 354_CD the_ATI reaction_NN time_NN from_IN antigen_NN exposure_NN to_IN the_ATI onset_NN of_IN symptoms_NNS was_BEDZ reported_VBN in_IN 80_CD (_( 73%_CD )_) of_IN the_ATI 110_CD articles_NNS in_IN which_WDTR an_AT allergen_NN was_BEDZ identified_VBN figure_NN 1_CD1 describes_VBZ reaction_NN times_NNS in_IN 68_CD (_( 85%_JJ )_) of_IN the_ATI 80_CD reports_NNS , the_ATI reaction_NN occurred_VBD within_IN 30_CD minutes_NNS and_CC , in_IN 77_CD (_( 96%_NN )_) , the_ATI reaction_NN time_NN was_BEDZ less_AP than_IN 2_CD hours_NNS six_CD of_IN the_ATI nine_CD articles_NNS reporting_VBG reaction_NN times_NNS of_IN between_IN 30_CD and_CC 120_CD minutes_NNS either_DTX specifically_RB gave_VBD reaction_NN times_NNS of_IN within_IN 60_CD minutes_NNS (_( five_CD reports_NNS )_) or_CC the_ATI time_NN could_MD be_BE estimated_VBN to_IN be_BE within_IN 60_CD minutes_NNS thus_RB , 73_CD reaction_NN times_NNS (_( 91%_CD )_) of_IN the_ATI 80_CD reported_VBN were_BED within_IN 60_CD minutes_NNS , and_CC this_DT was_BEDZ the_ATI time_NN chosen_VBN for_IN the_ATI criteria_NNS for_IN anaphylaxis_NN 355_CD of_IN the_ATI three_CD reports_NNS that_CS described_VBN a_AT reaction_NN time_NN of_IN more_AP than_IN 2_CD hours_NNS , two_CD involved_VBN delayed_VBN systemic_JJ exposures_NNS : one_CD1 by_IN depot_NN injection_NN and_CC one_CD1 by_IN topical_JJ application_NN to_IN the_ATI conjunctiva_NN 356_CD ANAPHYLAXIS_NPT WITHOUT_NPT DERMATOLOGIC_NP FINDINGS_NP 357_CD there_EX were_BED 19_CD articles_NNS describing_VBG anaphylaxis_NN in_IN which_WDTR typical_JJ dermatologic_JJ manifestations_NNS were_BED absent_JJ a_AT specific_JJ allergen_NN was_BEDZ identified_VBN in_IN all_ABN but_CC one_CD1 report_NN , and_CC in_IN that_DT one_CD1 report_NN of_IN simulated_VBN intraoperative_JJ anaphylaxis_NN , symptoms_NNS began_VBD within_IN minutes_NNS of_IN administration_NN of_IN the_ATI first_OD drug_NN in_IN general_JJ , the_ATI distribution_NN of_IN systemic_JJ signs_NNS and_CC symptoms_NNS was_BEDZ the_ATI same_AP as_CS for_IN the_ATI complete_JJ set_NN of_IN articles_NNS hypotension_NN was_BEDZ the_ATI most_QL frequent_JJ manifestation_NN 358_CD THE_NP CRITERIA_NP 359_CD from_IN the_ATI signs_NNS and_CC symptoms_NNS , relevant_JJ exposures_NNS , and_CC reaction_NN times_NNS described_VBN in_IN the_ATI 116_CD articles_NNS , two_CD separate_JJ criteria_NNS for_IN recognizing_VBG anaphylaxis_NN were_BED devised_VBN and_CC are_BER presented_VBN in_IN Table_NP 4_CD these_DTS criteria_NNS satisfied_JJ 92_CD (_( 79%_JJ )_) of_IN the_ATI 116_CD analyzed_JJ articles_NNS seventy-six_NN articles_NNS reported_VBN an_AT exposure_NN to_IN an_AT allergen_NN within_IN 1_CD1 hour_NN with_IN at_RB least_RB one_CD1 systemic_JJ sign_NN sixteen_CD articles_NNS did_DOD not_XNOT depict_VB an_AT exposure_NN to_IN an_AT allergen_NN within_IN 1_CD1 hour_NN but_CC described_VBD urticaria_NN and_or_CC angioedema_NN in_IN conjunction_NN with_IN at_RB least_RB one_CD1 systemic_JJ sign_NN 360_CD an_AT additional_JJ criterion_NN was_BEDZ considered_VBN for_IN cases_NNS in_IN which_WDTR no_ATI exposure_NN to_IN an_AT allergen_NN within_IN 1_CD1 hour_NN was_BEDZ suspected_VBN and_CC for_IN which_WDTR no_ATI urticaria_NN or_CC angioedema_NN was_BEDZ observed_VBN : anaphylaxis_NN should_MD be_BE considered_VBN if_CS two_CD systemic_JJ manifestations_NNS are_BER observed_VBN the_ATI addition_NN of_IN this_DT criterion_NN would_MD describe_VB three_CD additional_JJ communications_NNS , for_IN a_AT total_NN of_IN 95_CD (_( 82%_JJ )_) of_IN the_ATI articles_NNS it_PP3 was_BEDZ concluded_VBN that_CS the_ATI first_OD two_CD criteria_NNS characterized_VBN the_ATI majority_NN of_IN the_ATI articles_NNS , and_CC the_ATI addition_NN of_IN this_DT criterion_NN would_MD not_XNOT significantly_RB increase_VB the_ATI number_NN of_IN articles_NNS described_VBN 361_CD there_EX was_BEDZ insufficient_JJ information_NN about_IN the_ATI events_NNS called_VBN anaphylactic_VBN in_IN 18_CD reports_NNS (_( 16%_CD )_) to_TO determine_VB whether_CS any_DTI of_IN the_ATI three_CD criteria_NNS under_IN consideration_NN fit_NN twelve_CD did_DOD not_XNOT record_VB either_DTX the_ATI observed_JJ signs_NNS or_CC the_ATI reaction_NN time_NN , and_CC another_DT four_CD did_DOD not_XNOT state_VB a_AT reaction_NN time_NN four_CD reports_NNS discussed_VBN immunologic_JJ tests_NNS and_CC not_XNOT the_ATI clinical_JJ events_NNS the_ATI criteria_NNS did_DOD not_XNOT fit_VB two_CD case_NN reports_NNS or_CC one_CD1 report_NN of_IN a_AT laboratory_NN investigation_NN of_IN isolated_JJ human_JJ mast_NN cells_NNS of_IN the_ATI 98_NN articles_NNS with_IN sufficient_JJ information_NN to_TO analyze_VB the_ATI criteria_NNS , 92_CD (_( 96%_NN )_) satisfied_JJ the_ATI first_OD two_CD criteria_NNS 362_CD COMMENT_NP 363_CD there_EX are_BER few_AP controlled_JJ investigations_NNS of_IN the_ATI clinical_JJ presentation_NN of_IN anaphylaxis_NN because_CS rapid_JJ diagnosis_NN may_MD be_BE elusive_JJ but_CC lifesaving_VBG , an_AT attempt_NN to_TO extract_VB useful_JJ criteria_NNS for_IN recognition_NN from_IN recent_JJ literature_NN was_BEDZ undertaken_VBN schwid_NN and_CC O_ZZ 'Donnell_NP$ illustrated_VBN the_ATI difficulty_NN in_IN identifying_VBG anaphylaxis_NN in_IN their_PP$ study_NN of_IN the_ATI management_NN of_IN simulated_JJ anesthesia_NN emergencies_NNS they_PP3AS found_VBD that_CS anaphylaxis_NN was_BEDZ recognized_VBN by_IN only_RB 40%_NP of_IN the_ATI participating_VBG anesthesiologists_NNS (_( 10_CD residents_NNS , 10_CD faculty_NN , and_CC 10_CD private_JJ practitioners_NNS )_) even_RB though_IN the_ATI simulation_NN represented_VBN a_AT classic_JJ presentation_NN : rash_NN , hypotension_NN , tachycardia_NN , vasodilatation_NN , and_CC wheeze_NN occurring_VBG within_IN minutes_NNS of_IN the_ATI administration_NN of_IN the_ATI first_OD drug_NN 364_CD among_IN the_ATI 160_CD identified_JJ articles_NNS , there_EX were_BED only_RB five_CD controlled_VBN studies_NNS involving_VBG the_ATI initial_JJ clinical_JJ presentation_NN , and_CC the_ATI majority_NN were_BED case_NN reports_NNS thus_RB , one_CD1 would_MD like_VB to_IN abstract_JJ information_NN from_IN uncontrolled_JJ studies_NNS in_IN a_AT meaningful_JJ way_NN case_NN reports_NNS are_BER anecdotal_JJ accounts_NNS , and_CC this_DT retrospective_JJ analysis_NN may_MD describe_VB the_ATI most_QL easily_RB identified_JJ cases_NNS or_CC merely_RB record_NN cases_NNS satisfying_JJ commonly_RB accepted_VBN descriptions_NNS of_IN anaphylaxis_NN keeping_VBG these_DTS limitations_NNS in_IN mind_NN , such_ABL an_AT analysis_NN may_MD provide_VB useful_JJ information_NN on_IN the_ATI relevant_JJ signs_NNS and_CC symptoms_NNS , exposures_NNS , and_CC reaction_NN times_NNS in_IN the_ATI absence_NN of_IN prospective_JJ studies_NNS 365_CD 35_CD different_JJ controls_NNS may_MD need_VB to_TO be_BE developed_VBN for_IN assessing_VBG anaphylactic_JJ events_NNS examples_NNS from_IN the_ATI cited_VBN reports_NNS include_VB the_ATI comparison_NN of_IN patients_NNS with_IN themselves_PPLS before_CS and_CC after_IN the_ATI institution_NN of_IN prophylaxis_NN and_CC the_ATI controlled_VBN challenges_VBZ of_IN a_AT single_JJ individual_JJ to_TO confirm_VB the_ATI allergen_NN and_CC to_TO evaluate_VB a_AT prophylactic_JJ regimen_NNS recently_RB , this_DT technique_NN has_HVZ been_BEN formalized_VBN , using_VBG randomized_VBN controlled_VBN blinded_VBD trials_NNS on_IN a_AT single_JJ subject_NN , for_IN examining_VBG the_ATI efficacy_NN of_IN a_AT therapeutic_JJ intervention_NN these_DTS N_ZZ of_IN 1_CD1 randomized_VBN controlled_JJ trials_NNS , which_WDTR are_BER a_AT modification_NN of_IN the_ATI blinded_VBD crossover_NN method_NN , may_MD be_BE useful_JJ for_IN studying_VBG several_AP aspects_NNS of_IN anaphylaxis_NN : prophylactic_JJ regimens_NNS , clinical_JJ presentation_NN , and_CC therapy_NN 366_CD analysis_NN of_IN these_DTS clinical_JJ reports_NNS suggests_VBZ that_CS the_ATI diagnosis_NN of_IN anaphylaxis_NN has_HVZ three_CD elements_NNS : (_( 1_CD1 )_) signs_NNS and_CC symptoms_NNS , (_( 2_CD )_) the_ATI presence_NN of_IN an_AT identifiable_JJ allergen_NN , and_CC (_( 3_CD )_) the_ATI reaction_NN time_NN these_DTS three_CD elements_NNS form_VB the_ATI foundation_NN for_IN the_ATI criteria_NNS if_CS all_ABN three_CD are_BER present_JJ , the_ATI diagnosis_NN is_BEZ straightforward_JJ but_CC anaphylaxis_NN may_MD occur_VB without_IN an_AT identifiable_JJ allergen_NN , for_IN example_NN , in_IN idiopathic_JJ anaphylaxis_NN in_IN these_DTS cases_NNS , not_XNOT only_RB is_BEZ there_EX no_ATI identified_JJ allergen_NN , but_CC also_RB no_ATI reaction_NN time_NN can_MD be_BE determined_JJ occasionally_RB , anaphylaxis_NN may_MD take_VB place_VB more_QL than_IN 1_CD1 hour_NN after_IN exposure_NN to_IN an_AT allergen_NN , usually_RB in_IN the_ATI setting_NN of_IN a_AT depot_NN injection_NN or_CC an_AT exposure_NN in_IN which_WDTR systemic_JJ absorption_NN is_BEZ delayed_VBN Diagnostic_NP criteria_NNS must_MD be_BE specific_JJ enough_QLP to_TO include_VB the_ATI instances_NNS when_WRB all_ABN three_CD elements_NNS are_BER present_JJ on_IN the_ATI other_AP hand_NN , these_DTS rules_NNS must_MD be_BE broad_JJ enough_QLP to_TO point_VB out_RP those_DTS presentations_NNS in_IN which_WDTR elements_NNS are_BER missing_JJ but_CC the_ATI diagnosis_NN should_MD be_BE considered_VBN 367_CD checking_VBG that_CS the_ATI devised_VBN diagnostic_JJ criteria_NNS described_VBN more_AP than_IN 80%_NP of_IN the_ATI MEDLINE-identified_NP articles_NNS was_BEDZ a_AT means_NNS of_IN testing_VBG the_ATI scope_NN of_IN the_ATI criteria_NNS neglecting_VBG the_ATI 18_CD articles_NNS that_CS did_DOD not_XNOT provide_VB sufficient_JJ data_NNS for_IN the_ATI determination_NN of_IN the_ATI appropriateness_NN of_IN the_ATI criteria_NNS , two_CD criteria_NNS failed_VBN to_TO suit_VB only_RB six_CD articles_NNS if_CS the_ATI third_OD criterion_NN is_BEZ considered_VBN , only_RB three_CD reports_NNS were_BED excluded_VBN 368_CD although_CS the_ATI third_OD criterion_NN was_BEDZ not_XNOT necessary_JJ to_TO describe_VB the_ATI majority_NN of_IN the_ATI presentations_NNS , it_PP3 should_MD still_RB be_BE considered_VBN criterion_NN 3_CD has_HVZ a_AT much_RB broader_JJR differential_JJ diagnosis_NN , including_IN visceral_JJ hemorrhage_NN or_CC infarct_NN , pulmonary_NN embolism_NN , myocardial_JJ infarction_NN , and_CC sepsis_NN a_AT situation_NN satisfying_JJ only_RB criterion_NN 3_CD would_MD represent_VB a_AT somewhat_RB atypical_JJ presentation_NN of_IN anaphylaxis_NN , and_CC such_ABL cases_NNS may_MD be_BE underrepresented_VBN in_IN the_ATI literature_NN reviewed_VBN here_RN the_ATI sudden_JJ onset_NN of_IN manifestations_NNS consistent_JJ with_IN criterion_NN 3_CD for_IN which_WDTR no_ATI diagnosis_NN is_BEZ immediately_RB apparent_JJ should_MD precipitate_VB a_AT review_NN of_IN all_ABN diagnostic_JJ and_CC therapeutic_JJ agents_NNS administered_VBN in_IN the_ATI previous_JJ hour_NN 369_CD signs_NNS and_CC Symptoms_NP 370_CD signs_NNS and_CC symptoms_NNS were_BED grouped_VBN by_IN organ_NN system_NN for_IN analysis_NN with_IN the_ATI exception_NN of_IN cardiovascular_NN signs_NNS , the_ATI organ_NN systems_NNS most_QL frequently_RB cited_VBN were_BED those_DTS directly_RB exposed_VBN to_IN the_ATI environment_NN : skin_NN , respiratory_JJ tract_NN , and_CC gastrointestinal_JJ tract_NN systems_NNS in_IN each_DT category_NN , an_AT attempt_NN was_BEDZ made_VBN to_TO identify_VB the_ATI most_QL prominent_JJ and_CC specific_JJ manifestations_NNS for_IN use_NN in_IN the_ATI diagnostic_JJ criteria_NNS thus_RB , urticaria_NN and_CC angioedema_NN were_BED included_VBN as_IN the_ATI most_QL frequent_JJ dermatologic_JJ manifestations_NNS , and_CC hypotension_NN was_BEDZ cited_VBN as_IN the_ATI most_QL frequently_RB mentioned_JJ cardiovascular_NN sign_NN 371_CD an_AT abstract_JJ by_IN Wolf_NP and_CC Lieberman_NP reported_VBD very_QL similar_JJ frequencies_NNS of_IN urticaria_NN and_or_CC angioedema_NN and_CC respiratory_JJ tract_NN findings_NNS , but_CC these_DTS authors_NNS reported_VBN hypotension_NN in_IN only_RB 24%_JJ of_IN 89_CD retrospectively_RB reviewed_VBN cases_NNS our_PP$ review_NN would_MD suggest_VB it_PP3 is_BEZ important_JJ to_TO consider_VB anaphylaxis_NN in_IN cases_NNS of_IN hypotension_NN in_IN which_WDTR the_ATI cause_NN is_BEZ not_XNOT obvious_JJ 372_CD this_DT analysis_NN also_RB identified_VBN the_ATI clinical_JJ findings_NNS that_WPR appeared_VBD commonly_RB and_CC , although_CS they_PP3AS were_BED not_XNOT used_VBN in_IN the_ATI diagnostic_JJ criteria_NNS , may_MD be_BE prodromal_JJ examples_NNS include_VB nasal_JJ congestion_NN , rhinorrhea_NN , flushing_VBG , pruritus_NN , and_CC cough_NN indeed_RB , in_IN one_CD1 MEDLINE-identified_NP article_NN , of_IN 11_CD cases_NNS of_IN food-dependent_NN , exercise-induced_JJ anaphylaxis_NN , flushing_VBG , pruritus_NN , cough_NN , nasal_JJ discharge_NN , dyspnea_NN , colic_JJ , nausea_NN , and_CC headache_NN were_BED reported_VBN as_CS early_JJ manifestations_NNS another_DT sign_NN that_CS was_BEDZ noted_VBN occasionally_RB was_BEDZ uterine_NN cramping_VBG and_CC , although_CS not_XNOT diagnostic_JJ , may_MD be_BE underreported_JJ 373_CD allergen_NN Identification_NN 374_CD a_AT specific_JJ allergen_NN was_BEDZ identified_VBN in_IN 95%_NN of_IN the_ATI 116_CD articles_NNS analyzed_VBN when_WRB one_CD1 can_MD be_BE identified_VBN , diagnosis_NN should_MD be_BE easier_JJR because_CS reaction_NN time_NN also_RB can_MD be_BE defined_VBN specific_JJ allergens_NNS were_BED not_XNOT used_VBN in_IN the_ATI criteria_NNS because_CS the_ATI cited_VBN allergens_NNS from_IN a_AT 1-year_CD-CD survey_NN reflected_VBD interest_NN in_IN solving_VBG current_JJ problems_NNS thus_RB , it_PP3 was_BEDZ likely_JJ that_CS cases_NNS involving_VBG latex_NN allergy_NN were_BED overrepresented_VBN whereas_CS beta-lactam_NN reactions_NNS , which_WDTR have_HV been_BEN described_VBN more_QL extensively_RB in_IN past_NN years_NNS , were_BED underrepresented_VBN by_IN sampling_NN from_IN a_AT specific_JJ year_NN the_ATI most_AP commonly_RB recognized_JJ allergens_NNS in_IN this_DT series_NN were_BED diagnostic_JJ and_CC therapeutic_JJ agents_NNS it_PP3 is_BEZ important_JJ to_TO consider_VB anaphylaxis_NN in_IN any_DTI patient_NN who_WPR presents_VBZ with_IN the_ATI described_VBN systemic_JJ signs_NNS within_IN 1_CD1 hour_NN of_IN exposure_NN to_IN a_AT diagnostic_JJ or_CC therapeutic_JJ agent_NN , and_CC it_PP3 is_BEZ important_JJ to_TO know_VB which_WDTR agents_NNS are_BER most_QL frequently_RB implicated_VBN in_IN episodes_NNS of_IN anaphylaxis_NN 375_CD there_EX were_BED only_RB six_CD articles_NNS in_IN which_WDTR no_ATI allergen_NN was_BEDZ reported_VBN and_CC three_CD in_IN which_WDTR an_AT extensive_JJ investigation_NN had_HVD been_BEN undertaken_VBN this_DT analysis_NN raises_VBZ the_ATI question_NN as_CS to_TO whether_CS idiopathic_JJ anaphylaxis_NN is_BEZ truly_RB a_AT rare_JJ event_NN or_CC whether_CS it_PP3 is_BEZ underreported_JJ because_CS this_DT important_JJ issue_NN has_HVZ not_XNOT been_BEN resolved_VBN , the_ATI criteria_NNS are_BER structured_VBN to_TO identify_VB episodes_NNS of_IN idiopathic_JJ anaphylaxis_NN so_QL they_PP3AS may_MD be_BE examined_VBN further_JJB 376_CD reaction_NN Time_NP 377_CD the_ATI reaction_NN time_NN chosen_VBN for_IN the_ATI criteria_NNS was_BEDZ 1_CD1 hour_NN , which_WDTR is_BEZ consistent_JJ with_IN that_DT used_VBN by_IN Levine_NP in_IN the_ATI 1960s_CDS for_IN describing_VBG penicillin_NN allergy_NN although_CS delayed_JJ reactions_NNS , ie_NN , those_DTS with_IN reaction_NN times_NNS greater_JJR than_IN 1_CD1 hour_NN , have_HV been_BEN reported_VBN and_CC also_RB were_BED noted_VBN in_IN this_DT review_NN , these_DTS were_BED not_XNOT frequent_JJ and_CC in_IN some_DTI may_MD be_BE due_JJ to_TO depot_NN administration_NN on_IN the_ATI other_AP hand_NN , in_IN 85%_NN of_IN the_ATI reviewed_VBN articles_NNS with_IN identified_JJ reaction_NN times_NNS , the_ATI onset_NN of_IN symptoms_NNS occurred_VBD within_IN 30_CD minutes_NNS a_AT reaction_NN time_NN of_IN 60_CD minutes_NNS is_BEZ broad_JJ enough_QLP to_TO include_VB almost_RB all_ABN immediate_JJ reactions_NNS while_CS tending_VBG to_TO eliminate_VB many_AP equivocal_JJ ones_CD1S Severe_NP delayed_VBD reactions_NNS would_MD still_RB be_BE recognized_VBN by_IN the_ATI likely_JJ presence_NN of_IN urticaria_NN and_or_CC angioedema_NN or_CC more_AP than_IN one_CD1 systemic_JJ sign_NN 378_CD anaphylaxis_NN Without_NP Dermatologic_NP Findings_NNS 379_CD cases_NNS in_IN which_WDTR diagnosis_NN may_MD be_BE particularly_RB difficult_JJ are_BER those_DTS in_IN which_WDTR common_JJ dermatologic_JJ presentations_NNS are_BER absent_JJ that_DT the_ATI largest_JJT group_NN of_IN articles_NNS from_IN a_AT nonallergy_NN specialty_NN came_VBD from_IN anesthesiologists_NNS may_MD reflect_VB the_ATI difficulty_NN in_IN recognizing_VBG the_ATI syndrome_NN in_IN a_AT setting_VBG where_WRB the_ATI most_QL characteristic_JJ findings_NNS may_MD be_BE obscured_VBN by_IN surgical_JJ drapes_NNS in_IN the_ATI subgroup_NN of_IN articles_NNS in_IN which_WDTR dermatologic_JJ signs_NNS were_BED absent_JJ , the_ATI same_AP physical_JJ findings_NNS and_CC reaction_NN times_NNS were_BED noted_VBN as_CS in_IN the_ATI entire_JJB collection_NN of_IN 116_CD articles_NNS , but_CC the_ATI number_NN , 19_CD articles_NNS , was_BEDZ small_JJ it_PP3 is_BEZ possible_JJ that_CS this_DT group_NN , too_RB , is_BEZ underreported_JJ , but_CC using_VBG the_ATI criteria_NNS prospectively_RB could_MD clarify_VB this_DT issue_NN 380_CD CONCLUSION_NPT AND_NP SUMMARY_NP 381_CD anaphylaxis_NN can_MD be_BE recognized_VBN by_IN a_AT history_NN of_IN exposure_NN to_IN an_AT allergen_NN within_IN 1_CD1 hour_NN of_IN the_ATI onset_NN of_IN symptoms_NNS or_CC by_IN classical_JJ dermatologic_JJ findings_NNS (_( urticaria_NN or_CC angioedema_NN )_) accompanied_VBN by_IN one_CD1 or_CC more_QL systemic_JJ signs_NNS in_IN the_ATI absence_NN of_IN an_AT identifiable_JJ allergen_NN exposure_NN or_CC dermatologic_JJ findings_NNS , two_CD or_CC more_QL systemic_JJ manifestations_NNS (_( cardiovascular_NN , upper_JJB or_CC lower_JJR respiratory_JJ tract_NN , or_CC gastrointestinal_JJ tract_NN )_) are_BER suggestive_JJ of_IN anaphylaxis_NN in_IN the_ATI cases_NNS reviewed_VBN , dermatologic_JJ manifestations_NNS were_BED noted_VBN in_IN 76%_NN of_IN the_ATI reports_NNS ; cardiovascular_NN manifestations_NNS , in_IN 75%_NN ; and_CC respiratory_JJ tract_NN manifestations_NNS , in_IN 70%_NP gastrointestinal_JJ tract_NN and_CC laryngeal_JJ or_CC pharyngeal_JJ signs_NNS were_BED common_JJ but_CC less_QL frequently_RB described_VBN (_( 28%_NN and_CC 26%_NN , respectively_RB )_) JORDEE rosacea_NN : pathophysiology_NN and_CC Treatment_NP 2_CD however_RB , to_TO directly_RB pursue_VB these_DTS theories_NNS would_MD be_BE premature_JJ without_IN a_AT brief_JJ note_NN on_IN what_WDT rosacea_NN really_RB is_BEZ (_( and_CC is_BEZ not_XNOT )_) rosacea_NN is_BEZ not_XNOT a_AT disease_NN rosacea_NN is_BEZ a_AT typology_NN , namely_RB , a_AT cluster_NN of_IN persons_NNS with_IN a_AT characteristic_JJ combination_NN of_IN cutaneous_JJ stigmata_NN given_VBN the_ATI typologic_JJ model_NN , the_ATI epicenter_NN of_IN rosacea_NN is_BEZ occupied_VBN by_IN a_AP few_AP unfortunate_JJ patients_NNS with_IN flushing_VBG , erythema_NN , telangiectasia_NN , facial_JJ edema_NN , papules_NNS , pustules_NNS , ocular_JJ lesions_NNS , and_CC rhinophyma_NN most_AP patients_NNS , of_RB course_RB , have_HV less_AP than_IN the_ATI full_RB set_VBN of_IN these_DTS stigmata_NN senior_JJ medical_JJ students_NNS who_WPR have_HV invested_VBN a_AT month_NN in_IN a_AT clinical_JJ dermatology_JJ elective_JJ are_BER able_JJ to_TO recognize_VB rosacea_NN in_IN its_PP$ fullest_JJT expression_NN during_IN residency_NN training_NN , one_CD1 begins_VBZ to_TO discover_VB in_IN the_ATI dermatology_NN clinic_NN patients_NNS with_IN fewer_AP variables_NNS experiencing_VBG rosacea_NN in_IN this_DT manner_NN , dermatologists_NNS are_BER gradually_RB mapping_NN the_ATI area_NN around_IN the_ATI nodal_JJ point_NN , the_ATI typological_JJ center_NN far_RB away_RP from_IN the_ATI center_NN in_IN the_ATI periphery_NN , the_ATI variables_NNS are_BER so_QL few_AP and_CC their_PP$ expressions_NNS so_QL vague_JJ that_CS identification_NN of_IN rosacea_NN becomes_VBZ increasingly_RB uncertain_JJ thus_RB , rosacea_NN is_BEZ well_RB defined_VBN in_IN its_PP$ center_NN but_CC not_XNOT in_IN its_PP$ periphery_NN 3_CD as_IN knowledge_NN of_IN a_AT disease_NN increases_NNS , it_PP3 often_RB becomes_VBZ possible_JJ for_IN the_ATI definition_NN to_TO be_BE moved_VBN from_IN a_AT more_QL primitive_JJ mode_NN , eg_NN , the_ATI typology_NN , to_IN a_AT definition_NN based_VBN on_IN disordered_JJ anatomy_NN or_CC physiology_NN or_CC , finally_RB , to_IN a_AT definition_NN based_VBN on_IN causality_NN despite_IN its_PP$ primitive_JJ nature_NN , the_ATI typologic_JJ approach_NN is_BEZ of_IN considerable_JJ heuristic_JJ value_NN typologically_RB , rosacea_NN may_MD be_BE considered_VBN a_AT reaction_NN pattern_NN , a_AT phenotype_NN that_WPR may_MD be_BE elicited_VBN by_IN a_AT variety_NN of_IN causes_NNS in_IN _** rosacea-prone_NN _** individuals_NNS Identifying_NP and_CC cataloguing_NN these_DTS various_JJ , putative_JJ _** causes_NNS _** invites_VBZ speculation_NN on_IN the_ATI predominant_JJ physiologic_JJ pathway_NN involved_VBN in_IN rosacea_NN If_NP subsequently_RB verified_VBN by_IN experiment_NN , a_AT definition_NN based_VBN on_IN disordered_JJ physiology_NN can_MD be_BE established_VBN , and_CC the_ATI definition_NN of_IN rosacea_NN will_MD be_BE moved_VBN from_IN a_AT less_QL primitive_JJ to_IN a_AT more_QL advanced_JJ state_NN 4_CD not_XNOT only_RB are_BER erythema_NN and_CC telangiectasia_NN obviously_RB vascular_JJ in_IN nature_NN , but_CC even_RB those_DTS features_NNS of_IN rosacea_NN that_CS are_BER not_XNOT primarily_RB vascular_NN may_MD derive_VB from_IN this_DT same_AP pathophysiology_NN rosacea_NN is_BEZ essentially_RB a_AT cutaneous_JJ vascular_NN disorder_NN first_OD , there_EX are_BER several_AP lines_NNS of_IN evidence_NN for_IN flushing_VBG in_IN the_ATI pathogenesis_NN of_IN rosacea_NN there_EX is_BEZ an_AT increased_JJ frequency_NN of_IN flushing_VBG with_IN rosacea_NN there_EX is_BEZ a_AT correlation_NN between_IN severity_NN of_IN ocular_JJ rosacea_NN and_CC a_AT tendency_NN to_IN strong_JJ flushing_VBG Intravenously_NP administered_VBD xanthinol_NN nicotinate_NN produces_VBZ a_AT dilation_NN of_IN the_ATI small_JJ conjunctival_JJ vessels_NNS , with_IN a_AT particularly_RB noticeable_JJ appearance_NN of_IN the_ATI collateral_JJ vessels_NNS patients_NNS with_IN severe_JJ flushing_VBG due_JJ to_TO carcinoid_VB develop_VB all_ABN the_ATI various_JJ stigmata_NN , including_IN ocular_JJ rosacea_NN , facial_JJ telangiectasia_NN , and_CC severe_JJ connective_JJ tissue_NN hypertrophy_NN 5_CD likewise_RB , patients_NNS with_IN severe_JJ flushing_VBG due_JJ to_TO mastocytosis_VB can_MD develop_VB a_AT rapidly_RB progressive_JJ rosacea_NN mild_JJ rosacea_NN often_RB appears_VBZ in_IN women_NNS after_IN age_NN 35_CD years_NNS when_WRB the_ATI frequency_NN of_IN _** hot_JJ flashes_NNS _** and_CC flushing_VBG increases_NNS flushing_VBG is_BEZ invariably_RB the_ATI earliest_JJT component_NN of_IN rosacea_NN to_TO be_BE apparent_JJ , and_CC recurrent_JJ flushing_VBG in_IN a_AT rosacea-prone_NN individual_JJ may_MD be_BE regarded_VBN as_IN _** prerosacea_NN _** (_( Figure_NP 1_CD1 )_) 6_CD the_ATI first_OD definitive_JJ stage_NN of_IN rosacea_NN is_BEZ vascular_JJ early_JJ vascular_NN rosacea_JJ consists_VBZ of_IN simple_JJ erythema_NN (_( or_CC cyanosis_NN on_IN cold_JJ days_NNS )_) this_DT erythema_NN represents_VBZ the_ATI increased_JJ numbers_NNS of_IN erythrocytes_NNS in_IN a_AT mildly_RB inflamed_JJ superficial_JJ vasculature_NN no_ATI microorganisms_NNS have_HV been_BEN consistently_RB identified_VBN , and_CC so_PN it_PP3 is_BEZ tempting_JJ to_TO speculate_VB that_CS a_AT low- grade_NN , sterile_JJ dermal_JJ cellulitis_NN may_MD result_VB from_IN the_ATI extravascular_NN fluid_NN that_QL accumulates_VBZ as_IN the_ATI result_NN of_IN multiple_JJ provocative_JJ factors_NNS Certainly_NP , local_JJ irritants_NNS , such_ABL as_CS some_DTI topical_JJ medications_NNS , astringents_NNS , toners_NNS , aeroirritants_NNS , wind_NN , and_CC temperature_NN extremes_NNS , will_MD directly_RB lead_NN to_TO extravascular_VB fluid_NN accumulations_NNS in_IN the_ATI superficial_JJ dermis_NN flushing_VBG reactions_NNS , regardless_RB of_IN whether_CS the_ATI cause_NN is_BEZ menopausal_JJ , blushing_VBG , vasodilator_NN drug_NN therapy_NN , carcinoidosis_NN , mastocytosis_NN , ethanol_NN , or_CC food_NN intolerance_NN , consist_VB of_IN an_AT increased_VBN blood_NN flow_NN in_IN the_ATI superficial_JJ dermis_NN this_DT leads_VBZ to_IN an_AT increase_NN in_IN the_ATI extracellular_NN fluid_NN that_CS accumulates_VBZ faster_RBR than_IN the_ATI lymphatics_NNS can_MD remove_VB it.=20_CD 7_CD when_WRB facial_JJ cutaneous_JJ lymphatic_JJ vessels_NNS are_BER acutely_RB damaged_VBN , inflammatory_JJ edema_NN can_MD appear_VB rapidly_RB chronic_JJ progressive_JJ lymphatic_JJ damage_NN may_MD occur_VB subclinically_RB from_IN the_ATI low-grade_NN cellulitis_NN and_CC actinic_JJ changes_NNS (_( see_VB below_IN )_) the_ATI frequent_JJ occurrence_NN of_IN overt_JJ facial_JJ edema_NN in_IN the_ATI course_NN of_IN rosacea_NN has_HVZ been_BEN documented_VBN 8_CD rosacea_NN responds_VBZ to_TO massage_VB therapy_NN , supporting_VBG the_ATI theory_NN that_CS flushing_VBG leads_VBZ to_TO edema_VB , which_WDTR then_RN leads_VBZ to_IN the_ATI other_AP stigmata_NN Although_NP local_JJ massage_VB significantly_RB enhances_VBZ clearance_NN of_IN isotope_NN tracers_NNS in_IN cutaneous_JJ lymphatics_NNS , the_ATI most_QL effective_JJ massage_VB is_BEZ a_AT milking_NN motion_NN at_IN a_AT downstream_RB site_NN , rather_RB than_IN massage_VB of_IN the_ATI lymphedematous_JJ area_NN (_( T._NP J._NP Ryan_NP , DM_NNU , FRCP_NP , oral_JJ communication_NN , October_NR 17_CD , 1988_CD )_) rosacea_NN stigmata_NN are_BER typically_RB found_VBN in_IN those_DTS areas_NNS of_IN the_ATI face_NN overlying_JJ relatively_RB inactive_JJ musculature_NN , where_WRB the_ATI edema_NN caused_VBN by_IN the_ATI flushing_VBG tends_VBZ to_TO persist_VB _** extrafacial_JJ rosacea_NN _** seems_VBZ to_TO occur_VB in_IN extrafacial_JJ areas_NNS of_IN flushing_VBG rhinophyma_NN may_MD be_BE explained_VBN by_IN the_ATI observation_NN that_CS chronic_JJ cutaneous_JJ edema_NN is_BEZ frequently_RB followed_VBN by_IN connective_JJ tissue_NN hypertrophy_NN and_CC fibroplasia_NN and_CC may_MD be_BE due_JJ to_TO factor_NN XIII_NP expression_NN 9_CD Ryan_NP has_HVZ emphasized_VBN that_CS the_ATI elastin_NN network_NN that_CS surrounds_VBZ the_ATI lymphatic_JJ system_NN in_IN the_ATI skin_NN serves_VBZ two_CD important_JJ functions_NNS first_OD , it_PP3 is_BEZ a_AT tethering_VBG that_CS permits_VBZ the_ATI lymphatic_JJ endothelium_NN to_TO be_BE sensitive_JJ to_TO the_ATI volume_NN of_IN fluids_NNS in_IN the_ATI vicinity_NN of_IN the_ATI lymphatic_JJ vessels_NNS , so_CS that_CS any_DTI increased_JJ volume_NN results_NNS in_IN greater_JJR tension_NN on_IN the_ATI anchoring_VBG filaments_NNS second_OD , the_ATI elastin_NN network_NN provides_VBZ a_AT low_JJ resistance_NN pathway_NN through_IN the_ATI interstitium_NN along_IN which_WDTR macromolecules_NN pass_VB to_IN the_ATI lymphatic_JJ vessels_NNS elastin_NN degeneration_NN due_JJ to_IN actinic_JJ exposure_NN is_BEZ probably_RB a_AT common_JJ cause_NN of_IN lymphatic_JJ failure_NN in_IN the_ATI rosacea_NN distribution_NN 10_CD further_JJB , as_IN rosacea_NN progresses_VBZ , the_ATI continued_VBD activity_NN of_IN proteases_NNS during_IN inflammation_NN will_MD release_VB the_ATI cytoskeleton_NN from_IN the_ATI attachment_NN of_IN the_ATI cell_NN membrane_NN neutrophils_NNS can_MD exacerbate_VB the_ATI rapid_JJ degradation_NN of_IN a_AT variety_NN of_IN extracellular_NN matrix_NN macromolecules_NNS , especially_RB elastin_JJ , in_IN inflammatory_JJ disease_NN states_NNS neutrophil_NN elastase_NN also_RB degrades_VBZ type_NN IV_NP collagen_NN in_IN the_ATI extracellular_NN matrix_NN on_IN which_WDTR the_ATI integrity_NN of_IN the_ATI capillary_JJ wall_NN depends_VBZ thus_RB , the_ATI sterile_JJ superficial_JJ dermal_JJ cellulitis_NN in_IN rosacea_NN will_MD lead_VB to_IN the_ATI separation_NN of_IN the_ATI elastin_NN from_IN the_ATI lymphatic_JJ vessels_NNS with_IN a_AT loss_NN of_IN the_ATI superficial_JJ lymphatic_JJ microvascular_NN function_NN , any_DTI extravascular_NN fluid_NN accumulation_NN at_IN this_DT site_NN (_( such_ABL as_CS may_MD occur_VB with_IN flushing_VBG )_) will_MD tend_VB to_TO persist_VB longer_RBR 11_CD lymphatic_JJ failure_NN results_NNS in_IN a_AT sustained_VBN inflammatory_JJ response_NN in_IN cutaneous_JJ cellulitis_NN in_IN fact_NN , in_IN the_ATI setting_NN of_IN lymphatic_JJ failure_NN , any_DTI factor_NN able_JJ to_TO trigger_VB an_AT exudation_NN of_IN protein_NN will_MD produce_VB a_AT self-sustained_JJ inflammation_NN these_DTS proteins_NNS that_CS cannot_NN be_BE cleared_VBN from_IN the_ATI interstitium_JJ because_CS of_IN lymphatic_JJ failure_NN are_BER denatured_VBN , becoming_VBG phlogistic_JJ factors_NNS the_ATI accumulating_JJ plasma_NN proteins_NNS may_MD also_RB play_VB an_AT important_JJ role_NN in_IN the_ATI fibroplasia_NN , which_WDTR underlies_VBZ the_ATI development_NN of_IN rhinophyma_NN the_ATI chronic_JJ sterile_JJ dermal_JJ cellulitis_NN also_RB leads_VBZ to_IN an_AT increased_JJ microvascular_NN capacitance_NN , which_WDTR then_RN acutely_RB increases_VBZ further_JJB with_IN vasodilator_NN stimuli_NNS leading_JJ to_IN the_ATI subjective_JJ notion_NN that_CS flushing_VBG occurs_VBZ much_AP more_QL frequently_RB in_IN patients_NNS with_IN rosacea_NN stigmata_NN 12_CD telangiectasia_NN represents_VBZ the_RB later_RBR phase_NN of_IN the_ATI vascular_JJ stage_NN of_IN rosacea_NN (_( Figure_NP )_) one_CD1 key_NN causative_JJ factor_NN is_BEZ a_AT reduction_NN in_IN the_ATI mechanical_JJ integrity_NN of_IN the_ATI upper_JJB dermal_JJ connective_JJ tissue_NN , allowing_VBG a_AT passive_JJ dilation_NN of_IN the_ATI vasculature_NN the_ATI perivascular_JJ inflammatory_JJ cell_NN infiltrate_VB and_CC increased_VBN endothelial_JJ labeling_NN index_NN underlie_VB the_ATI vessel_NN wall_NN damage_NN that_CS contributes_VBZ to_TO rosacea_VB pathology_NN dilation_NN of_IN both_ABX small_JJ dermal_JJ blood_NN vessels_NNS and_CC lymphatics_NNS is_BEZ prominent_JJ in_IN rosacea_NN the_ATI ablation_NN of_IN these_DTS vessels_NNS by_IN flash_NN lamp_NN pumped_VBN dye_NN laser_NN is_BEZ followed_VBN by_IN fewer_AP inflammatory_JJ lesions_NNS 13_CD angiogenesis_NN may_MD also_RB contribute_VB to_IN the_ATI telangiectasia_NN of_IN rosacea_NN Angiogenesis_NN depends_VBZ on_IN the_ATI availability_NN of_IN a_AT space_NN into_IN which_WDTR endothelial_JJ cells_NNS can_MD grow_VB thus_RB , edema_NN of_IN the_ATI cornea_NN , which_WDTR may_MD result_VB from_IN severe_JJ flushing_VBG , reduces_VBZ the_ATI corneal_JJ compactness_NN , permitting_VBG its_PP$ vascularization_NN ocular_JJ rosacea_NN is_BEZ principally_RB vascular_JJ and_CC correlates_NNS with_IN the_ATI severity_NN of_IN flushing_VBG since_IN lymphatic_JJ failure_NN can_MD result_VB in_IN the_ATI sustained_VBN inflammatory_JJ response_NN in_IN the_ATI sterile_JJ cellulitis_NN of_IN rosacea_NN , a_AT variety_NN of_IN features_NNS may_MD favor_NN angiogenesis_NN proteases_NNS may_MD release_VB angiogenetic_JJ factors_NNS stored_VBN in_IN the_ATI extracellular_NN matrix_NN , macrophages_NNS may_MD be_BE attracted_VBN and_CC activated_VBN to_TO release_VB angiogenic_JJ factors_NNS , and_CC endothelial_JJ factors_NNS may_MD be_BE released_VBN from_IN inhibitory_NN control_NN 14_CD recently_RB , rosacea_NN has_HVZ emerged_VBN as_IN an_AT important_JJ dermatosis_NN , in_IN part_NN because_CS of_IN its_PP$ prevalence_NN rosacea_NN is_BEZ a_AT common_JJ dermatosis_NN the_ATI only_AP study_NN in_IN which_WDTR investigators_NNS systematically_RB examined_VBN the_ATI facial_JJ skin_NN of_IN people_NNS in_IN a_AT community- based_JJ nonmedical_JJ setting_NN found_VBN that_CS 10%_CD of_IN office_NN employees_NNS had_HVD rosacea_NN even_RB 10%_CD of_IN the_ATI population_NN may_MD be_BE an_AT underestimate_VB , since_CS workers_NNS are_BER usually_RB healthier_JJR than_IN the_ATI general_JJ population_NN this_DT observation_NN that_CS healthier_JJR people_NNS are_BER more_QL likely_JJ to_TO both_ABX get_VB jobs_NNS and_CC continue_VB to_TO work_VB is_BEZ known_VBN as_IN the_ATI _** healthy_JJ worker_NN effect_NN _** thus_RB , people_NNS with_IN severe_JJ rosacea_NN may_MD not_XNOT seek_VB office_NN employment_NN or_CC may_MD not_XNOT be_BE selected_VBN for_IN office_NN employment_NN with_IN the_ATI graying_NN of_IN North_NP America_NP and_CC Europe_NP , demographic_JJ changes_NNS will_MD increase_VB the_ATI already_RB substantial_JJ prevalence_NN of_IN rosacea_NN the_ATI pharmaceutical_JJ industry_NN has_HVZ recently_RB recognized_VBN the_ATI potential_JJ market_NN created_VBN by_IN this_DT chronic_JJ dermatosis_NN that_CS affects_VBZ a_AT more_QL affluent_JJ segment_NN of_IN the_ATI population_NN 15_CD although_CS , on_IN close_RB scrutiny_NN , every_AT patient_NN with_IN rosacea_NN appears_VBZ to_TO be_BE different_JJ from_IN all_ABN the_ATI others_APS , something_PN can_MD be_BE done_VBN regardless_RB of_IN the_ATI combination_NN of_IN cutaneous_JJ stigmata_NN and_CC the_ATI individual_JJ patient's_NN$ exacerbating_VBG factors_NNS rosacea_NN is_BEZ a_AT treatable_JJ disorder_NN avoiding_VBG flushing_VBG and_CC anything_PN that_CS causes_NNS stinging_VBG of_IN facial_JJ skin_NN can_MD be_BE sufficient_JJ in_IN some_DTI patients_NNS to_TO sustain_VB remissions_NNS in_IN the_ATI patient_NN with_IN severe_JJ rhinophyma_NN and_CC abundant_JJ telangiectases_NNS , such_ABL preventive_JJ measures_NNS are_BER akin_JJ to_IN sunscreens_NNS for_IN extensive_JJ actinic_JJ keratosis_NN and_CC skin_NN cancers_NNS ; namely_RB , they_PP3AS are_BER insufficient_JJ to_TO reduce_VB all_ABN of_IN the_ATI damage_NN that_WPR has_HVZ already_RB occurred_VBN , but_CC may_MD prevent_VB further_JJB damage_NN 16_CD in_IN this_DT regard_NN , a_AT laudable_JJ goal_NN is_BEZ the_ATI recognition_NN of_IN patients_NNS with_IN _** prerosacea_NN _** a_AT typical_JJ patient_NN is_BEZ one_CD1 who_WPR blushes_NNS or_CC flushes_NNS frequently_RB , has_HVZ a_AT strong_JJ family_NN history_NN of_IN rosacea_NN , and_CC often_RB first_OD comes_VBZ to_IN the_ATI dermatologist's_NP$ attention_NN because_CS of_IN an_AT unusually_RB brisk_JJ and_CC persistent_JJ erythema_NN to_TO anti-acne_VB or_CC other_AP topicals_NNS avoidance_NN of_IN facial_JJ skin_NN irritants_NNS and_CC controlling_VBG flushing_VBG reactions_NNS may_MD prevent_VB the_ATI development_NN or_CC slow_JJ the_ATI progression_NN of_IN rosacea_NN stigmata_NN in_IN such_ABL patients_NNS 17_CD the_ATI earliest_JJT component_NN of_IN the_ATI vascular_NN stage_NN , erythema_NN , often_RB responds_VBZ to_IN topical_JJ and_CC systemic_JJ antibiotics_NNS , but_CC not_XNOT dependably_RB to_IN the_ATI extent_NN that_CS promises_NNS can_MD be_BE made_VBN to_IN the_ATI patients_NNS in_IN particularly_RB dramatic_JJ cases_NNS , however_RB , the_ATI response_NN may_MD be_BE complete_JJ , occasionally_RB resulting_JJ in_IN distress_NN to_IN the_ATI patient_JJ due_JJ to_IN the_ATI phenomenon_NN of_IN PERT_NP (_( posterythema-revealed_JJ telangiectasia_NN )_) the_ATI telangiectasia_NN was_BEDZ present_JJ all_ABN along_IN ; however_RB , it_PP3 was_BEDZ masked_VBN by_IN the_ATI erythema_NN I_PP1A now_RN counsel_NN patients_NNS with_IN particularly_RB intense_JJ erythema_NN about_IN this_DT possibility_NN to_TO preempt_JJ subsequent_JJ worries_NNS that_CS the_ATI antibiotic_JJ therapy_NN _** produced_VBN _** the_ATI telangiectasia_NN 18_CD the_RB later_RBR vascular_NN stage_NN includes_VBZ telangiectases_NNS of_IN varying_JJ caliber_NN from_IN very_QL fine_JJ to_TO very_QL coarse_JJ the_ATI treatment_NN for_IN telangiectasia_NN is_BEZ surgical_JJ , consisting_VBG of_IN electrodestruction_NN or_CC laser_NN techniques_NNS Importantly_NP , after_IN destruction_NN of_IN the_ATI telangiectasia_NN , patients_NNS may_MD have_HV fewer_AP papules_NNS and_CC pustules_NNS ocular_JJ rosacea_NN is_BEZ largely_RB vascular_JJ in_IN its_PP$ origin_NN and_CC is_BEZ frequently_RB treated_VBN with_IN systemic_JJ antibiotics_NNS flushing_VBG reactions_NNS in_IN patients_NNS with_IN ocular_JJ rosacea_NN must_MD be_BE controlled_VBN 19_CD the_ATI inflammatory_JJ lesions_NNS of_IN rosacea_NN , the_ATI papules_NNS and_CC pustules_NNS , and_CC occasionally_RB nodules_VBZ and_CC plaques_NNS , are_BER easily_RB treated_VBN in_IN most_QL patients_NNS , unless_CS they_PP3AS appear_VB superimposed_VBN on_IN rhinophyma_NN and_CC other_AP phymatous_JJ changes_NNS of_IN the_ATI skin_NN the_ATI response_NN to_IN treatment_NN with_IN systemic_JJ tetracycline_NN and_CC other_AP members_NNS of_IN the_ATI tetracycline_NN family_NN is_BEZ typically_RB prompt_JJ and_CC complete_JJ in_IN patients_NNS who_WPR have_HV not_XNOT responded_VBN to_IN my_PP$ _** first_OD tier_NN _** oral_JJ agents_NNS , I_PP1A have_HV gone_VBN on_RP to_IN those_DTS of_IN the_ATI _** second_OD tier_NN , _** including_IN sulfamethoxazole- trimethoprim_NN , trimethoprim_JJ alone_JJ , metronidazole_NN , dapsone_NN , isotretinoin_NN , and_CC prednisone_NN in_IN a_AT small_JJ number_NN of_IN patients_NNS , I_PP1A have_HV resorted_VBN to_IN the_ATI Helicobacter_NP pylori_NN eradication_NN therapy_NN consisting_VBG of_IN amoxicillin_NN , metronidazole_NN , and_CC bismuth_NN subsalicylate_NN although_CS some_DTI of_IN the_ATI edema_NN of_IN rhinophyma_NN may_MD subside_VB with_IN this_DT therapy_NN , the_ATI eradication_NN of_IN the_ATI connective_JJ tissue_NN hypertrophy_NN in_IN rhinophyma_NN is_BEZ surgical_JJ 20_CD 20_CD rosacea_NN is_BEZ unpredictably_JJ , but_CC potentially_RB , progressive_JJ and_CC relapsing_NN in_IN my_PP$ experience_VB the_ATI patients_NNS who_WPR have_HV the_ATI greatest_JJT difficulty_NN with_IN progression_NN or_CC relapse_NN are_BER those_DTS with_IN patulous_JJ follicles_NNS (_( the_ATI earliest_JJT harbinger_NN of_IN rhinophyma_NN )_) or_CC severe_JJ ocular_JJ rosacea_NN most_AP patients_NNS will_MD do_DO well_RB with_IN 1_CD1 g_ZZ of_IN tetracycline_NN a_AT day_NN in_IN divided_JJ doses_NNS for_IN 2_CD or_CC 3_CD weeks_NNS and_CC then_RN 0.5_CD g_ZZ a_AT day_NN for_IN the_ATI next_AP 2_CD or_CC 3_CD weeks_NNS topical_JJ metronidazole_NN is_BEZ the_ATI only_AP topically_RB applied_JJ agent_NN currently_RB approved_VBN to_TO be_BE marketed_VBN for_IN rosacea_NN , and_CC I_PP1A usually_RB add_VB this_DT preparation_NN twice_RB daily_JJ from_IN the_ATI beginning_NN although_CS I_PP1A attribute_VB most_AP of_IN the_ATI improvement_NN to_IN the_ATI systemic_JJ tetracycline_NN , the_ATI topical_JJ antibiotic_JJ likely_JJ provides_VBZ an_AT additional_JJ effect_NN also_RB , it_PP3 is_BEZ a_AT useful_JJ replacement_NN for_IN the_ATI widespread_JJ over-the-counter_NN corticosteroids_NNS that_CS many_AP of_IN my_PP$ patients_NNS had_HVD used_VBN in_IN the_ATI past_NN 21_CD besides_IN replacing_VBG topical_JJ corticosteroids_NNS or_CC other_AP agents_NNS with_IN a_AT topical_JJ agent_NN that_WPR has_HVZ intrinsic_JJ benefit_NN , this_DT regimen_VBZ also_RB prepares_VBZ the_ATI patient_NN for_IN what_WDT I_PP1A view_VB as_IN the_ATI greatest_JJT clinical_JJ value_NN of_IN topical_JJ metronidazole_NN , namely_RB , a_AT remission_NN maintaining_VBG agent_NN typically_RB , after_IN 1_CD1 to_IN 3_CD months_NNS of_IN systemic_JJ tetracycline_NN plus_IN topical_JJ metronidazole_NN , I_PP1A can_MD wean_VB patients_NNS from_IN the_ATI systemic_JJ agent_NN completely_RB to_IN the_ATI topical_JJ metronidazole_JJ alone_JJ knight_NN and_CC Vickers_NP studied_VBD 68_CD patients_NNS who_WPR achieved_VBN remission_NN with_IN systemic_JJ tetracycline_NN within_IN 1_CD1 month_NN of_IN tetracycline_NN withdrawal_NN , 25%_NN of_IN these_DTS patients_NNS relapsed_VBN within_IN 6_CD months_NNS , two_CD thirds_NNS of_IN the_ATI patients_NNS relapsed_VBN in_IN my_PP$ practice_NN , topical_JJ agents_NNS , such_IN as_IN metronidazole_NN , appear_VB to_TO maintain_VB the_ATI remission_NN at_IN significantly_RB higher_JJR levels_NNS than_IN those_DTS in_IN the_ATI untreated_JJ patients_NNS of_IN Knight_NP and_CC Vickers_NP since_CS topical_JJ agents_NNS for_IN the_ATI treatment_NN of_IN rosacea_NN achieve_VB initial_JJ control_NN only_RB after_IN longer_RBR courses_NNS of_IN therapy_NN than_IN systemic_JJ antibiotics_NNS and_CC may_MD provide_VB a_AT less_AP than_IN complete_JJ maintenance_NN of_IN remission_NN , it_PP3 is_BEZ clear_JJ that_CS more_QL potent_JJ topical_JJ agents_NNS for_IN the_ATI treatment_NN of_IN rosacea_NN would_MD be_BE welcomed_VBN 22_CD tretinoin_NN offers_VBZ not_XNOT only_RB this_DT possibility_NN , but_CC several_AP theoretical_JJ advantages_NNS as_IN well_RB topical_JJ 0.1%_CD tretinoin_NN cream_NN produces_VBZ an_AT increase_NN in_IN collagen_NN I_PP1A in_IN the_ATI papillary_NN dermis_NN in_IN photodamaged_VBN human_JJ skin_NN the_ATI dystrophic_JJ process_NN in_IN the_ATI superficial_JJ dermis_NN in_IN rosacea_NN might_MD be_BE reversed_VBN by_IN this_DT active_JJ repair_NN of_IN dermal_JJ collagen_NN topical_JJ tretinoin_NN also_RB has_HVZ significant_JJ effects_NNS on_IN the_ATI non- sun-exposed_JJ , protected_JJ skin_NN of_IN the_ATI elderly_JJ , including_IN increases_NNS in_IN dermal_JJ glycosaminoglycan_NN deposition_NN , elastic_JJ fibers_NNS , and_CC new_JJ blood_NN vessel_NN formation_NN 23_CD however_RB , there_EX may_MD be_BE disadvantages_NNS of_IN tretinoin_NN as_IN well_RB first_OD , tretinoin_NN may_MD provoke_VB a_AT severe_JJ erythema_NN in_IN patients_NNS with_IN rosacea_NN Flushing_NP reactions_NNS will_MD have_HV a_AT more_QL intense_JJ redness_NN and_CC an_AT enhancement_NN of_IN the_ATI inflammatory_JJ process_NN likewise_RB , the_ATI irritation_NN from_IN the_ATI tretinoin_NN may_MD exacerbate_VB directly_RB the_ATI underlying_JJ inflammatory_JJ reaction_NN 24_CD second_OD , the_ATI tretinoin_NN may_MD cause_VB angiogenesis_VB in_IN the_ATI rosacea_NN distribution_NN Kligman_NP et_&FW al_APS have_HV remarked_VBN that_CS _** angiogenesis_NN was_BEDZ particularly_RB noteworthy_JJ

_** in_IN non-sun-exposed_JJ protected_JJ skin_NN of_IN the_ATI elderly_JJ treated_VBN with_IN topical_JJ tretinoin_NN likewise_RB , Weiss_NN et_&FW al_APS observed_VBN wider_JJR vascular_NN lumina_NN in_IN the_ATI papillary_JJ dermis_NN of_IN tretinoin-treated_JJ skin_NN compared_VBN with_IN untreated_JJ areas_NNS 25_CD third_OD , the_ATI tretinoin-induced_JJ erythema_NN may_MD mask_NN the_ATI worsening_NN angiogenesis_NN and_CC telangiectasia_NN I_PP1A have_HV seen_VBN several_AP patients_NNS who_WPR had_HVD bright_JJ red_JJ faces_NNS during_IN treatment_NN with_IN topical_JJ tretinoin_NN when_WRB they_PP3AS discontinued_VBN the_ATI tretinoin_NN , they_PP3AS were_BED impressed_VBN (_( negatively_RB )_) by_IN the_ATI apparent_JJ increase_NN in_IN telangiectasia_NN , the_ATI PERT_NP phenomenon_NN the_ATI study_NN by_IN Ertl_NP et_&FW al_APS does_DOZ not_XNOT provide_VB the_ATI information_NN that_WPR would_MD allay_VB the_ATI concerns_VBZ regarding_IN tretinoin_NN and_CC the_ATI PERT_NP phenomenon_NN 26_CD Ertl_NP et_&FW al_APS report_NN that_CS _** Tretinoin_NP cream_NN has_HVZ not_XNOT been_BEN previously_RB reported_VBN as_IN a_AT therapeutic_JJ alternative_NN in_IN rosacea_NN

_** in_IN fact_NN , a_AT study_NN larger_JJR than_IN theirs_PP$$ was_BEDZ conducted_VBN in_IN Moscow_NP and_CC reported_VBN in_IN 1977_CD Verbenko_NP and_CC Katsman_NP reported_VBD that_CS _** complete_JJ resolution_NN of_IN nodular_NN elements_NNS came_VBD in_IN 23_CD (_( patients_NNS )_) with_IN rosacea_NN and_CC visible_JJ improvement_NN in_RP

9_CD with_IN rosacea_NN as_CS shown_VBN by_IN our_PP$ observations_NNS , Retin-A_NP appears_VBZ to_TO be_BE an_AT effective_JJ remedy_NN in_IN the_ATI treatment_NN

of_IN rosacea.=20_CD 27_CD the_ATI studies_NNS both_ABX by_IN Verbenko_NP and_CC Katsman_NP and_CC later_RBR Ertl_NP et_&FW al_APS emphasize_VB the_ATI inflammatory_JJ lesions_NNS of_IN rosacea_NN , the_ATI papules_NNS and_CC pustules_NNS In_NP most_AP patients_NNS , the_ATI inflammatory_JJ process_NN can_MD be_BE controlled_VBN with_IN systemic_JJ and_CC topical_JJ antibiotics_NNS without_IN exacerbating_VBG the_ATI underlying_JJ vascular_NN process_NN since_IN rosacea_NN appears_VBZ to_TO be_BE in_IN its_PP$ most_QL fundamental_JJ elements_NNS a_AT vascular_NN disorder_NN , it_PP3 would_MD be_BE wise_JJ to_TO first_OD do_DO no_ATI harm_NN Until_NP further_JJB studies_NNS are_BER conducted_VBN on_IN the_ATI retinoids_NNS , specifically_RB looking_VBG for_IN the_ATI PERT_NP phenomenon_NN , it_PP3 would_MD be_BE premature_JJ to_TO take_VB the_ATI results_NNS of_IN Ertl_NP et_&FW al_APS as_IN the_ATI basis_NN for_IN treating_VBG rosacea_NN patients_NNS with_IN topical_JJ tretinoin_NN 28_CD is_BEZ Allergic_NPT Contact_NPT Dermatitis_NPT Being_NP Overlooked_NP ? >_&FO 29_CD contact_NN dermatitis_NN is_BEZ very_QL common_JJ contact_NN dermatitis_NN is_BEZ important_JJ to_TO recognize_VB since_IN there_EX are_BER prevention_NN and_CC intervention_NN strategies_NNS that_CS may_MD be_BE of_IN great_JJ help_NN to_IN the_ATI patient.=20_CD 30_CD contact_NN dermatitis_NN , particularly_RB involving_VBG the_ATI hands_NNS , is_BEZ the_ATI most_QL common_JJ occupational_JJ disease_NN the_ATI clinical_JJ features_NNS can_MD be_BE similar_JJ to_IN a_AT wide_JJ variety_NN of_IN other_AP dermatologic_JJ conditions_NNS , such_IN as_IN atopic_JJ dermatitis_NN (_( eczema_NN )_) , psoriasis_NN , seborrheic_JJ dermatitis_NN , and_CC dermatophytosis_NN , which_WDTR may_MD make_VB it_PP3 difficult_JJ to_TO appreciate_VB an_AT exogenous_JJ agent_NN as_IN the_ATI cause_NN of_IN or_CC contributing_JJ factor_NN to_IN the_ATI dermatitis.=20_CD 31_CD therefore_RB , it_PP3 is_BEZ important_JJ for_IN physicians_NNS to_TO recognize_VB identifying_VBG features_NNS of_IN contact_NN dermatitis_NN so_CS that_CS appropriate_JJ diagnostic_JJ tests_NNS , avoidance_NN of_IN triggering_VBG factors_NNS , and_CC treatment_NN may_MD be_BE employed_VBN 32_CD ALLERGIC_NPT VS_NPT IRRITANT_NPT CONTACT_NP DERMATITIS_NP 33_CD the_ATI two_CD major_JJ types_NNS of_IN contact_NN dermatitis_NN may_MD be_BE indistinguishable_JJ in_IN clinical_JJ and_CC histological_JJ appearance_NN , but_CC each_DT has_HVZ a_AT different_JJ pathogenesis_NN allergic_JJ contact_NN dermatitis_NN (_( ACD_NP )_) is_BEZ a_AT type_NN IV_NP immunologic_JJ reaction_NN to_IN a_AT specific_JJ antigen_NN to_TO which_WDTR the_ATI individual_JJ has_HVZ been_BEN previously_RB sensitized_VBN poison_NN ivy_NN or_CC poison_NN oak_NN dermatitis_NN is_BEZ a_AT common_JJ example_NN of_IN acute_JJ ACD_NP irritant_NN contact_NN dermatitis_NN (_( ICD_NP )_) is_BEZ a_AT nonimmunologic_JJ reaction_NN in_IN which_WDTR an_AT exogenous_JJ substance_NN , without_IN previous_JJ sensitization_NN , causes_NNS direct_JJ damage_NN to_IN the_ATI skin_NN chapped_JJ skin_NN from_IN handwashing_VBG due_JJ to_IN frequent_JJ exposure_NN to_TO water_VB and_CC detergent_NN is_BEZ a_AT typical_JJ example_NN the_ATI irritant_NN variety_NN is_BEZ more_QL common_JJ , accounting_NN for_IN 80%_NP of_IN all_ABN cases_NNS of_IN contact_NN dermatitis.=20_CD 34_CD presentation_NN of_IN both_ABX entities_NNS can_MD be_BE acute_JJ , subacute_JJB , or_CC chronic.=20_CD 35_CD the_ATI acute_JJ variety_NN is_BEZ characterized_VBN by_IN erythema_NN , edema_NN , vesicles_NNS , and_CC bullae_NN , and_CC the_ATI subacute_NN and_CC chronic_JJ stages_NNS exhibit_VB erythema_NN , scaling_VBG , and_CC lichenification_NN (_( thickened_VBN appearance_NN )_) itching_VBG is_BEZ the_ATI most_QL common_JJ symptom_NN of_IN either_DTX type.=20_CD 36_CD since_IN the_ATI morphological_JJ features_NNS may_MD be_BE similar_JJ , points_VBZ in_IN the_ATI history_NN about_IN exposure_NN to_IN exogenous_JJ substances_NNS and_CC physician_NN knowledge_NN of_IN potential_JJ cutaneous_JJ irritants_NNS and_CC allergens_NNS can_MD be_BE helpful_JJ in_IN focusing_VBG on_IN a_AT diagnosis_NN of_IN contact_NN dermatitis_NN while_CS the_ATI diagnosis_NN of_IN ICD_NP is_BEZ made_VBN clinically_RB , there_EX is_BEZ a_AT diagnostic_JJ test_NN for_IN ACD_NP : the_ATI patch_NN test_NN 37_CD the_ATI prognosis_NN of_IN chronic_JJ contact_NN dermatitis_NN is_BEZ poor_JJ , with_IN as_QL many_AP as_IN 25%_NN of_IN workers_NNS with_IN occupational_JJ contact_NN dermatitis_NN being_BEG affected_VBN persistently_RB despite_IN job_NN modification_NN or_CC optimal_JJ medical_JJ management_NN .=20_CD 38_CD FEATURES_NPT SUGGESTIVE_NPT OF_NP ACD_NP 39_CD occasionally_RB a_AT patient_NN will_MD present_JJ complaining_VBG of_IN an_AT allergy_NN to_IN a_AT specific_JJ substance_NN for_IN example_NN , the_ATI patient_NN may_MD suspect_VB allergy_VB to_IN a_AT specific_JJ cosmetic_NN or_CC piece_NN of_IN jewelry_NN , and_CC the_ATI existence_NN of_IN an_AT allergy_NN should_MD be_BE confirmed_VBN , if_CS possible_JJ , with_IN a_AT patch_NN test_NN of_IN standard_NN substances_NNS in_IN cosmetics_NNS or_CC metals_NNS known_VBN to_TO cause_VB allergy_NN some_DTI physicians_NNS do_DO not_XNOT perform_VB patch_NN tests_NNS on_IN patients_NNS with_IN obvious_JJ allergies_NNS to_TO nickel_NN or_CC topical_JJ products_NNS it_PP3 is_BEZ important_JJ to_TO consider_VB doing_VBG so_QL because_CS clinical_JJ suspicion_NN may_MD be_BE wrong_JJ , and_CC specific_JJ allergen_NN identification_NN would_MD have_HV implications_NNS for_IN appropriate_JJ patient_NN education_NN , substitution_NN of_IN products_NNS to_TO avoid_VB the_ATI allergen_NN , and_CC sometimes_RB modification_NN of_IN occupational_JJ exposures_NNS .=20_CD 40_CD many_AP patients_NNS present_JJ with_IN a_AT dermatitis_NN whose_WP$R cause_NN is_BEZ unsuspected_JJ by_IN them_PP3OS , or_CC the_ATI patient_NN may_MD have_HV a_AT concern_NN about_IN possible_JJ triggering_NN factors_NNS (_( such_IN as_IN workplace_NN exposures_NNS )_) about_IN which_WDTR the_ATI physician_NN has_HVZ little_JJ knowledge_NN in_IN these_DTS cases_NNS it_PP3 is_BEZ up_RP to_IN the_ATI physician_NN to_TO recognize_VB several_AP features_NNS that_CS are_BER suggestive_JJ of_IN a_AT contact_NN dermatitis_NN 41_CD timing_NN 42_CD many_AP patients_NNS expect_VB outbreak_NN of_IN the_ATI eruption_NN to_TO quickly_RB follow_VB contact_NN with_IN the_ATI allergen_NN , when_WRB in_IN fact_NN the_ATI response_NN usually_RB occurs_VBZ 1_CD1 to_IN 2_CD days_NNS following_JJ contact_NN and_CC can_MD be_BE delayed_VBN up_RP to_IN a_AT week_NN a_AT feature_NN of_IN ACD_NP that_DT may_MD also_RB confuse_VB the_ATI picture_NN is_BEZ the_ATI fact_NN that_CS development_NN of_IN a_AT type_NN IV_NP hypersensitive_JJ allergic_JJ response_NN may_MD suddenly_RB occur_VB after_IN years_NNS of_IN contact_NN with_IN a_AT substance_NN 43_CD exposures_NNS 44_CD an_AT accurate_JJ history_NN of_IN exposures_NNS may_MD be_BE difficult_JJ to_TO obtain_VB because_CS people_NNS sometimes_RB are_BER not_XNOT aware_JJ of_IN or_CC forget_VB substances_NNS to_TO which_WDTR they_PP3AS are_BER exposed_VBN equally_RB important_JJ as_IN workplace_NN exposure_NN is_BEZ exposure_NN through_IN hobbies_NNS , second_OD jobs_NNS , or_CC household_NN activities.=20_CD 45_CD patients_NNS may_MD initially_RB suspect_VB a_AT certain_JJ substance_NN as_IN an_AT allergen_NN but_CC later_RBR discount_VB this_DT theory_NN when_WRB repeated_VBN substituting_VBG of_IN products_NNS is_BEZ not_XNOT successful_JJ in_IN ameliorating_VBG the_ATI dermatitis_NN however_RB , many_AP personal_JJ care_NN products_NNS share_NN common_JJ ingredients_NNS and_CC thus_RB may_MD perpetuate_VB contact_VB with_IN the_ATI possible_JJ cause_NN of_IN the_ATI dermatitis_NN despite_IN product_NN substitution_NN 46_CD distribution_NN 47_CD the_ATI distribution_NN is_BEZ usually_RB the_ATI single_JJ most_QL important_JJ clue_NN to_IN the_ATI diagnosis_NN of_IN contact_NN dermatitis_NN but_CC can_MD also_RB lead_VB to_TO confusion_NN when_WRB presentation_NN is_BEZ not_XNOT typical_JJ it_PP3 is_BEZ possible_JJ for_IN contact_NN dermatitis_NN to_TO occur_VB unilaterally_RB , even_RB though_IN exposure_NN is_BEZ bilateral_JJ (_( as_IN in_IN the_ATI case_NN of_IN shoe_NN dermatitis_NN )_) the_ATI eruption_NN may_MD be_BE patchy_VB instead_RB of_IN uniform_JJ in_IN sites_NNS where_WRB the_ATI stratum_NN corneum_NN is_BEZ thinner_JJR , thereby_RB allowing_VBG greater_JJR penetration_NN of_IN the_ATI allergen_NN (_( as_IN in_IN the_ATI case_NN of_IN eyelid_NN dermatitis_NN following_JJ exposure_NN to_TO nail_VB polish_NN )_) , the_ATI rash_NN may_MD be_BE more_QL severe_JJ than_CS at_IN other_AP contact_NN points_NNS all_ABN areas_NNS of_IN the_ATI body_NN may_MD be_BE affected_VBN , including_IN the_ATI palms_NNS and_CC soles_NNS 48_CD misconceptions_NNS 49_CD misconceptions_NNS about_IN contact_NN dermatitis_NN can_MD confuse_VB patients_NNS and_CC physicians_NNS alike_RB patients_NNS who_WPR have_HV undergone_VBN evaluation_NN by_IN an_AT allergist_NN or_CC other_AP physician_NN often_RB believe_VB erroneously_RB that_CS negative_JJ test_NN results_NNS for_IN immediate_JJ IgE_NP reactions_NNS (_( radioallergosorbent_NN test_NN or_CC immediate_JJ scratch_NN or_CC prick_JJ test_NN )_) rule_NN out_RP ACD_NP , yet_RB the_ATI immune_JJ mechanisms_NNS are_BER different_JJ more_AP misconceptions_NNS exist_VB as_CS to_IN the_ATI characteristic_JJ appearance_NN of_IN ACD_NP often_RB patients_NNS expect_VB the_ATI rash_NN to_TO occur_VB only_RB at_IN the_ATI site_NN of_IN contact_NN with_IN an_AT allergen_NN , but_CC because_CS allergens_NNS are_BER frequently_RB spread_JJ to_TO other_AP parts_NNS of_IN the_ATI body_NN (_( especially_RB from_IN the_ATI hands_NNS )_) , dermatitis_NN may_MD occur_VB at_IN distant_JJ sites_NNS patients_NNS and_CC physicians_NNS often_RB incorrectly_RB rule_NN out_RP contact_NN dermatitis_NN when_WRB there_EX have_HV been_BEN no_ATI new_JJ exposures_NNS , not_XNOT realizing_VBG that_CS contact_NN allergy_NN to_IN substances_NNS can_MD develop_VB after_IN years_NNS of_IN intermittent_JJ or_CC frequent_JJ exposure_NN 50_CD WHO_NPT SHOULD_NPT UNDERGO_NPT PATCH_NP TESTING_NP ? 51_CD at_IN present_NN , the_ATI only_AP scientific_JJ method_NN for_IN diagnosing_VBG ACD_NP is_BEZ the_ATI patch_NN test_NN , which_WDTR entails_VBZ placing_VBG test_NN substances_NNS on_IN the_ATI patient's_NN$ skin_NN (_( back_RP )_) , covering_VBG the_ATI substance_NN with_IN tape_NN , and_CC examining_VBG the_ATI skin_NN 48_CD and_CC 72_CD hours_NNS later_RBR for_IN signs_NNS of_IN reaction_NN the_ATI patch_NN test_NN is_BEZ indicated_VBN when_WRB an_AT allergic_JJ component_NN of_IN the_ATI dermatitis_NN is_BEZ suspected.The_JJ patch_NN test_NN may_MD also_RB be_BE useful_JJ in_IN evaluation_NN of_IN ICD_NP by_IN demonstrating_VBG that_CS a_AT common_JJ allergen_NN is_BEZ not_XNOT part_NN of_IN the_ATI pathogenesis_NN of_IN a_AT contact_NN dermatitis_NN (_( negative_JJ patch_NN test_NN results).=20_CD 52_CD the_ATI patch_NN test_NN is_BEZ a_AT simple_JJ and_CC relatively_RB inexpensive_JJ test_NN the_ATI current_JJ recommendations_NNS are_BER to_TO use_VB the_ATI Finn_NP Chamber_NP (_( Hermal_NP Pharmaceutical_NP Laboratories_NNS , Delmar_NP , NY_NP )_) with_IN ScanPor_NP tape_NN (_( Allerderm_NP Laboratories_NNS , Mill_NPL Valley_NPL , Calif_NP )_) and_CC the_ATI Patch_NPT Test_NP Allergen_NP kit_NN (_( Hermal_NP Pharmaceuticals_NP )_) the_ATI standard_NN tray_NN consists_VBZ of_IN 20_CD common_JJ allergens_NNS (_( Table_NP 2_CD )_) that_CS are_BER diluted_VBN to_IN standardized_JJ nonirritant_NN concentrations.=20_CD 53_CD once_RB the_ATI patches_NNS have_HV been_BEN in_IN place_NN for_IN 48_CD hours_NNS , the_ATI patient_NN should_MD return_VB for_IN initial_JJ readings_NNS ; each_DT individual_JJ substance_NN site_NN is_BEZ given_VBN a_AT numerical_JJ score_NN using_VBG the_ATI following_JJ guide:=20_CD 54_CD 1_CD1 indicates_VBZ a_AT weak_JJ (_( nonvesicular_NN )_) positive_JJ reaction_NN with_IN erythema_NN , infiltration_NN , and_CC possible_JJ papules;=20_CD 55_CD 2_CD , a_AT strong_JJ (_( vesicular_NN )_) positive_JJ reaction_NN with_IN erythema_NN , infiltration_NN , papules_NNS , and_CC vesicles;=20_CD 56_CD 3_CD , an_AT extreme_JJ positive_JJ reaction_NN with_IN bullae_NN or_CC confluent_NN vesicles;=20_CD 57_CD 4_CD , macular_NN erythema_NN only_RB (_( doubtful_JJ reaction);=20_CD 58_CD 5_CD , irritant_JJ morphological_JJ features_NNS (_( glazed_VBN or_CC ulcerated_VBN ) _) ; and=20_CD 59_CD 6_CD , negative_JJ 60_CD results_NNS are_BER recorded_VBN and_CC the_ATI patient_NN is_BEZ again_RB instructed_VBN to_TO keep_VB the_ATI test_NN sites_NNS dry_JJ until_IN returning_VBG 24_CD or_CC 48_CD hours_NNS later_RBR 61_CD COMMON_NPT CAUSES_NPT OF_NPT FALSE-NEGATIVE_NPT AND_NPT FALSE- POSITIVE_NP READINGS_NP 62_CD a_AT negative_JJ reading_NN may_MD be_BE due_JJ to_IN the_ATI absence_NN of_IN an_AT allergic_JJ cause_NN (_( true-negative_JJ reading_NN )_) or_CC failure_NN of_IN the_ATI patch_NN test_NN to_TO reproduce_VB the_ATI allergic_JJ reaction_NN (_( false-negative_JJ reading_NN )_) common_JJ causes_NNS of_IN false-negative_JJ responses_NNS include_VB the_ATI following_JJ : improper_JJ techniques_NNS , such_IN as_IN early_JJ removal_NN of_IN the_ATI patch_NN , Failure_NP to_TO read_VB test_NN results_NNS at_IN 72_CD hours_NNS , Using_NP too_QL low_JJ a_AT concentration_NN of_IN test_NN substance_NN , Application_NN of_IN topical_JJ corticosteroids_NNS to_IN the_ATI test_NN site_NN for_IN several_AP days_NNS prior_RB to_IN the_ATI test_NN ; and_CC Failure_NP to_TO test_VB the_ATI actual_JJ offending_JJ allergen_NN 63_CD false-positive_JJ responses_NNS are_BER also_RB a_AT source_NN of_IN error_NN in_IN patch_NN testing_NN common_JJ causes_NNS of_IN false-positive_JJ responses_NNS include_VB the_ATI following_JJ : 64_CD use_NN of_IN irritant_NN substances_NNS , with_IN irritant_NN reactions_NNS characterized_VBN by_IN sharply_RB demarcated_JJ margins_NNS confined_VBN to_IN an_AT area_NN covered_VBN by_IN the_ATI disk_NN Burning_NP and_CC pain_NN , and_CC not_XNOT itching_VBG , are_BER indicative_NN of_IN an_AT irritant_NN reaction_NN one_CD1 blister_NN covering_VBG the_ATI entire_JJB disk_NN area_NN , as_QL well_RB as_IN an_AT ulceration_NN , is_BEZ also_RB more_QL characteristic_NN of_IN an_AT irritant_NN reaction_NN angry_JJ back_RP phenomenon_NN , a_AT regional_JJ phenomenon_NN whereby_WRB one_CD1 or_CC two_CD strong_JJ positive_JJ reactions_NNS may_MD trigger_VB an_AT exaggerated_JJ response_NN at_IN other_AP test_NN sites_NNS pressure_NN reaction_NN , an_AT edematous_JJ response_NN to_IN the_ATI pressure_NN of_IN an_AT applied_JJ substance_NN , often_RB more_QL severe_JJ on_IN the_ATI periphery_NN 65_CD initial_JJ management_NN of_IN ACD_NP : 66_CD try_VB to_TO identify_VB a_AT triggering_VBG agent_NN (_( eg_NN , poison_NN ivy_NN , topical_JJ product_NN , or_CC metal_NN )_) 67_CD have_HV the_ATI patient_NN avoid_VB the_ATI suspected_VBD agent_NN or_CC related_JJ substances_NNS 68_CD have_HV the_ATI patient_NN avoid_VB additional_JJ topical_JJ agents_NNS that_DT could_MD irritate_VB the_ATI inflamed_JJ sites_NNS and_CC minimize_VB the_ATI effects_NNS of_IN topical_JJ therapy_NN 69_CD avoid_VB topical_JJ medications_NNS with_IN common_JJ allergens_NNS (_( eg_NN , benzocaine_NN , neomycin_NN )_) 70_CD treat_VB secondary_JJ infection_NN with_IN oral_JJ antibiotics_NNS to_TO cover_VB Staphylococcus_&FW aureus_&FW and_CC beta-hemolytic_JJ streptococcus_JJ 71_CD if_CS systemic_JJ corticosteroids_NNS are_BER used_VBN , courses_NNS of_IN 2_CD to_IN 3_CD weeks_NNS are_BER preferable_JJ to_IN shorter_JJR courses_NNS 72_CD consider_VB temporary_JJ removal_NN from_IN usual_JJ workplace_NN exposures_NNS , but_CC be_BE aware_JJ that_CS improvement_NN may_MD be_BE slow_JJ 73_CD avoid_VB excessive_JJ water_evaporative_JJ exposure_NN to_IN inflamed_JJ skin_NN 74_CD initial_JJ management_NN of_IN chronic_JJ contact_NN dermatitis_NN : 75_CD same_AP as_IN above_RI obtain_VB a_AT careful_JJ history_NN of_IN multiple_JJ exposures_NNS and_CC try_VB to_TO clarify_VB repeated_VBN or_CC cumulative_JJ exposures_NNS , even_RB to_IN common_JJ substances_NNS such_IN as_IN water_NN 76_CD determine_VB use_NN of_IN protective_JJ clothing_NN (_( eg_NN , gloves_NNS )_) and_CC how_WRB the_ATI use_NN correlated_VBN with_IN signs_NNS and_CC symptoms_NNS 77_CD remember_VB emollients_ointments_NNS such_IN as_IN petroleum_NN jelly_NN may_MD be_BE as_CS helpful_JJ as_CS topical_JJ corticosteroids_NNS at_IN this_DT point_NN remember_VB systemic_JJ corticosteroids_NNS may_MD have_HV a_AT minimal_JJ effect_NN now_RN 78_CD develop_VB a_AT time_NN line_NN of_IN dermatitis_NN , workplace_NN and_CC home_NR exposures_NNS , and_CC treatments_NNS 79_CD further_JJB evaluation_NN should_MD be_BE considered_VBN for_IN both_ABX if_CS the_ATI dermatitis_NN : 80_CD recurs_VBZ frequently_RB 81_CD rebounds_NNS after_IN corticosteroid_NN therapy_NN 82_CD responds_VBZ only_RB to_IN frequent_JJ systemic_JJ corticosteroid_NN therapy_NN 83_CD may_MD be_BE caused_VBN by_IN a_AT topical_JJ product_NN or_CC class_NN of_IN product_NN (_( eg_NN , cosmetics_NNS )_) that_CS the_ATI patient_NN is_BEZ not_XNOT willing_JJ to_TO avoid_VB 84_NN interferes_VBZ with_IN work_NN or_CC social_JJ interaction_NN 85_CD has_HVZ been_BEN examined_VBN by_IN a_AT number_NN of_IN physicians_NNS 86_CD presentations_NNS of_IN Diabetic_NP Feet_NP 87_CD those_DTS afflicted_VBN with_IN diabetes_NN mellitus_JJ have_HV high_JJ rates_NNS of_IN morbidity_NN and_CC mortality_NN owing_IN to_IN the_ATI many_AP complications_NNS of_IN the_ATI disease_NN the_ATI complications_NNS can_MD manifest_JJ themselves_PPLS as_CS ophthalmic_JJ , renal_JJ , vascular_JJB , neurologic_JJ , and_CC pedal_NN diseases_NNS unfortunately_RB , the_ATI most_QL often_RB overlooked_VBN or_CC neglected_JJ complications_NNS involve_VB the_ATI feet_NNS it_PP3 is_BEZ estimated_VBN that_CS in_IN the_ATI United_NP States_NP foot_NN disease_NN is_BEZ five_CD times_NNS more_QL prevalent_JJ in_IN diabetic_JJ patients_NNS than_CS in_IN those_DTS without_IN diabetes_NN in_IN fact_NN , 20%_NP of_IN all_ABN diabetic_JJ patients_NNS admitted_VBN to_IN hospitals_NNS in_IN the_ATI United_NP States_NP are_BER admitted_VBN for_IN foot_NN disease_NN , with_IN foot_NN and_CC ankle_NN ulcers_NNS being_BEG the_ATI most_QL common_JJ presentation_NN 88_CD the_ATI amputation_NN rate_NN in_IN diabetic_JJ patients_NNS in_IN the_ATI United_NP States_NP is_BEZ reported_VBN to_TO be_BE as_QL high_JJ as_IN 15_CD times_NNS that_CS of_IN nondiabetic_JJ patients_NNS , and_CC of_IN all_ABN nontraumatic_JJ amputations_NNS performed_VBN , approximately_RB 50%_NP are_BER in_IN patients_NNS with_IN diabetes_NN more_AP than_IN half_ABN of_IN the_ATI diabetic_JJ patients_NNS who_WPR undergo_VB limb_NN amputation_NN will_MD require_VB contralateral_JJ limb_NN amputation_NN within_IN 5_CD years_NNS , and_CC 60%_NP will_MD die_VB within_IN the_ATI first_OD 5_CD years_NNS after_IN amputation_NN for_IN these_DTS reasons_NNS , it_PP3 is_BEZ important_JJ that_CS primary_JJ care_NN physicians_NNS thoroughly_RB examine_VB the_ATI feet_NNS and_CC become_VB familiar_JJ with_IN the_ATI various_JJ presentations_NNS of_IN the_ATI diabetic_JJ foot_NN the_ATI American_JNP Diabetes_NP Association_NN recommends_VBZ that_CS an_AT examination_NN of_IN diabetic_JJ feet_NNS be_BE done_VBN at_IN every_AT regular_JJ visit_NN 89_CD the_ATI increased_JJ risk_NN for_IN foot_NN disease_NN in_IN diabetic_JJ patients_NNS is_BEZ primarily_RB due_JJ to_IN the_ATI combined_JJ effects_NNS of_IN peripheral_JJ vascular_NN disease_NN and_CC peripheral_JJ and_CC autonomic_JJ neuropathies_NNS these_DTS may_MD result_VB in_IN decreased_VBD sensation_NN , dry_JJ , cracked_JJ skin_NN , and_CC loss_NN of_IN the_ATI intrinsic_JJ muscle_NN function_NN of_IN the_ATI foot_NN patients_NNS may_MD have_HV a_AT deformed_JJ foot_NN with_IN the_ATI inability_NN to_TO sense_NN repeated_JJ trauma_NN this_DT may_MD lead_VB to_IN further_JJB deformity_NN , tissue_NN necrosis_NN , and_CC subsequent_JJ ulceration_NN if_CS not_XNOT properly_RB treated_VBN , soft-tissue_NN infection_NN , osteomyelitis_NN , and_CC sepsis_NN may_MD result_VB this_DT may_MD necessitate_VB lower-limb_NN amputation_NN 90_CD often_RB , with_IN proper_JJ foot_NN care_NN , this_DT scenario_NN can_MD be_BE avoided_VBN , resulting_JJ in_IN fewer_AP lower-extremity_NN amputations_NNS as_QL well_RB as_IN a_AT decrease_NN in_IN the_ATI overall_JJB disease-related_JJ morbidity_NN and_CC mortality_NN the_ATI National_NP Diabetes_NPT Advisory_NP Board_NP reported_VBD in_IN 1987_CD that_CS there_EX are_BER a_AT number_NN of_IN patient_NN care_NN programs_NNS and_CC available_JJ preventive_JJ and_CC therapeutic_JJ strategies_NNS that_CS have_HV the_ATI potential_JJ for_IN reducing_VBG the_ATI number_NN of_IN amputations_NNS , but_CC these_DTS strategies_NNS are_BER not_XNOT optimally_RB used_VBN in_IN public_JJ and_CC private_JJ health_NN system_NN settings_NNS 91_CD the_ATI purpose_NN of_IN this_DT report_NN is_BEZ to_TO review_VB the_ATI vascular_NN , neurologic_JJ , muscular_JJ , and_CC infectious_JJ foot_NN manifestations_NNS of_IN diabetes_NN and_CC thereby_RB familiarize_VB the_ATI primary_JJ care_NN physician_NN with_IN the_ATI more_QL common_JJ foot_NN complications_NNS of_IN diabetes_NN mellitus_JJ 92_CD VASCULAR_NPT PRESENTATION_NPT OF_NPT THE_NPT DIABETIC_NP FOOT_NP 93_CD assessing_VBG vascular_NN function_NN is_BEZ an_AT essential_JJ component_NN of_IN examining_VBG the_ATI diabetic_JJ foot_NN diabetes_NN , genetic_JJ factors_NNS , hypertension_NN , cigarette_NN smoking_VBG , hypercholesterolemia_NN , and_CC age_NN have_HV been_BEN shown_VBN to_TO increase_VB the_ATI risk_NN of_IN atherosclerotic_JJ disease_NN diabetes_NN alone_JJ confers_VBZ a_AT two_CD to_IN six_CD times_NNS increase_VB in_IN the_ATI likelihood_NN of_IN developing_VBG peripheral_JJ vascular_NN or_CC coronary_JJ artery_NN diseases_NNS insulin_NN resistance_NN and_CC hyperinsulinemia_NN commonly_RB seen_VBN in_IN patients_NNS with_IN diabetes_NN mellitus_JJ promote_VB atherosclerosis_NN by_IN retarding_VBG the_ATI fibrinolytic_JJ process_NN , by_IN stimulating_JJ vascular_JJ smooth_JJ muscle_NN cell_NN proliferation_NN , and_CC by_IN increasing_JJ platelet- clotting_NN tendencies_NNS furthermore_RB , chronic_JJ hyperglycemia_NN itself_PPL has_HVZ direct_JJ toxic_JJ effects_NNS on_IN vascular_JJ endothelial_JJ cells_NNS and_CC promotes_VBZ the_ATI formation_NN of_IN glycosylation_NN products_NNS in_IN vascular_NN walls_NNS , ultimately_RB resulting_JJ in_IN increased_JJ vascular_NN remodeling_VBG and_CC atherosclerosis_NN as_IN a_AT result_NN , vascular_NN disease_NN is_BEZ the_ATI major_JJ cause_NN of_IN morbidity_NN and_CC mortality_NN in_IN patients_NNS with_IN diabetes_NN mellitus_JJ 94_CD vascular_NN disease_NN generally_RB can_MD be_BE divided_VBN into_IN microvascular_NN and_CC macrovascular_NN diseases_NNS macrovascular_NN disease_NN involves_VBZ the_ATI large_JJ , muscular_JJ , elastic_JJ arteries_NNS and_CC can_MD result_VB in_IN occlusive_JJ disease_NN affecting_VBG cerebral_JJ , coronary_JJ , and_CC peripheral_JJ arteries_NNS microvascular_NN disease_NN affects_VBZ only_RB the_ATI capillary_JJ basement_NN membranes_NNS diabetic_JJ patients_NNS have_HV a_AT significantly_RB higher_JJR incidence_NN of_IN microvascular_NN and_CC macrovascular_NN disease_NN than_IN nondiabetic_JJ individuals_NNS , but_CC certainly_RB not_XNOT all_ABN patients_NNS with_IN diabetes_NN have_HV physical_JJ evidence_NN of_IN vascular_NN disease_NN although_CS there_EX is_BEZ no_ATI evidence_NN of_IN occlusive_JJ disease_NN , diabetic_JJ patients_NNS may_MD have_HV functional_JJ abnormalities_NNS of_IN the_ATI capillaries_NNS that_WPR contribute_VB to_TO ulceration_NN of_IN the_ATI diabetic_JJ foot_NN 95_CD vascularity_NN of_IN the_ATI lower_JJR extremities_NNS should_MD be_BE assessed_VBN frequently_RB Historical_NP features_NNS that_DT may_MD suggest_VB arterial_JJ insufficiency_NN include_VB rest_NN pain_NN , calf_NN pain_NN after_IN walking_VBG short_JJ distances_NNS (_( intermittent_JJ claudication_NN )_) , or_CC constantly_RB cold_JJ feet_NNS questioning_NN patients_NNS about_IN the_ATI distance_NN they_PP3AS can_MD walk_VB before_CS experiencing_VBG pain_NN may_MD help_VB quantitate_VB the_ATI degree_NN of_IN ischemia_NN rest_NN pain_NN often_RB reflects_VBZ the_ATI most_QL severe_JJ ischemic_JJ disease_NN patients_NNS often_RB describe_VB an_AT intense_JJ pain_NN or_CC burning_VBG sensation_NN that_CS frequently_RB presents_VBZ at_IN night_NN this_DT is_BEZ thought_VBN to_TO be_BE caused_VBN by_IN the_ATI shunting_NN of_IN blood_NN from_IN the_ATI lower_JJR extremities_NNS when_WRB the_ATI patient_NN is_BEZ in_IN the_ATI supine_NN position_NN patients_NNS may_MD have_HV to_TO dangle_VB their_PP$ legs_NNS off_IN the_ATI bed_NN to_TO help_VB return_NN some_DTI of_IN the_ATI blood_NN flow_NN to_IN the_ATI periphery_NN and_CC thereby_RB relieve_VB the_ATI symptoms_NNS 96_CD the_ATI dorsalis_NN pedis_NN and_CC posterior_JJ tibial_JJ pulses_NNS should_MD be_BE assessed_VBN when_WRB the_ATI lower_JJR extremities_NNS are_BER examined_VBN when_WRB the_ATI pulses_NNS are_BER diminished_VBN , Doppler_NP ultrasound_NN with_IN ankle-arm_NN index_NN determinations_NNS , segmental_JJ pressures_NNS , and_CC digital_JJ photoplethysmography_NN are_BER excellent_JJ initial_JJ investigative_JJ modalities_NNS the_ATI temperature_NN of_IN the_ATI skin_NN should_MD be_BE determined_JJ and_CC a_AT comparison_NN made_VBN with_IN the_ATI other_AP limb_NN this_DT is_BEZ especially_RB important_JJ in_IN patients_NNS with_IN ulcerations_NNS or_CC a_AT history_NN of_IN previous_JJ skin_NN breakdown_NN (_( Figure_NP 1_CD1 )_) 97_CD when_WRB dorsalis_NN pedis_NN pulses_NNS are_BER absent_JJ , obtaining_VBG digital_JJ pressures_NNS with_IN a_AT digital_JJ photoplethysmographer_NN can_MD assess_VB whether_CS collateral_JJ circulation_NN is_BEZ adequately_RB perfusing_VBG the_ATI foot_NN capillary_JJ filling_NN time_NN is_BEZ a_AT useful_JJ initial_JJ test_NN to_TO help_VB determine_VB if_CS the_ATI digits_NNS have_HV a_AT patent_NN arterial_JJ blood_NN supply_NN edema_RB , whether_CS pitting_NN or_CC nonpitting_VBG , should_MD also_RB be_BE investigated_VBN since_CS it_PP3 may_MD be_BE due_JJ to_TO either_DTX local_JJ or_CC systemic_JJ disease_NN If_NP venous_JJ insufficiency_NN is_BEZ suspected_VBN , circumference_NN measurements_NNS of_IN the_ATI leg_NN are_BER useful_JJ in_IN monitoring_VBG the_ATI disease_NN and_CC the_ATI efficacy_NN of_IN treatment_NN Arterial_NP disease_NN is_BEZ much_AP more_AP of_IN an_AT immediate_JJ concern_NN than_IN either_DTX venous_JJ or_CC lymphatic_JJ disease_NN and_CC warrants_NNS prompt_JJ attention_NN 98_NN diabetic_JJ patients_NNS may_MD also_RB present_JJ with_IN excellent_JJ peripheral_JJ circulation_NN , leading_JJ the_ATI clinician_NN to_TO believe_VB that_CS there_EX is_BEZ no_ATI vascular_NN disease_NN however_RB , this_DT may_MD be_BE misleading_JJ if_CS there_EX are_BER associated_VBN calcified_JJ vessels_NNS , Charcot's_NP$ disease_NN , infection_NN , or_CC trauma_NN these_DTS are_BER conditions_NNS in_IN which_WDTR the_ATI foot_NN may_MD take_VB on_IN a_AT hypervascular_NN appearance_NN More_NP than_IN 80%_NP of_IN patients_NNS with_IN diabetic_JJ osteoarthropathy_NN have_HV been_BEN reported_VBN to_TO have_HV calcified_JJ vessels_NNS , and_CC along_RP with_IN impairment_NN of_IN sympathetic_JJ tone_NN may_MD present_JJ with_IN bounding_VBG pulses_NNS because_CS of_IN the_ATI inability_NN to_TO vasoconstrict_VB (_( Figure_NP 2_CD )_) 99_CD with_IN relatively_RB simple_JJ office_NN examinations_NNS , the_ATI primary_JJ care_NN physician_NN can_MD detect_VB the_ATI early_JJ stages_NNS of_IN vascular_NN disease_NN and_CC provide_VB proper_JJ treatment_NN or_CC refer_VB the_ATI patient_NN to_IN an_AT appropriate_JJ specialist_JJ 100_CD NEUROLOGIC_NPT PRESENTATION_NPT OF_NPT THE_NPT DIABETIC_NP FOOT_NP 101_CD sensory_JJ and_CC autonomic_JJ neuropathy_NN may_MD be_BE considered_VBN the_ATI primary_JJ causes_NNS of_IN diabetic_JJ foot_NN complications_NNS approximately_RB three_CD times_NNS as_CS many_AP diabetic_JJ patients_NNS are_BER hospitalized_VBN for_IN disease_NN secondary_JJ to_TO trauma_VB in_IN a_AT neuropathic_JJ foot_NN than_IN are_BER admitted_VBN for_IN ischemic_JJ pain_NN without_IN routine_NN foot_NN examinations_NNS , a_AT patient_NN with_IN an_AT insensate_NN foot_NN may_MD develop_VB an_AT undetected_JJ infection_NN , diabetic_JJ osteoarthropathy_NN , ulceration_NN , or_CC traumatic_JJ injury_NN 102_CD distal_JJ symmetric_JJ polyneuropathy_NN is_BEZ the_ATI most_QL common_JJ form_NN of_IN diabetic_JJ neuropathy_NN this_DT typically_RB produces_VBZ sensory_JJ deficits_NNS that_CS manifest_JJ in_IN the_ATI lower_JJR extremities_NNS the_ATI most_AP common_JJ symptoms_NNS are_BER paresthesias_NNS , dysesthesias_NNS , allodynia_NN , and_CC hyperpathia_NN paresthesias_NNS are_BER abnormal_JJ spontaneous_JJ sensations_NNS of_IN numbness_NN , itching_VBG , or_CC burning_NN dysesthesias_NNS are_BER more_QL painful_JJ paresthesias_NNS allodynia_NN is_BEZ the_ATI sensation_NN of_IN severe_JJ pain_NN produced_VBN by_IN a_AT normal_JJ stimulus_NN hyperpathia_NN is_BEZ constant_JJ exaggerated_JJ pain_NN Metabolic_NP abnormalities_NNS of_IN the_ATI neuron_NN cell_NN body_NN , axon_NN , and_CC Schwann_NP cell_NN have_HV been_BEN reported_VBN to_TO relate_VB etiologically_RB to_IN the_ATI neuropathic_JJ symptoms_NNS The_NP duration_NN of_IN diabetes_NN and_CC degree_NN of_IN blood_NN glucose_NN level_NN control_NN are_BER known_JJ factors_NNS associated_VBN with_IN the_ATI development_NN of_IN neuropathy_NN it_PP3 has_HVZ been_BEN postulated_JJ that_CS near-normal_JJ control_NN of_IN blood_NN glucose_NN levels_NNS in_IN the_ATI early_JJ years_NNS after_IN diabetes_NN onset_NN may_MD help_VB delay_VB the_ATI development_NN of_IN clinically_RB significant_JJ neuropathy_NN 103_CD autonomic_JJ neuropathy_NN can_MD affect_VB the_ATI gastrointestinal_JJ , cardiovascular_NN , and_CC genitourinary_NN systems_NNS distal_JJ anhydrosis_JJ leading_JJ to_TO increased_VBN dry_JJ , cracked_JJ skin_NN of_IN the_ATI feet_NNS is_BEZ a_AT lesser_JJR known_JJ result_NN of_IN autonomic_JJ neuropathy_NN (_( Figure_NP 3_CD )_) significant_JJ findings_NNS of_IN sensory_JJ neuropathy_NN related_VBN to_IN the_ATI lower_JJR extremity_NN may_MD include_VB decreased_VBD proprioception_NN , light_NN touch_NN sensation_NN , sharp_dull_NN discrimination_NN , and_CC vibratory_NN perception_NN 104_CD many_AP diabetic_JJ patients_NNS have_HV a_AT decreased_VBN protective_JJ threshold_NN and_CC are_BER not_XNOT able_JJ to_TO recognize_VB trauma_NN that_WPR will_MD cause_VB soft-tissue_VB breakdown.=20_CD 105_CD as_IN a_AT result_NN , continued_VBD microtraumatic_JJ episodes_NNS to_IN the_ATI bottom_NN of_IN the_ATI foot_NN can_MD cause_VB tissue_NN necrosis_NN , hypertrophic_JJ bone_NN formation_NN , pathologic_JJ fractures_NNS , or_CC ulceration_NN such_ABL neurotrophic_JJ ulcerations_NNS tend_VB to_TO be_BE associated_VBN with_IN an_AT intact_JJ vascular_NN status_NN as_QL well_RB as_CS exuberant_JJ peripheral_JJ callus_JJ formation_NN (_( Figure_NP 4_CD )_) without_IN intact_JJ sensation_NN , something_PN as_QL simple_JJ as_IN a_AT pebble_NN or_CC a_AT bobby_NN pin_NN in_IN a_AT shoe_NN can_MD progress_VB to_TO major_JJ complications_NNS ill-fitting_NN shoes_NNS , tight_JJ stockings_NNS , and_CC extremes_NNS in_IN temperature_NN , coupled_VBN with_IN sensory_JJ loss_NN , xerosis_NN , increased_JJ plantar_NN pressures_NNS , and_CC diminished_JJ circulation_NN predispose_NN patients_NNS to_TO foot_NN ulceration_NN a_AT superimposed_JJ infection_NN may_MD lead_VB to_IN thrombosis_NN of_IN the_ATI digital_JJ vessels_NNS and_CC consequently_RB to_TO gangrene_NN of_IN the_ATI toes_NNS pressure_NN necrosis_NN can_MD occur_VB because_CS of_IN irritation_NN from_IN a_AT stocking_NN or_CC shoe_NN Prolonged_NP cold_JJ exposure_NN can_MD progress_VB to_TO frostbite_NN and_CC chilblains_NNS 106_CD in_IN an_AT insensate_NN foot_NN , heat_NN may_MD not_XNOT be_BE perceived_VBN and_CC as_IN a_AT result_NN can_MD easily_RB burn_VB the_ATI skin_NN , with_IN subsequent_JJ ulcer_NN formation_NN by_IN the_ATI time_NN patients_NNS discover_VB their_PP$ own_AP foot_NN ulcers_NNS or_CC notice_NN any_DTI significant_JJ disease_NN , irreversible_JJ damage_NN may_MD have_HV already_RB ensued_VBD therefore_RB , patients_NNS with_IN an_AT insensate_NN foot_NN must_MD be_BE instructed_VBN on_IN inspecting_JJ their_PP$ shoes_NNS and_CC stockings_NNS daily_JJ for_IN foreign_JJ objects_NNS 107_CD as_CS is_BEZ true_JJ for_IN vascular_NN disease_NN , not_XNOT all_ABN diabetic_JJ patients_NNS have_HV neurologic_JJ dysfunction_NN diabetic_JJ patients_NNS can_MD have_HV intact_JJ epicritic_JJ sensation_NN without_IN any_DTI neuropathic_JJ symptoms_NNS a_AT thorough_JJ neurologic_JJ examination_NN of_IN the_ATI lower_JJR extremities_NNS should_MD include_VB patellar_VB and_CC achilles_NNS deep_JJ tendon_NN reflexes_NNS , inspection_NN for_IN breaks_VBZ in_IN the_ATI integument_NN , and_CC evaluation_NN of_IN sensation_NN of_IN touch_NN , vibration_NN , and_CC proprioception_NN While_NP tuning_NN forks_NNS , pins_NNS , reflex_NN hammers_NNS , and_CC feathers_NNS are_BER valuable_JJ diagnostic_JJ neurologic_JJ tools_NNS , Semmes- Weinstein_NP monofilaments_NNS of_IN differing_JJ diameters_NNS are_BER state-of- the-art_NN for_IN determining_VBG protective_JJ threshold_NN 108_CD with_IN the_ATI patient_NN in_IN the_ATI supine_NN position_NN and_CC the_ATI eyes_NNS closed_VBN , monofilaments_NNS of_IN differing_JJ diameters_NNS are_BER placed_VBN on_IN the_ATI skin_NN when_WRB bent_VBD against_IN the_ATI skin_NN , each_DT correlates_VBZ to_IN a_AT given_JJ amount_NN of_IN pressure_NN if_CS the_ATI patient_NN is_BEZ able_JJ to_TO perceive_VB the_ATI 5.07_NP monofilament_NN , then_RN protective_JJ threshold_NN is_BEZ considered_VBN to_TO be_BE intact_JJ this_DT would_MD signify_VB that_CS a_AT patient_NN is_BEZ able_JJ to_TO sense_VB trauma_NN that_WPR could_MD potentially_RB cause_VB soft-tissue_NN breakdown_NN 109_CD if_CS a_AT diabetic_JJ patient_NN has_HVZ developed_VBN a_AT neuropathic_JJ ulcer_NN on_IN the_ATI plantar_JJ aspect_NN of_IN the_ATI foot_NN , the_ATI ulcer_NN needs_NNS to_TO be_BE treated_VBN with_IN regular_JJ debridements_NNS , dressing_NN changes_NNS , and_CC removal_NN of_IN the_ATI weight-bearing_NN forces_NNS across_IN the_ATI ulcer_NN site_NN debridement_NN of_IN neuropathic_JJ ulcers_NNS is_BEZ performed_VBN as_CS needed_VBN (_( usually_RB once_RB or_CC twice_RB a_AT week_NN )_) to_TO remove_VB only_RB the_ATI excessive_JJ keratosis_NN on_IN the_ATI rim_NN of_IN the_ATI ulcer_NN the_ATI granulation_NN tissue_NN base_NN should_MD be_BE kept_VBN intact_JJ sterile_JJ saline_NN dressings_NNS are_BER changed_VBN daily_JJ topical_JJ ointments_NNS , debriders_NNS , and_CC powders_NNS should_MD not_XNOT be_BE used_VBN special_JJ shoes_NNS are_BER designed_VBN for_IN the_ATI patient's_NN$ foot_NN to_TO remove_VB weight-bearing_NN forces_NNS across_IN the_ATI ulcer_NN 110_CD to_TO prevent_VB recurrence_NN once_RB the_ATI ulcer_NN has_HVZ healed_VBN , abnormal_JJ forces_NNS that_CS produced_VBN the_ATI ulcer_NN need_NN to_TO be_BE removed_VBN or_CC reduced_VBN since_CS underlying_JJ bony_JJ prominences_NNS are_BER the_ATI most_QL frequent_JJ cause_NN of_IN abnormal_JJ pedal_NN pressure_NN , strategies_NNS to_TO prevent_VB ulceration_NN should_MD address_VB the_ATI bony_JJ prominences_NNS in_IN cases_NNS in_IN which_WDTR the_ATI deforming_NN force_NN is_BEZ mild_JJ or_CC in_IN patients_NNS who_WPR represent_VB a_AT high_JJ surgical_JJ risk_NN , the_ATI treatment_NN includes_VBZ the_ATI use_NN of_IN multidensity_NN orthotic_JJ devices_NNS when_WRB possible_JJ , surgical_JJ intervention_NN to_TO remove_VB the_ATI underlying_JJ bony_JJ prominence_NN should_MD be_BE performed_VBN 111_CD the_ATI importance_NN of_IN continuously_RB educating_VBG diabetic_JJ patients_NNS in_IN foot_NN care_NN cannot_NN be_BE overemphasized_VBN patients_NNS with_IN diabetes_NN ought_MD to_TO be_BE taught_VBN simple_JJ common_JJ sense_NN approaches_NNS to_TO foot_NN hygiene_NN and_CC daily_JJ feet_NNS inspection_NN techniques_NNS and_CC should_MD be_BE advised_VBN about_IN choosing_VBG proper_JJ shoe_NN wear_NN this_DT is_BEZ especially_RB important_JJ for_IN neuropathic_JJ patients_NNS simple_JJ reminders_NNS , such_ABL as_CS always_RB wearing_VBG protective_JJ footwear_NN or_CC looking_VBG for_IN objects_NNS inside_IN shoes_NNS before_CS putting_VBG them_PP3OS on_RP , are_BER essential_NN in_IN preventing_VBG ulceration_NN or_CC infections_NNS also_RB , trimming_NN nails_NNS , corns_NNS , and_CC calluses_NNS should_MD be_BE performed_VBN only_RB by_IN appropriate_JJ health_NN care_NN providers_NNS 112_CD DIABETIC_NP OSTEOARTHROPATHY_NP 113_CD diabetic_JJ osteoarthropathy_NN , or_CC Charcot's_NP$ disease_NN , is_BEZ a_AT progressive_JJ degeneration_NN of_IN single_JJ or_CC multiple_JJ foot_NN joints_NNS caused_VBN by_IN an_AT underlying_JJ neuropathy_NN with_IN maintenance_NN of_IN good_JJ vascularity_NN this_DT commonly_RB misdiagnosed_JJ process_NN usually_RB presents_VBZ in_IN diabetic_JJ patients_NNS between_IN the_ATI ages_NNS of_IN 40_CD and_CC 60_CD years_NNS its_PP$ prevalence_NN has_HVZ been_BEN reported_VBN to_TO be_BE as_CS high_JJ as_CS one_CD1 of_IN every_AT 680_CD patients_NNS with_IN diabetes_NN patients_NNS typically_RB have_HV had_HVD diabetes_NN for_IN more_AP than_IN 12_CD years_NNS before_CS developing_VBG Charcot_NP changes_NNS 114_CD the_ATI classic_JJ presentation_NN of_IN Charcot's_NP$ disease_NN is_BEZ a_AT warm_JJ , erythematous_JJ , swollen_VBN , essentially_RB nonpainful_JJ foot_NN (_( Figure_NP 5_CD )_) some_DTI patients_NNS report_NN some_DTI pain_NN or_CC discomfort_NN , but_CC much_AP less_AP than_IN would_MD be_BE expected_VBN for_IN the_ATI degree_NN of_IN disease_NN the_ATI tarsometatarsal_JJ joint_JJB is_BEZ the_ATI most_QL commonly_RB affected_JJ area_NN , followed_VBN by_IN the_ATI midtarsal_JJ joint_NN Associated_NP neuromuscular_NN deformities_NNS , consisting_VBG of_IN hammer_NN toes_NNS , a_AT cocked-up_NN hallux_NN , a_AT prominent_JJ and_CC hypertrophied_JJ naviculocuneiform_NN joint_JJB , and_CC intrinsic_JJ muscular_JJ atrophy_RB , are_BER common_JJ findings_NNS (_( Figure_NP 6_CD )_) a_AT later_RBR finding_VBG may_MD be_BE a_AT rocker-bottom_JJ configuration_NN of_IN the_ATI foot_NN 115_CD diabetic_JJ osteoarthropathy_NN has_HVZ three_CD phases_NNS : developmental_JJ , coalescent_NN , and_CC reconstruction_NN during_IN the_ATI developmental_JJ phase_NN , there_EX may_MD be_BE fragmentation_NN , interarticular_NN debris_NN , synovial_JJ effusion_NN , edema_NN , and_CC erythema_NN the_ATI coalescent_NN phase_NN demonstrates_VBZ early_JJ repair_NN and_CC is_BEZ recognized_VBN by_IN periosteal_JJ new_JJ bone_NN formation_NN and_CC subchondral_JJ sclerosis_NN During_NP the_ATI reconstruction_NN phase_NN , there_EX is_BEZ revascularization_JJ and_CC remodeling_VBG of_IN bone_NN fragments_NNS with_IN the_ATI possible_JJ appearance_NN of_IN ankylosis_NN 116_CD the_ATI disease_NN is_BEZ thought_VBN to_TO be_BE of_IN either_DTX neurovascular_NN or_CC neurotraumatic_JJ origin_NN the_ATI neurovascular_NN theory_NN regards_VBZ autonomic_JJ neuropathy_NN as_IN the_ATI primary_JJ causative_JJ factor_NN loss_NN of_IN autonomic_JJ vascular_NN regulation_NN results_NNS in_IN greater_JJR blood_NN vessel_NN diameter_NN and_CC increased_VBD local_JJ blood_NN flow_NN vasodilation_NN with_IN increased_VBN peripheral_JJ and_CC osseous_JJ perfusion_NN leads_VBZ to_TO accelerated_VBD bone_NN resorption_NN and_CC osteopenia_NN fracture_NN and_CC repair_NN occur_VB secondarily_RB dysfunction_NN of_IN the_ATI small_JJ vasculature_NN and_CC sweat_NN glands_NNS explains_VBZ the_ATI clinical_JJ appearance_NN of_IN the_ATI warm_JJ , erythematous_JJ , edematous_JJ , and_CC anhydrotic_JJ foot.=20_CD 117_CD the_ATI neurotraumatic_JJ theory_NN proposes_VBZ that_CS peripheral_JJ sensory_JJ neuropathy_NN with_IN subsequent_JJ loss_NN of_IN protective_JJ threshold_NN is_BEZ the_ATI primary_JJ causative_JJ factor_NN repeated_VBN undetected_JJ trauma_NN can_MD cause_VB large_JJ effusions_NNS , ligamentous_JJ laxity_NN , and_CC joint_JJB instability_NN with_IN further_JJB trauma_NN , there_EX is_BEZ subluxation_NN , dislocation_NN , and_CC osteochondral_JJ fragmentation_NN owing_IN to_IN the_ATI fact_NN that_CS peripheral_JJ circulation_NN is_BEZ intact_JJ , exuberant_JJ osseous_JJ repair_NN ensues_VBZ 118_CD the_ATI roentgenographic_JJ appearance_NN along_RP with_IN positive_JJ bone_NN scans_NNS often_RB lead_NN physicians_NNS to_TO incorrectly_RB diagnose_VB diabetic_JJ osteoarthropathy_NN as_IN osteomyelitis_NN (_( Figure_NP 7_CD )_) in_IN addition_NN to_TO osteomyelitis_VB , other_AP conditions_NNS to_TO consider_VB in_IN the_ATI differential_JJ diagnosis_NN include_VB rheumatoid_NN arthritis_NN , gouty_NN arthritis_NN , and_CC soft-tissue_NN infections_NNS 119_CD early_JJ recognition_NN and_CC treatment_NN are_BER essential_JJ for_IN preventing_VBG progression_NN of_IN this_DT deformity_NN immediate_JJ referral_JJ to_IN an_AT appropriate_JJ foot_NN specialist_JJ and_CC a_AT strict_JJ non-weight-bearing_NN regimen_NNS should_MD be_BE initiated_VBN The_NP goal_NN is_BEZ to_TO get_VB these_DTS patients_NNS out_RP of_IN the_ATI acute_JJ developmental_JJ phase_NN and_CC into_IN the_ATI coalescent_NN and_CC reconstructive_JJ phases_NNS as_QL soon_RB as_IN possible_JJ Since_NP there_EX is_BEZ no_ATI way_NN to_IN reverse_JJ the_ATI damage_NN , treatment_NN is_BEZ directed_VBN at_IN protection_NN of_IN the_ATI foot_NN to_TO reduce_VB the_ATI chance_NN of_IN further_JJB deformity_NN during_IN the_ATI acute_JJ phase_NN , the_ATI foot_NN is_BEZ protected_VBN from_IN fracturing_VBG and_CC collapse_NN with_IN a_AT non-weight-bearing_NN regimen_NNS and_CC total_JJ contact_NN casts_NNS total_JJ contact_NN casts_NNS are_BER used_VBN until_IN superficial_JJ skin_NN temperatures_NNS equilibrate_NN , then_RN gradual_JJ weight_NN bearing_VBG of_IN the_ATI affected_JJ limb_NN is_BEZ begun_VBN 120_CD MUSCULAR_NPT PRESENTATION_NPT OF_NPT THE_NPT DIABETIC_NP FOOT_NP 121_CD neuropathy_NN can_MD affect_VB the_ATI musculature_NN of_IN the_ATI foot_NN and_CC leg_NN Sixty-five_NP percent_NNU of_IN patients_NNS with_IN neuropathies_NNS have_HV associated_JJ muscle_NN weakness_NN motor_NN neuropathies_NNS manifest_JJ themselves_PPLS as_CS myopathic_JJ changes_NNS and_CC are_BER the_ATI result_NN of_IN demyelination_NN , axonal_JJ swelling_NN , endoneural_JJ edema_NN , and_CC fibrosis_NN in_IN the_ATI intramuscular_NN nerve_NN branches_NNS when_WRB such_ABL nerve_NN degeneration_NN occurs_VBZ in_IN the_ATI pelvic_JJ girdle_NN and_CC thigh_NN musculature_NN associated_VBN with_IN muscular_JJ atrophy_RB and_CC subacute_JJ painful_JJ weakness_NN , it_PP3 is_BEZ referred_VBN to_TO as_IN diabetic_JJ amyotrophy_NN it_PP3 occassionally_RB can_MD affect_VB distal_JJ muscles_NNS , such_IN as_IN the_ATI tibialis_NN and_CC peroneal_JJ muscles_NNS 122_CD intrinsic_JJ muscular_JJ wasting_VBG and_CC progressive_JJ forefoot_NN contracture_NN can_MD contribute_VB to_TO foot_NN deformity_NN with_IN paresis_NN of_IN the_ATI intrinsic_JJ musculature_NN , the_ATI metatarsal_JJ phalangeal_JJ joints_NNS become_VB destabilized_VBN and_CC as_IN a_AT result_NN digital_JJ contractures_NNS develop_VB and_CC progress_NN dorsal_JJ contracture_NN increases_NNS the_ATI retrograde_NN plantar-flexor_NN force_NN through_IN the_ATI metatarsal_JJ heads_NNS the_ATI plantar_NN fat_NN pad_NN also_RB tends_VBZ to_TO displace_VB distally_RB , further_JJB increasing_JJ the_ATI pressure_NN over_IN the_ATI metatarsal_JJ heads_NNS and_CC predisposing_VBG the_ATI foot_NN to_TO soft- tissue_NN breakdown_NN and_CC ulceration_NN 123_CD deformities_NNS arising_VBG from_IN neuropathies_NNS are_BER not_XNOT only_RB attributable_JJ to_TO the_ATI intrinsic_JJ musculature_NN but_CC to_IN the_ATI proximal_JJ musculature_NN as_IN well_RB the_ATI extensor_NN halluces_NNS longus_JJ muscle_NN may_MD be_BE affected_VBN early_RB in_IN the_ATI course_NN of_IN neuropathy_NN weakness_NN of_IN this_DT long_JJ extensor_NN creates_VBZ hammering_VBG of_IN the_ATI hallux_NN by_IN the_ATI overriding_JJ pull_NN of_IN the_ATI long_JJ flexor_NN (_( Figure_NP 8_CD )_) subacute_NN motor_NN neuropathy_NN can_MD cause_VB gradual_JJ weakness_NN of_IN the_ATI anterior_JJ muscle_NN group_NN of_IN the_ATI leg_NN , enabling_VBG the_ATI posterior_JJ muscles_NNS to_TO gain_VB a_AT mechanical_JJ advantage_NN over_IN the_ATI anterior_JJ muscles_NNS this_DT can_MD lead_VB to_IN limitation_NN of_IN ankle_NN joint_JJB dorsiflexion_NN and_CC further_JJB increase_VB the_ATI stress_NN on_IN the_ATI plantar_NN forefoot_NN when_WRB digital_JJ and_CC ray_NN resections_NNS are_BER required_VBN , the_ATI weight-bearing_NN forces_NNS are_BER profoundly_RB altered_VBN by_IN shifting_JJ the_ATI stress_NN to_TO adjacent_JJ structures_NNS all_ABN of_IN these_DTS developments_NNS act_NN to_IN further_JJB place_VB the_ATI patient_NN with_IN diabetes_NN at_IN an_AT increased_JJ risk_NN for_IN soft- tissue_NN breakdown_NN , prolonged_JJ ulceration_NN , and_CC infection_NN 124_CD early_JJ recognition_NN of_IN motor_NN neuropathies_NNS can_MD aid_VB in_IN limiting_JJ breakdown_NN , ulceration_NN , and_CC infection_NN of_IN the_ATI feet_NNS the_ATI primary_JJ care_NN physician_NN should_MD examine_VB the_ATI diabetic_JJ patient_NN for_IN progressive_JJ hammering_JJ of_IN the_ATI digits_NNS with_IN dorsal_JJ contracture_NN , a_AT decrease_NN in_IN muscle_NN power_NN of_IN the_ATI legs_NNS , and_CC atrophy_RB of_IN the_ATI intrinsic_JJ foot_NN musculature_NN proper_JJ referral_JJ for_IN electromyography_NN and_CC nerve-conduction_NN velocity_NN studies_NNS can_MD expedite_VB the_ATI diagnosis_NN treatment_NN consisting_VBG of_IN palliation_NN , shoe_NN gear_NN modification_NN , and_CC accommodative_JJ shoe_NN inserts_VBZ can_MD significantly_RB decrease_VB the_ATI associated_VBN morbidity_NN in_IN patients_NNS with_IN motor_NN neuropathy_NN 125_CD INFECTIOUS_NPT PRESENTATION_NPT OF_NPT THE_NPT DIABETIC_NP FOOT_NP 126_CD the_ATI most_AP common_JJ complication_NN of_IN diabetes_NN mellitus_NN is_BEZ a_AT foot_NN infection_NN more_AP inpatient_NN days_NNS are_BER used_VBN treating_VBG diabetic_JJ foot_NN infections_NNS than_IN any_DTI other_AP complication_NN of_IN diabetes_NN it_PP3 has_HVZ been_BEN reported_VBN that_CS 25%_NN of_IN patients_NNS with_IN diabetes_NN have_HV a_AT history_NN of_IN significant_JJ cutaneous_JJ infection_NN and_CC that_CS 10%_CD have_HV an_AT active_JJ infection_NN at_IN any_DTI one_CD1 time_NN although_CS it_PP3 is_BEZ commonly_RB stated_VBN that_CS patients_NNS with_IN diabetes_NN are_BER more_QL susceptible_JJ to_IN infection_NN than_IN nondiabetic_JJ individuals_NNS , there_EX is_BEZ no_ATI convincing_JJ evidence_NN that_CS these_DTS patients_NNS are_BER immunologically_RB compromised_VBD reported_VBN defects_NNS in_IN the_ATI immune_JJ function_NN relate_VB to_IN white_JJ blood_NN cell_NN dysfunction_NN with_IN respect_NN to_TO diapedesis_VB , adherence_NN , chemotaxis_NN , and_CC phagocytosis_NN these_DTS defects_NNS are_BER thought_VBN to_TO be_BE aggravated_VBN by_IN poor_JJ glucose_NN control_NN 127_CD neuropathy_JJ leading_JJ to_IN an_AT insensate_NN , dry_JJ , fissured_JJ foot_NN will_MD predispose_VB to_TO ulcer_NN formation_NN pathogenic_JJ bacteria_NNS gain_VB a_AT portal_NN of_IN entry_NN through_IN such_ABL wounds_NNS and_CC can_MD progress_VB to_IN an_AT infection_NN often_RB , the_ATI initial_JJ lesion_NN is_BEZ at_IN a_AT weight-bearing_NN area_NN improperly_RB fitting_JJ shoes_NNS , trauma_NN , and_CC puncture_NN wounds_NNS are_BER common_JJ initiating_JJ factors_NNS symptoms_NNS may_MD be_BE minimal_JJ , although_CS an_AT associated_JJ cellulitis_NN may_MD result_VB in_IN fever_NN , pain_NN , tenderness_NN , and_CC peripheral_JJ leukocytosis_NN neuropathic_JJ ulcers_NNS are_BER typically_RB surrounded_VBN by_IN thickened_VBN , hyperkeratotic_JJ skin_NN , so_RB the_ATI actual_JJ size_NN and_CC depth_NN will_MD be_BE difficult_JJ to_TO determine_VB before_IN debridement_NN Purulent_NP drainage_NN with_IN edema_NN and_CC erythema_NN are_BER some_DTI associated_VBN local_JJ findings_NNS systemic_JJ signs_NNS are_BER often_RB absent_JJ , with_IN the_ATI only_AP evidence_NN of_IN an_AT infection_NN being_BEG an_AT unexplained_JJ loss_NN of_IN glucose_NN control_NN in_IN the_ATI absence_NN of_IN proper_JJ foot_NN care_NN , the_ATI presence_NN of_IN a_AT septic_JJ foot_NN ulcer_NN may_MD remain_VB undetected_JJ until_IN the_ATI odor_NN , hyperglycemia_NN , or_CC circulatory_NN collapse_NN cause_NN the_ATI patient_NN to_TO seek_VB medical_JJ attention_NN 128_CD 43_CD after_IN a_AT complete_JJ medical_JJ history_NN is_BEZ obtained_VBN and_CC a_AT physical_JJ examination_NN performed_VBN (_( including_IN probing_VBG of_IN the_ATI ulcer_NN site_NN )_) , obtaining_VBG a_AT complete_JJ blood_NN cell_NN count_NN and_CC appropriate_JJ cultures_NNS , measuring_VBG the_ATI erythrocyte_NN sedimentation_NN rate_NN and_CC the_ATI blood_NN glucose_NN level_NN , and_CC performing_VBG urinalysis_NN are_BER recommended_VBN bacterial_JJ culture_NN sensitivities_NNS and_CC liver_NN and_CC renal_JJ function_NN ought_MD to_TO be_BE assessed_VBN in_IN deciding_VBG on_IN proper_JJ antibiotic_JJ therapy_NN while_CS the_ATI erythrocyte_NN sedimentation_NN rate_NN is_BEZ usually_RB elevated_VBD , it_PP3 is_BEZ a_AT very_QL nonspecific_JJ marker_NN for_IN infection_NN if_CS it_PP3 is_BEZ extremely_RB high_JJ , it_PP3 is_BEZ suggestive_JJ of_IN osteomyelitis_NN , but_CC a_AT normal_JJ value_NN does_DOZ not_XNOT exclude_VB the_ATI diagnosis_NN the_ATI white_JJ blood_NN cell_NN count_NN and_CC serum_NN glucose_NN level_NN may_MD be_BE normal_JJ or_CC elevated_VBD 129_CD gas_NN within_IN the_ATI soft_JJ tissue_NN may_MD be_BE palpated_VBN as_IN crepitant_JJ pockets_NNS of_IN air_NN and_CC indicate_VB the_ATI need_NN for_IN immediate_JJ surgical_JJ intervention_NN the_ATI infected_JJ ulcers_NNS should_MD be_BE probed_VBD to_TO determine_VB their_PP$ depth_NN and_CC to_TO help_VB in_IN their_PP$ classification_NN the_ATI most_AP common_JJ ulcer_NN classification_NN system_NN was_BEDZ originated_VBN by_IN F._NP William_NP Wagner_NP , Jr_NP , MD_NP , and_CC is_BEZ based_VBN on_IN the_ATI depth_NN of_IN penetration_NN and_CC extent_NN of_IN tissue_NN necrosis_NN grade_NN 0_CD ulcers_NNS have_HV no_ATI open_JJ lesions_NNS ; rather_RB , there_EX is_BEZ deformity_NN , cellulitis_NN , or_CC callused_VBN preulcerative_JJ lesions_NNS grade_NN 1_CD1 ulcers_NNS are_BER defined_VBN as_CS superficial_JJ ulcerations_NNS invading_JJ the_ATI dermis_NN but_CC not_XNOT the_ATI subcutaneous_JJ tissue_NN (_( Figure_NP 9_CD )_) grade_NN 2_CD ulcers_NNS penetrate_VB deeper_JJR , through_IN the_ATI subcutaneous_JJ tissue_NN to_TO the_ATI tendon_NN or_CC joint_JJB capsule.=20_CD 130_CD grade_NN 3_CD ulcers_NNS involve_VB the_ATI periosteum_NN and_CC are_BER associated_VBN with_IN deep_JJ abscess_NN formation_NN and_CC osteomyelitis_NN grade_NN 4_CD ulcers_NNS present_JJ with_IN partial_JJ gangrene_NN of_IN the_ATI foot_NN extensive_JJ gangrene_NN of_IN the_ATI entire_JJB foot_NN is_BEZ considered_VBN a_AT grade_NN 5_CD ulcer_NN , and_CC a_AT major_JJ amputation_NN is_BEZ usually_RB required_VBN Gangrene_NP typically_RB occurs_VBZ when_WRB vascular_NN insufficiency_NN produces_VBZ tissue_NN necrosis_NN that_CS becomes_VBZ secondarily_RB infected_VBN arterial_JJ insufficiency_NN with_IN superimposed_VBN regional_JJ increased_JJ tissue_NN turgor_NN and_CC metabolic_JJ rate_NN increases_VBZ the_ATI tissue_NN demand_NN while_CS reducing_VBG the_ATI delivery_NN of_IN oxygen_NN 131_CD after_IN the_ATI ulcer_NN is_BEZ classified_VBN , a_AT properly_RB collected_JJ specimen_NN for_IN anaerobic_JJ and_CC aerobic_JJ culture_NN and_CC sensitivity_NN along_RP with_IN a_AT Gram's_NN$ stain_NN should_MD be_BE obtained_VBN the_ATI optimum_JJ specimen-gathering_NN technique_NN involves_VBZ initial_JJ debridement_NN of_IN the_ATI ulcer_NN to_TO remove_VB overlying_JJ necrotic_JJ and_CC presumably_RB superficially_RB colonized_JJ tissue_NN followed_VBN by_IN dermal_JJ curettage_JJ of_IN the_ATI base_NN of_IN the_ATI ulcer_NN diabetic_JJ foot_NN ulcer_NN infections_NNS have_HV been_BEN extensively_RB reported_VBN in_IN the_ATI literature_NN as_CS being_BEG polymicrobial_JJ although_CS the_ATI foot_NN ulcer_NN infections_NNS are_BER generally_RB polymicrobial_JJ , the_ATI associated_VBN bacteremia_NN is_BEZ usually_RB monomicrobial_JJ 132_CD neuropathic_JJ patients_NNS with_IN diabetes_NN and_CC infected_JJ ulcerations_NNS frequently_RB develop_VB osteomyelitis_NN in_IN fact_NN , at_RB least_RB one_CD1 third_OD of_IN all_ABN patients_NNS with_IN osteomyelitis_NN are_BER diabetic_JJ roentgenograms_NNS may_MD be_BE helpful_JJ in_IN identifying_VBG gas_NN and_CC osteomyelitis_NN bone_NN scans_NNS are_BER another_DT useful_JJ diagnostic_JJ modality_NN technetium_NN phosphate-99m_NN is_BEZ taken_VBN up_RP at_IN areas_NNS of_IN increased_JJ bone_NN vascularity_NN and_CC at_IN areas_NNS of_IN reactive_JJ bone_NN formation_NN this_DT is_BEZ considered_VBN to_TO be_BE a_AT highly_RB sensitive_JJ , but_CC fairly_RB nonspecific_JJ , diagnostic_JJ tool_NN gallium_NN citrate-67_NN is_BEZ localized_VBN in_IN tissues_NNS to_TO which_WDTR there_EX is_BEZ increased_JJ blood_NN flow_NN and_CC thus_RB is_BEZ considerably_RB more_QL specific_JJ for_IN soft-tissue_NN infections_NNS the_ATI most_AP specific_JJ radionucleotide_NN examination_NN uses_VBZ indium_NN 111_CD , which_WDTR is_BEZ particularly_RB useful_JJ in_IN differentiating_VBG osteomyelitis_NN from_IN diabetic_JJ osteoarthropathy_NN 133_CD the_ATI primary_JJ care_NN physician_NN should_MD be_BE able_JJ to_TO recognize_VB a_AT diabetic_JJ foot_NN infection_NN and_CC initiate_VB appropriate_JJ diagnostic_JJ testing_NN this_DT includes_VBZ probing_VBG , classifying_VBG , and_CC culturing_VBG the_ATI ulceration_NN , along_RP with_IN obtaining_VBG appropriate_JJ blood_NN work_NN and_CC roentgenograms_NNS empiric_JJ antibiotic_JJ therapy_NN should_MD be_BE started_VBN primary_JJ care_NN physicians_NNS can_MD coordinate_VB a_AT team_NN of_IN specialists_NNS in_IN vascular_NN surgery_NN , infectious_JJ diseases_NNS , and_CC foot_NN and_CC ankle_NN disease_NN to_TO deal_VB with_IN the_ATI difficult_JJ problems_NNS of_IN diabetic_JJ foot_NN infection_NN and_CC significantly_RB reduce_VB patient_NN morbidity_NN and_CC mortality_NN 134_CD SUMMARY_NP 135_CD the_ATI primary_JJ care_NN physician_NN plays_NNS a_AT vital_JJ role_NN in_IN maintaining_VBG the_ATI health_NN and_CC welfare_NN of_IN those_DTS afflicted_VBN with_IN diabetes_NN mellitus_JJ patients_NNS most_QL often_RB rely_VB on_IN their_PP$ primary_JJ care_NN physicians_NNS for_IN prevention_NN , initial_JJ diagnosis_NN , and_CC treatment_NN of_IN disease_NN proper_JJ lower-extremity_NN evaluation_NN is_BEZ essential_NN in_IN recognizing_VBG the_ATI various_JJ diseases_NNS that_WPR occur_VB in_IN patients_NNS with_IN diabetes_NN without_IN proper_JJ foot_NN inspection_NN , many_AP diabetic_JJ foot_NN problems_NNS continue_VB to_TO go_VB undetected_JJ and_CC progress_NN to_TO more_QL serious_JJ and_CC possibly_RB life-threatening_JJ illnesses_NNS the_ATI degree_NN of_IN morbidity_NN and_CC mortality_NN associated_VBN with_IN diabetic_JJ foot_NN disease_NN could_MD be_BE dramatically_RB reduced_VBN by_IN early_JJ recognition_NN and_CC proper_JJ treatment_NN 136_CD the_ATI lower_JJR extremity_NN ought_MD to_TO be_BE assessed_VBN as_QL frequently_RB as_IN possible_JJ Vascular_NP diagnostic_JJ modalities_NNS , such_IN as_IN Doppler_NP ultrasound_NN and_CC skin_NN temperature_NN thermometers_NNS , are_BER very_QL useful_JJ in_IN this_DT assessment_NN neurologic_JJ examination_NN should_MD include_VB evaluation_NN of_IN deep_JJ tendon_NN reflexes_NNS , proprioception_NN and_CC vibratory_JJ sensory_JJ testing_NN , and_CC determination_NN of_IN protective_JJ threshold_NN inspection_NN for_IN any_DTI breaks_VBZ in_IN the_ATI integument_NN and_CC xerotic-appearing_NN skin_NN should_MD be_BE noted_VBN tuning_NN forks_NNS , Semmes-Weinstein_NP monofilaments_NNS , and_CC reflex_NN hammers_NNS are_BER excellent_JJ modalities_NNS for_IN assessing_VBG neurologic_JJ integrity_NN the_ATI presence_NN of_IN hammered_VBD digits_NNS with_IN dorsally_RB contracted_VBN metatarsal_JJ phalangeal_JJ joints_NNS indicates_VBZ associated_JJ motor_NN neuropathy_NN electromyography_NN and_CC nerve-conduction_NN velocities_NNS are_BER useful_JJ in_IN confirming_VBG the_ATI presence_NN of_IN this_DT disease_NN erythematous_JJ , warm_JJ , and_CC edematous_JJ feet_NNS should_MD be_BE assessed_VBN for_IN evidence_NN of_IN infectious_JJ disease_NN and_CC diabetic_JJ osteoarthropathy_NN 137_CD early_JJ recognition_NN , proper_JJ evaluation_NN , and_CC initial_JJ treatment_NN will_MD significantly_RB reduce_VB foot_NN complications_NNS in_IN patients_NNS with_IN diabetes_NN we_PP1AS recommend_VB using_VBG a_AT team_NN approach_NN when_WRB treating_VBG those_DTS who_WPR develop_VB complicated_JJ diabetic_JJ foot_NN disease_NN 138_CD conservative_JJ Treatment_NP of_IN the_ATI Scoliotic_NP and_CC Kyphotic_NP Patient_NP : brace_NN Treatment_NP and_CC Other_NP Modalities_NNS >_&FO 139_CD although_CS various_JJ forms_NNS of_IN nonoperative_JJ treatment_NN have_HV been_BEN applied_VBN to_IN spinal_JJ deformities_NNS over_IN the_ATI centuries_NNS , it_PP3 was_BEDZ the_ATI development_NN of_IN the_ATI original_JJ Milwaukee_NP brace_NN , a_AT cervicothoracic-lumbosacral_JJ orthosis_NN (_( CTLSO_NP )_) , by_IN Blount_NP and_CC Schmidt_NP in_IN the_ATI middle_JJB 1940s_CDS that_CS heralded_VBN a_AT new_JJ era_NN of_IN nonoperative_JJ treatment_NN and_CC that_WPR has_HVZ led_VBN to_TO much_AP of_IN the_ATI success_NN we_PP1AS enjoy_VB with_IN nonoperative_JJ treatment_NN today_NR furthermore_RB , as_IN our_PP$ understanding_NN of_IN the_ATI natural_JJ history_NN of_IN scoliosis_NN has_HVZ grown_VBN and_CC our_PP$ recognition_NN of_IN the_ATI specific_JJ genetic_JJ , curvature-related_JJ , or_CC neurophysiological_JJ factors_NNS that_CS predispose_NN patients_NNS to_TO curvature_NN progression_NN has_HVZ improved_JJ , so_QL has_HVZ our_PP$ ability_NN to_TO successfully_RB treat_VB patients_NNS by_IN nonoperative_JJ means_NNS 140_CD although_CS there_EX continue_VB to_TO be_BE some_DTI authors_NNS who_WPR voice_NN skepticism_NN over_IN the_ATI efficacy_NN of_IN bracing_JJ for_IN idiopathic_JJ scoliosis_NN , it_PP3 remains_VBZ the_ATI only_RB nonoperative_JJ modality_NN consistently_RB shown_VBN to_TO alter_VB the_ATI natural_JJ progression_NN of_IN these_DTS curvatures_NNS the_ATI recent_JJ report_NN by_IN Nachemson_NP and_CC Peterson_NP of_IN the_ATI results_NNS of_IN a_AT prospective_JJ , randomized_JJ study_NN of_IN adolescent_JJ girls_NNS is_BEZ the_ATI latest_JJT and_CC soundest_JJT proof_NN of_IN the_ATI efficacy_NN of_IN bracing_JJ , showing_VBG not_XNOT only_RB that_CS bracing_JJ significantly_RB curtailed_VBN curvature_NN progression_NN but_CC that_CS another_DT popular_JJ modality_NN , electrical_JJ stimulation_NN , was_BEDZ of_IN no_ATI benefit_NN whatsoever_WDT while_CS the_ATI CTLSO_NP remains_VBZ the_ATI gold_NN standard_NN for_IN orthotic_JJ treatment_NN in_IN adolescent_JJ idiopathic_JJ scoliosis_NN and_CC kyphosis_NN , many_AP new_JJ braces_NNS have_HV been_BEN developed_VBN that_WPR appear_VB to_TO provide_VB comparable_JJ control_NN , with_IN the_ATI added_VBD benefits_NNS of_IN improved_JJ patient_NN compliance_NN and_CC more_QL satisfactory_JJ brace_NN wear_NN nonetheless_RB , clear-cut_JJ answers_NNS to_TO many_AP questions_NNS regarding_IN the_ATI timing_NN and_CC the_ATI efficacy_NN of_IN bracing_JJ do_DO not_XNOT exist_VB at_IN this_DT time_NN 141_CD OBSERVATION_NP 142_CD 5_CD knowing_VBG what_WDT we_PP1AS do_DO about_IN the_ATI natural_JJ history_NN of_IN scoliosis_NN , the_ATI most_QL reasonable_JJ initial_JJ approach_NN to_IN most_QL patients_NNS with_IN spinal_JJ deformities_NNS is_BEZ observation_NN while_CS measurable_JJ curvature_NN (_( greater_JJR than_IN 10_CD degrees_NNS in_IN magnitude_NN )_) may_MD be_BE found_VBN in_IN roughly_RB 3%_CD of_IN school- aged_JJ children_NNS , curvature_NN progressing_VBG to_IN greater_JJR than_IN 30_CD degrees_NNS in_IN magnitude_NN is_BEZ found_VBN in_IN less_AP than_IN 0.15%_CD of_IN that_DT population_NN the_ATI prevalence_NN of_IN scoliotic_JJ deformities_NNS requiring_VBG surgery_NN is_BEZ quite_RB low_JJ ; for_IN every_AT 30_CD patients_NNS with_IN measurable_JJ curvature_NN , only_RB two_CD or_CC three_CD will_MD require_VB bracing_JJ , and_CC only_RB one_CD1 will_MD require_VB surgical_JJ treatment_NN curvature_NN progression_NN , defined_VBD as_IN an_AT increase_NN in_IN angulation_NN of_IN more_AP than_IN 5_CD degrees_NNS , does_DOZ not_XNOT of_IN itself_PPL require_VB treatment_NN , but_CC persistent_JJ progression_NN , particularly_RB in_IN young_JJ patients_NNS , will_MD require_VB intervention_NN to_TO prevent_VB severe_JJ curvature_NN Skeletal_NP immaturity_NN at_IN diagnosis_NN , determined_VBN by_IN Risser_NP stages_NNS of_IN ossification_NN (_( Figure_NP 1_CD1 )_) , is_BEZ another_DT predictor_NN of_IN outcome_NN , as_IN is_BEZ the_ATI degree_NN of_IN deformity_NN at_IN initial_JJ presentation_NN although_CS we_PP1AS can_MD identify_VB a_AT number_NN of_IN risk_NN factors_NNS that_DT may_MD suggest_VB that_CS specific_JJ curvature_NN will_MD progress_VB , observation_NN remains_VBZ a_AT necessary_JJ mode_NN of_IN treatment_NN for_IN almost_RB all_ABN patients_NNS initially_RB 143_CD despite_IN the_ATI advent_NN of_IN modified_JJ inclinometers_NNS such_IN as_IN the_ATI scoliosometer_NN and_CC the_ATI use_NN of_IN other_AP measuring_VBG systems_NNS such_IN as_IN Moire_NP topography_NN , serial_JJ roentgenography_NN remains_VBZ the_ATI standard_NN for_IN following_JJ up_RP developmental_JJ spinal_JJ deformities_NNS once_RB a_AT significant_JJ rib_NN prominence_NN has_HVZ been_BEN noted_VBN on_IN forward_RB bending_NN (_( 2_CD to_IN 3_CD cm_NNU of_IN rib_NN elevation_NN or_CC more_AP than_IN 5_CD degrees_NNS of_IN trunk_NN rotation_NN by_IN scoliosmeter_NN )_) , a_AT single_JJ screening_NN posteroanterior_NN roentgentogram_NN is_BEZ warranted_VBD deformities_NNS of_IN lesser_JJR magnitude_NN require_VB reexamination_NN at_IN 6_CD to_IN 12_CD months_NNS but_CC no_ATI roentgenogram_NN The_NP frequency_NN with_IN which_WDTR roentgenograms_NN should_MD be_BE obtained_VBN thereafter_RB is_BEZ determined_VBN by_IN both_ABX the_ATI patient's_NN$ age_NN and_CC the_ATI severity_NN of_IN curvature_NN at_IN presentation_NN patients_NNS with_IN high-degree_NN curvature_NN presenting_VBG during_IN their_PP$ growth_NN spurts_NNS or_CC with_IN additional_JJ risk_NN factors_NNS such_IN as_IN neurologic_JJ dysfunction_NN or_CC strong_JJ genetic_JJ histories_NNS should_MD be_BE followed_VBN up_RP more_QL frequently_RB than_IN patients_NNS with_IN low-degree_NN curvature_NN presenting_VBG before_CS or_CC after_IN their_PP$ growth_NN spurts_NNS for_IN patients_NNS with_IN curvature_NN greater_JJR than_IN 10_CD degrees_NNS , follow-up_NN should_MD be_BE continued_VBN until_IN skeletal_JJ maturity_NN patients_NNS with_IN curvature_NN greater_JJR than_IN 20_CD degrees_NNS may_MD require_VB follow-up_NN for_IN 2_CD to_IN 4_CD years_NNS after_IN skeletal_JJ maturity_NN to_TO access_NN possible_JJ progression_NN in_IN adulthood_NN 144_CD in_IN following_JJ up_RP patients_NNS with_IN scoliosis_NN , serial_JJ roentgenograms_NNS should_MD always_RB be_BE viewed_VBN in_IN a_AT series_NN as_CS increases_NNS of_IN 2_CD degrees_NNS to_IN 3_CD degrees_NNS in_IN the_ATI deformity_NN may_MD be_BE dismissed_VBN as_IN a_AT measurement_NN error_NN , it_PP3 is_BEZ always_RB important_JJ to_TO compare_VB current_JJ films_NNS with_IN the_ATI initial_JJ films_NNS taken_VBN at_IN presentation_NN it_PP3 is_BEZ also_RB important_JJ to_TO be_BE sure_JJ that_CS all_ABN films_NNS being_BEG compared_VBN are_BER taken_VBN in_IN the_ATI same_AP manner_NN films_NNS taken_VBN at_IN an_AT outside_IN facility_NN may_MD not_XNOT be_BE comparable_JJ to_IN those_DTS taken_VBN at_IN a_AT scoliosis_NN center_NN , and_CC differences_NNS in_IN measurements_NNS between_IN the_ATI two_CD are_BER not_XNOT necessarily_RB dependable_JJ 145_CD the_ATI timing_NN of_IN follow-up_NN depends_VBZ on_IN the_ATI individual_JJ young_JJ patients_NNS with_IN relatively_RB minor_JJ curvature_NN should_MD be_BE seen_VBN every_AT 6_CD months_NNS to_TO 1_CD1 year_NN for_IN examination_NN and_CC roentgenography_NN likewise_RB , patients_NNS nearing_VBG maturity_NN who_WPR have_HV relatively_RB minor_JJ curvature_NN may_MD also_RB be_BE seen_VBN on_IN a_AT yearly_JJ basis_NN Patients_NP with_IN more_QL significant_JJ curvature_NN and_CC those_DTS entering_VBG the_ATI rapid-growth_JJ phase_NN of_IN development_NN should_MD be_BE seen_VBN every_AT 3_CD to_IN 4_CD months_NNS for_IN an_AT examination_NN with_IN roentgenography_NN if_CS curvature_NN appears_VBZ stable_JJ , roentgenograms_NNS may_MD be_BE taken_VBN at_IN every_AT other_AP visit_NN , but_CC it_PP3 is_BEZ important_JJ to_TO examine_VB these_DTS patients_NNS on_IN a_AT frequent_JJ and_CC regular_JJ basis.=20_CD 146_CD patients_NNS who_WPR have_HV entered_VBN into_IN a_AT bracing_JJ program_NN should_MD be_BE seen_VBN at_IN least_RB every_AT 3_CD to_IN 4_CD months_NNS for_IN a_AT clinical_JJ evaluation_NN , and_CC roentgenograms_NNS should_MD be_BE obtained_VBN every_AT 6_CD months_NNS and_CC any_DTI time_NN there_EX is_BEZ an_AT apparent_JJ change_NN in_IN the_ATI contour_NN of_IN the_ATI back_RP or_CC the_ATI fit_NN of_IN the_ATI brace_NN 147_CD observation_NN is_BEZ not_XNOT appropriate_JJ for_IN certain_JJ patients_NNS skeletally_RB immature_JJ patients_NNS (_( at_IN Risser_NP stages_NNS 0_CD to_IN 2_CD )_) presenting_VBG with_IN 30_CD degrees_NNS to_IN 40_CD degrees_NNS curvature_NN may_MD warrant_VB immediate_JJ bracing_JJ , as_IN a_AT delay_NN may_MD result_VB in_IN curvature_NN progression_NN , necessitating_VBG surgical_JJ intervention_NN Likewise_NP , the_ATI patient_NN with_IN flaccid_JJ paralysis_NN and_CC 20_CD degrees_NNS or_CC more_AP of_IN curvature_NN may_MD benefit_VB from_IN early_JJ brace_NN immobilization_NN , obtaining_VBG significant_JJ trunk_NN growth_NN prior_RB to_IN surgical_JJ intervention_NN the_ATI use_NN of_IN bracing_NN in_IN spastic_JJ patients_NNS is_BEZ more_QL controversial_JJ , although_CS some_DTI authors_NNS have_HV shown_VBN that_CS , even_RB in_IN face_NN of_IN mild_JJ spasticity_NN , bracing_JJ can_MD be_BE beneficial_JJ at_IN an_AT early_JJ stage_NN 148_CD ORTHOTIC_NP TREATMENT_NP 149_CD despite_IN great_JJ innovation_NN and_CC complexity_NN of_IN treatment_NN , success_NN in_IN controlling_VBG scoliotic_JJ deformities_NNS was_BEDZ not_XNOT reliably_RB obtained_VBN until_IN the_ATI 1900s_CD in_IN 1946_CD , Blount_NP and_CC Schmidt_NP demonstrated_VBD their_PP$ CTLSO_NP at_IN the_ATI annual_JJ meeting_NN of_IN the_ATI American_JNP Academy_NP of_IN Orthopaedic_NP Surgeons_NP Initially_NP intended_VBD as_IN a_AT postoperative_JJ support_NN , the_ATI Milwaukee_NP brace_NN was_BEDZ soon_RB recognized_VBN as_CS being_BEG effective_JJ in_IN the_ATI nonoperative_JJ treatment_NN of_IN early_JJ scoliotic_JJ curvature_NN the_ATI principle_NN of_IN the_ATI device_NN is_BEZ based_VBN on_IN control_NN of_IN the_ATI lumbar_NN lordosis_NN , pressure_NN over_IN the_ATI apices_NNS of_IN the_ATI curve_NN , and_CC application_NN of_IN longitudinal_JJ traction_NN through_IN the_ATI neck_NN ring_NN (_( Figure_NP 2).=20_CD 150_CD lower_JJR lumbar_NN curvature_NN is_BEZ controlled_VBN by_IN a_AT molded_JJ lumbar_NN pad_NN , and_CC thoracic_JJ curvature_NN is_BEZ controlled_VBN by_IN a_AT molded_VBN thoracic_JJ pad_NN placed_VBN just_RB below_IN the_ATI apex_NN of_IN the_ATI curve_NN on_IN the_ATI convex_NN side_NN the_ATI patient's_NN$ head_NN is_BEZ positioned_VBN against_IN the_ATI bilateral_JJ occipital_JJ pads_NNS , and_CC the_ATI anterior_JJ throat_NN mold_NN ensures_VBZ that_CS the_ATI patient_NN maintains_VBZ contact_NN with_IN these_DTS pads_NNS as_IN the_ATI head_NN rocks_NNS back_RP against_IN the_ATI pads_NNS , the_ATI resulting_JJ axial_JJ traction_NN acts_NNS to_TO further_JJB straighten_VB the_ATI upper_JJB thoracic_JJ and_CC the_ATI cervical_JJ spine_NN by_IN adjusting_VBG the_ATI position_NN of_IN the_ATI lumbar_NN and_CC the_ATI thoracic_JJ pads_NNS , a_AT wide_JJ variety_NN of_IN curvature_NN patterns_NNS can_MD be_BE controlled_VBN using_VBG the_ATI Milwaukee_NP brace_NN it_PP3 is_BEZ still_RB the_ATI brace_NN of_IN choice_NN for_IN any_DTI major_JJ thoracic_JJ curvature_NN with_IN the_ATI apex_NN above_IN the_ATI T-7_NP level_NN , for_IN cervicothoracic_JJ curvature_NN patterns_NNS , and_CC for_IN kyphotic_JJ thoracic_JJ deformities_NNS 151_CD a_AT wide_JJ variety_NN of_IN underarm_NN orthoses_NNS have_HV been_BEN developed_VBN over_IN the_ATI past_JJB 20_CD years_NNS , designed_VBD to_TO improve_VB on_IN the_ATI aesthetics_NN and_CC the_ATI comfort_NN of_IN the_ATI Milwaukee_NP brace_NN (_( Figure_NP 3_CD )_) taking_VBG advantage_NN of_IN new_JJ thermoplastic_JJ materials_NNS , these_DTS braces_NNS have_HV proven_VBN effective_JJ in_IN treating_VBG many_AP forms_NNS of_IN scoliotic_JJ curvature_NN , with_IN a_AT high_JJ degree_NN of_IN patient_NN acceptance_NN and_CC a_AT far_RB more_QL pleasant_JJ appearance_NN than_IN the_ATI Milwaukee_NP brace_NN while_CS the_ATI Milwaukee_NP brace_NN depends_VBZ to_IN some_DTI extent_NN on_IN the_ATI longitudinal_JJ traction_NN generated_VBN by_IN contact_NN with_IN the_ATI occipital_JJ posts_NNS , underarm_NN orthoses_NNS are_BER passive_JJ devices_NNS , depending_VBG on_IN fit_NN and_CC appropriate_JJ padding_VBG for_IN control_NN thoracic_JJ curvature_NN is_BEZ controlled_VBN by_IN a_AT built-in_JJB pad_NN set_VBN just_RB below_IN the_ATI apex_NN of_IN the_ATI curve_NN on_IN the_ATI convex_NN side.=20_CD 152_CD these_DTS orthoses_NNS are_BER primarily_RB effective_JJ in_IN patients_NNS with_IN thoracic_JJ curvature_NN , with_IN the_ATI apex_NN of_IN the_ATI curve_NN below_IN the_ATI T-7_NP level_NN , and_CC in_IN patients_NNS with_IN thoracolumbar_NN and_CC lumbar_NN curvature_NN 153_CD the_ATI Charleston_NP nighttime_NN bending_NN brace_NN is_BEZ a_AT custom- molded_JJ orthosis_NN designed_VBN to_TO reduce_VB scoliotic_JJ curvature_NN by_IN holding_VBG the_ATI patients_NNS in_IN a_AT markedly_RB reversed_JJ position_NN from_IN their_PP$ scoliotic_JJ curvature_NN the_ATI brace_NN is_BEZ molded_VBN in_IN maximal_JJ reverse_JJ bending_NN so_CS that_CS curvature_NN is_BEZ forcibly_RB straightened_VBD to_IN the_ATI greatest_JJT degree_NN allowed_VBN by_IN its_PP$ flexibility_NN the_ATI awkward_JJ position_NN imposed_VBN on_IN the_ATI patient_NN makes_VBZ walking_VBG very_QL difficult_JJ , and_CC , therefore_RB , the_ATI brace_NN is_BEZ worn_VBN only_RB at_IN night_NN preliminary_JJ results_NNS with_IN this_DT system_NN have_HV been_BEN good_JJ : 83%_CD of_IN skeletally_RB immature_JJ patients_NNS have_HV had_HVD satisfactory_JJ control_NN of_IN curvature_NN using_VBG the_ATI nighttime_NN brace_NN only_RB further_JJB study_NN and_CC analysis_NN of_IN the_ATI long-term_JJB results_NNS will_MD be_BE necessary_JJ before_CS this_DT brace_NN can_MD be_BE endorsed_VBN without_IN reservation_NN , however_RB , and_CC some_DTI authors_NNS have_HV questioned_VBN its_PP$ use_NN in_IN double_JJ major_JJ curvature_NN 154_CD despite_IN the_ATI variety_NN of_IN orthotic_JJ designs_NNS and_CC materials_NNS , the_ATI following_JJ objectives_NNS of_IN treatment_NN remain_VB the_ATI same_AP : (_( 1_CD1 )_) to_TO stop_VB the_ATI progression_NN of_IN scoliotic_JJ curvature_NN , (_( 2_CD )_) to_TO gain_VB permanent_JJ correction_NN in_IN anticipation_NN of_IN skeletal_JJ maturity_NN , and_CC (_( 3_CD )_) to_TO allow_VB for_IN continued_VBD growth_NN of_IN the_ATI spine_NN during_IN adolescence_NN orthotic_JJ devices_NNS are_BER better_JJR at_IN halting_VBG curvature_NN progression_NN than_CS at_IN correcting_VBG deformity_NN hence_RB , the_ATI degree_NN of_IN deformity_NN seen_VBN at_IN the_ATI start_NN of_IN bracing_NN is_BEZ usually_RB about_IN the_ATI same_AP as_IN the_ATI final_JJ outcome_NN seen_VBN after_IN completion_NN of_IN bracing_JJ for_IN this_DT reason_NN , it_PP3 is_BEZ important_JJ to_TO begin_VB brace_NN wear_NN before_CS curvature_NN reaches_VBZ an_AT unacceptable_JJ magnitude.=20_CD 155_CD the_ATI general_JJ indications_NNS for_IN orthotic_JJ treatment_NN in_IN idiopathic_JJ scoliosis_NN are_BER as_IN follows_VBZ : 156_CD children_NNS presenting_VBG with_IN curvature_NN of_IN 10_CD degrees_NNS to_IN 20_CD degrees_NNS are_BER almost_RB always_RB indicated_VBN for_IN observation_NN occasionally_RB a_AT young_JJ child_NN with_IN a_AT significant_JJ genetic_JJ history_NN or_CC other_AP risk_NN factors_NNS will_MD be_BE considered_VBN for_IN bracing_JJ with_IN curvature_NN of_IN less_AP than_IN 20_CD degrees_NNS , but_CC this_DT is_BEZ an_AT unusual_JJ situation_NN 157_CD children_NNS presenting_VBG with_IN curvature_NN of_IN 20_CD degrees_NNS to_IN 30_CD degrees_NNS should_MD also_RB be_BE observed_VBN , at_RB least_RB initially_RB roughly_RB 20%_NP of_IN patients_NNS in_IN this_DT group_NN will_MD show_VB no_ATI further_JJB progression_NN if_CS followed_VBN up_RP over_IN time_NN During_NP the_ATI observation_NN period_NN , roentgenograms_NNS should_MD be_BE obtained_VBN at_IN 3-_CD to_TO 6-month_VB intervals_NNS and_CC compared_VBN with_IN the_ATI original_JJ films_NNS if_CS the_ATI curvature_NN increases_NNS by_IN more_AP than_IN 5_CD degrees_NNS in_IN a_AT skeletally_RB immature_JJ patient_NN , bracing_NN is_BEZ indicated_VBN 158_CD children_NNS presenting_VBG with_IN 30_CD degrees_NNS to_IN 39_CD degrees_NNS curvature_NN require_VB prompt_JJ treatment_NN these_DTS patients_NNS are_BER at_IN high_JJ risk_NN of_IN progression_NN of_IN curvature_NN and_CC may_MD rapidly_RB progress_VB beyond_IN the_ATI point_NN at_IN which_WDTR bracing_NN is_BEZ effective_JJ once_RB curvature_NN exceeds_VBZ 40_CD degrees_NNS , surgical_JJ treatment_NN may_MD be_BE the_ATI only_AP means_NNS of_IN controlling_VBG and_CC correcting_VBG the_ATI deformity_NN children_NNS presenting_VBG with_IN curvature_NN of_IN 40_CD degrees_NNS to_IN 50_CD degrees_NNS in_IN magnitude_NN usually_RB require_VB surgical_JJ treatment_NN however_RB , if_CS the_ATI patient_NN has_HVZ a_AT well-balanced_JJ spine_NN and_CC the_ATI curvature_NN is_BEZ flexible_JJ , there_EX may_MD be_BE some_DTI benefit_NN to_IN bracing_JJ rather_RB than_IN surgery_NN in_IN very_AP young_JJ patients_NNS , bracing_JJ may_MD retard_VB progression_NN long_JJ enough_QLP to_TO allow_VB further_JJB trunk_NN growth_NN before_CS the_ATI inevitable_JJ fusion_NN 159_CD bracing_NN is_BEZ generally_RB ineffective_JJ in_IN controlling_JJ curvature_NN of_IN greater_JJR than_IN 50_CD degrees_NNS in_IN curvature_NN of_IN this_DT magnitude_NN , the_ATI Mehta_NP rib_NN angle_NN is_BEZ usually_RB such_ABL that_CS no_ATI significant_JJ corrective_NN pressure_NN can_MD be_BE applied_VBN over_IN the_ATI rib_NN cage_NN likewise_RB , the_ATI imbalance_NN of_IN the_ATI rib_NN hump_NN and_CC trunk_NN are_BER frequently_RB such_ABL that_CS bracing_JJ will_MD not_XNOT result_VB in_IN a_AT satisfactory_JJ outcome_NN these_DTS patients_NNS are_BER generally_RB best_JJT treated_VBN with_IN surgery_NN 160_CD lateral_JJ roentgenograms_NNS should_MD be_BE studied_VBN carefully_RB in_IN all_ABN patients_NNS indicated_VBN for_IN brace_NN treatment_NN ; those_DTS with_IN significant_JJ thoracic_JJ hypokyphosis_NN may_MD prove_VB impossible_JJ to_TO successfully_RB treat_VB with_IN bracing_JJ in_IN these_DTS patients_NNS , the_ATI thoracic_JJ pressure_NN pad_NN of_IN an_AT orthosis_NN may_MD tend_VB to_TO increase_VB the_ATI hypokyphosis_NN and_CC aggravate_VB the_ATI scoliotic_JJ deformity_NN these_DTS patients_NNS may_MD require_VB surgical_JJ treatment_NN at_IN an_AT earlier_RBR age_NN , because_CS of_IN both_ABX the_ATI difficulty_NN in_IN bracing_JJ this_DT type_NN of_IN curvature_NN and_CC its_PP$ high_JJ propensity_NN for_IN progression_NN 161_CD noncompliance_NN is_BEZ the_ATI primary_JJ cause_NN of_IN failure_NN in_IN orthotic_JJ treatment_NN programs_NNS the_ATI older_JJR the_ATI child_NN at_IN the_ATI beginning_NN of_IN treatment_NN , the_ATI less_QL likely_JJ he_PP3A or_CC she_PP3A is_BEZ to_TO comply_VB with_IN bracing_JJ compliance_NN is_BEZ better_JJR with_IN underarm_NN braces_NNS than_CS with_IN the_ATI more_QL cumbersome_JJ CTLSO_NP to_TO maximize_VB brace_NN compliance_NN and_CC minimize_NN treatment_NN failure_NN , it_PP3 is_BEZ important_JJ to_TO spend_VB time_NN fitting_JJ the_ATI brace_NN and_CC ensuring_VBG that_CS the_ATI brace_NN is_BEZ comfortable_JJ and_CC properly_RB padded_JJ and_CC trimmed_VBN the_ATI nursing_NN staff_NN and_CC the_ATI physician_NN should_MD spend_VB time_NN educating_VBG both_ABX patients_NNS and_CC parents.=20_CD 162_CD once_RB the_ATI brace_NN is_BEZ obtained_VBN , roentgenograms_NNS should_MD be_BE obtained_VBN to_TO document_NN the_ATI improvement_NN of_IN curvature_NN in_IN the_ATI brace_NN it_PP3 also_RB helps_VBZ to_TO have_HV some_DTI form_NN of_IN peer_NN support_NN from_IN other_AP patients_NNS with_IN braces_NNS special_JJ peer_NN support_NN groups_NNS established_VBN through_IN a_AT brace_NN clinic_NN may_MD help_VB adolescent_JJ patients_NNS deal_VB with_IN the_ATI social_JJ stigma_NN of_IN brace_NN wear_NN and_CC can_MD provide_VB them_PP3OS with_IN positive_JJ role_NN models_NNS for_IN treatment_NN compliance_NN 163_CD the_ATI length_NN of_IN time_NN that_CS a_AT brace_NN must_MD be_BE worn_VBN each_DT day_NN to_TO be_BE effective_JJ is_BEZ unknown_JJ patients_NNS using_VBG the_ATI Milwaukee_NP brace_NN were_BED originally_RB instructed_VBN to_TO wear_VB it_PP3 23_CD h_d_NN and_CC to_TO have_HV it_PP3 off_RP no_ATI more_AP than_IN 1_CD1 hour_NN for_IN bathing_VBG and_CC exercises_NNS the_ATI good_JJ outcomes_NNS reported_VBN by_IN many_AP authors_NNS in_IN long- term_JJB follow-up_NN studies_NNS on_IN the_ATI Milwaukee_NP brace_NN have_HV assumed_VBN that_CS patients_NNS wore_VBD their_PP$ braces_NNS for_IN the_ATI desired_JJ time_NN more_AP recent_JJ studies_NNS , however_RB , have_HV pointed_VBN out_RP that_CS patients_NNS rarely_RB wear_VB their_PP$ braces_NNS for_IN the_ATI full_JJ prescribed_JJ time_NN , and_CC that_CS partial_JJ brace_NN wear_NN is_BEZ usually_RB the_ATI norm_NN Subsequent_NP studies_NNS have_HV shown_VBN that_CS patients_NNS who_WPR wear_VB their_PP$ braces_NNS part-time_JJB have_HV had_HVD equally_RB satisfactory_JJ outcomes_NNS compared_VBN with_IN those_DTS patients_NNS who_WPR wear_VB their_PP$ braces_NNS full-time_JJB many_AP physicians_NNS now_RN recommend_VB part-time_JJB bracing_JJ as_IN their_PP$ standard_JJ nonoperative_JJ treatment_NN of_IN scoliosis_NN , usually_RB using_VBG a_AT 16-h_d_CD-CD protocol_NN 164_CD although_CS exercise_NN programs_NNS have_HV not_XNOT been_BEN shown_VBN to_TO affect_VB correction_NN of_IN curvature_NN or_CC final_JJ outcome_NN , most_QL physicians_NNS feel_VB that_CS a_AT general_JJ exercise_NN program_NN is_BEZ in_IN the_ATI patient's_NN$ best_JJT interest_NN for_IN this_DT reason,patients_NNS on_IN a_AT 16-h_d_CD-CD protocol_NN may_MD be_BE out_RP of_IN their_PP$ braces_NNS for_IN physical_JJ education_NN activities_NNS and_CC exercise_NN as_QL often_RB as_IN desired_VBN patients_NNS should_MD be_BE encouraged_VBN to_TO exercise_VB both_ABX in_IN and_CC out_RP of_IN the_ATI brace_NN and_CC should_MD not_XNOT be_BE restricted_JJ from_IN competitive_JJ athletic_JJ programs_NNS by_IN wearing_VBG their_PP$ braces_NNS 165_CD during_IN brace_NN treatment_NN , patients_NNS are_BER seen_VBN every_AT 3_CD to_IN 6_CD months_NNS , with_IN a_AT clinical_JJ examination_NN at_IN each_DT visit_NN (_( Figure_NP 4_CD )_) the_ATI skin_NN should_MD be_BE carefully_RB checked_VBN for_IN breakdown_NN or_CC dermatitis_NN , and_CC problems_NNS with_IN refitting_VBG of_IN the_ATI brace_NN should_MD be_BE corrected_VBN promptly_RB the_ATI patient's_NN$ weight_NN and_CC conditioning_NN should_MD be_BE assessed_VBN on_IN a_AT regular_JJ basis_NN , and_CC patients_NNS undergoing_VBG significant_JJ weight_NN gain_NN should_MD be_BE counseled_VBN about_IN exercise_NN and_CC diet.=20_CD 166_CD if_CS patients_NNS are_BER gaining_VBG significant_JJ amounts_NNS of_IN weight_NN , refitting_VBG or_CC replacement_NN of_IN the_ATI brace_NN may_MD be_BE necessary_JJ although_CS newer_JJR equipment_NN and_CC film_NN types_NNS have_HV markedly_RB reduced_VBN the_ATI amount_NN of_IN radiation_NN involved_VBN in_IN posteroanterior_JJ films_NNS of_IN scoliosis_NN , roentgenograms_NNS are_BER not_XNOT necessary_JJ at_IN every_AT visit_NN unless_CS there_EX is_BEZ clinical_JJ evidence_NN of_IN progression_NN , roentgenograms_NNS need_MD not_XNOT be_BE taken_VBN more_QL often_RB than_IN twice_RB a_AT year_NN in_IN most_QL cases_NNS 167_CD weaning_JJ from_IN the_ATI brace_NN can_MD begin_VB when_WRB the_ATI patient_NN reaches_VBZ skeletal_JJ maturity_NN this_DT process_NN usually_RB begins_VBZ when_WRB the_ATI patient_NN is_BEZ 2_CD years_NNS of_IN postmenarchal_JJ age_NN or_CC has_HVZ reached_VBN at_RB least_RB Risser_NP stage_NN 4_CD a_AT useful_JJ protocol_NN for_IN weaning_JJ usually_RB begins_VBZ by_IN allowing_VBG the_ATI patient_JJ out_RP of_IN the_ATI brace_NN an_AT additional_JJ 4_CD hours_NNS in_IN the_ATI afternoon_NN or_CC evening_NN and_CC increasing_JJ the_ATI time_NN allowed_VBN out_RP of_IN the_ATI brace_NN by_IN 4-hour_NN increments_NNS at_IN sequential_JJ visits_NNS 4_CD months_NNS apart_RP even_RB after_IN the_ATI patient_NN has_HVZ reached_VBN the_ATI point_NN when_WRB he_PP3A or_CC she_PP3A is_BEZ out_RP of_IN the_ATI brace_NN full- time_JJB during_IN the_ATI day_NN , the_ATI patient_NN is_BEZ encouraged_VBN to_TO continue_VB wearing_VBG the_ATI brace_NN at_IN night_NN for_IN an_AT additional_JJ year_NN after_IN that_DT time_NN , the_ATI brace_NN is_BEZ simply_RB eliminated_VBN 168_CD RESULTS_NP 169_CD orthotic_JJ treatment_NN of_IN scoliosis_NN results_NNS in_IN one_CD1 of_IN four_CD typical_JJ outcomes_NNS first_OD , there_EX are_BER a_JJ few_AP patients_NNS who_WPR will_MD experience_VB great_JJ improvement_NN in_IN curvature_NN while_CS wearing_VBG the_ATI orthosis_NN and_CC will_MD stabilize_VB at_IN this_DT corrected_VBN position_NN even_RB after_IN completing_VBG brace_NN wear_NN , these_DTS patients_NNS will_MD have_HV a_AT significant_JJ improvement_NN in_IN their_PP$ scoliosis_JJ relative_JJ to_IN original_JJ curvature_NN second_OD , a_AT much_RB larger_JJR group_NN of_IN patients_NNS will_MD experience_VB significant_JJ improvement_NN while_CS in_IN the_ATI brace_NN but_CC , after_IN weaning_JJ from_IN the_ATI brace_NN and_CC brace_NN removal_NN , will_MD lose_VB most_AP of_IN this_DT correction_NN These_NP patients_NNS tend_VB to_TO stabilize_VB with_IN final_JJ curvature_NN that_WPR is_BEZ a_AP few_AP degrees_NNS better_JJR than_IN curvature_NN with_IN which_WDTR they_PP3AS presented_VBD but_CC without_IN marked_JJ correction.=20_CD 170_CD a_AT third_OD group_NN of_IN patients_NNS will_MD suffer_VB some_DTI small_JJ increase_NN in_IN curvature_NN despite_IN bracing_JJ but_CC will_MD not_XNOT progress_VB to_IN the_ATI point_NN where_WRB surgical_JJ intervention_NN is_BEZ indicated_VBN a_AT final_JJ , small_JJ group_NN of_IN patients_NNS will_MD experience_VB relentless_JJ progression_NN of_IN curvature_NN despite_IN appropriate_JJ bracing_JJ and_CC good_JJ patient_NN compliance_NN these_DTS patients_NNS invariably_RB undergo_VB surgical_JJ intervention_NN and_CC spinal_JJ fusion_NN as_IN their_PP$ definitive_JJ treatment_NN This_NN last_AP group_NN represents_VBZ roughly_RB 10%_CD of_IN all_ABN children_NNS undergoing_VBG bracing_JJ 171_CD orthotic_JJ treatment_NN appears_VBZ to_TO have_HV equal_JJ efficacy_NN for_IN thoracic_JJ , thoracolumbar_NN , and_CC lumbar_NN curvature_NN although_CS patients_NNS with_IN thoracolumbar_NN and_CC lumbar_NN curvature_NN generally_RB see_VB a_AT greater_JJR degree_NN of_IN correction_NN when_WRB bracing_NN is_BEZ started_VBN , they_PP3AS often_RB demonstrate_VB a_AT greater_JJR decompensation_NN after_IN bracing_NN is_BEZ completed_VBN in_IN all_ABN three_CD curvature_NN patterns_NNS , patients_NNS generally_RB end_NN with_IN curvature_NN similar_JJ to_TO that_CS with_IN which_WDTR they_PP3AS presented_VBD with_IN respect_NN to_TO high-magnitude_VB curvature_NN , however_RB , thoracic_JJ curvature_NN does_DOZ tend_VB to_TO respond_VB to_IN bracing_JJ more_QL favorably_RB than_IN high-magnitude_NN thoracolumbar_NN and_CC lumbar_NN curvature_NN 172_CD BRACE_NPT TREATMENT_NPT FOR_NP BOYS_NP 173_CD recent_JJ studies_NNS have_HV identified_JJ differences_NNS in_IN the_ATI evolution_NN of_IN curvature_NN in_IN girls_NNS and_CC boys_NNS , which_WDTR have_HV implications_NNS in_IN treatment_NN decisions_NNS the_ATI likelihood_NN of_IN curvature_NN progression_NN in_IN boys_NNS with_IN idiopathic_JJ scoliosis_NN has_HVZ been_BEN linked_VBN to_TO curvature_NN magnitude_NN while_CS curvature_NN of_IN less_AP than_IN 25_CD degrees_NNS can_MD progress_VB in_IN patients_NNS at_IN Risser_NP stage_NN 0_CD , such_ABL progression_NN is_BEZ unlikely_JJ in_IN patients_NNS at_IN more_QL advanced_JJ Risser_NP stages_NNS in_IN curvature_NN larger_JJR than_IN 25_CD degrees_NNS , however_RB , progression_NN has_HVZ been_BEN documented_VBN in_IN nearly_RB one_CD1 third_OD of_IN boys_NNS at_IN Risser_NP stages_NNS 1_CD1 through_IN 4_CD in_IN addition_NN , in_IN studies_NNS of_IN boys_NNS at_IN Risser_NP stage_NN 4_CD , in_IN whom_WPOR curvature_NN was_BEDZ initially_RB believed_VBN to_TO be_BE stable_JJ , 15%_CD progressed_VBN in_IN the_ATI group_NN studied_VBN by_IN Karol_NP et_&FW al_APS , and_CC 30%_NP progressed_VBD in_IN the_ATI population_NN studied_VBN by_IN Suh_NP and_CC MacEwen_NP .=20_CD 174_CD based_VBN on_IN these_DTS data_NNS , conservative_JJ treatment_NN in_IN boys_NNS should_MD include_VB (_( 1_CD1 )_) observation_NN of_IN all_ABN curvature_NN until_IN Risser_NP stage_NN 5_CD (_( complete_JJ skeletal_JJ maturity_NN )_) is_BEZ reached_VBN ; (_( 2_CD )_) prescription_NN of_IN braces_NNS to_IN boys_NNS with_IN progressive_JJ curvature_NN in_IN excess_NN of_IN 25_CD degrees_NNS , including_IN those_DTS presenting_VBG at_IN Risser_NP stage_NN 4_CD ; and_CC (_( 3_CD )_) delayed_VBN weaning_JJ from_IN the_ATI brace_NN until_IN the_ATI boys_NNS are_BER nearer_RBR to_IN skeletal_JJ maturity_NN despite_IN these_DTS guidelines_NNS for_IN brace_NN treatment_NN in_IN boys_NNS with_IN scoliosis_NN , it_PP3 is_BEZ evident_JJ that_CS a_AT brace_NN sitting_VBG in_IN a_AT closet_NN will_MD have_HV no_ATI effect_NN on_IN curvature_NN compliance_NN in_IN boys_NNS is_BEZ a_AT distinct_JJ problem_NN , with_IN 36%_CD of_IN boys_NNS in_IN the_ATI series_NN by_IN Karol_NP et_&FW al_APS documented_VBN as_CS poor_JJ users_NNS or_CC nonusers_NNS of_IN their_PP$ braces_NNS 175_CD SCHEUERMANN_NP 'S_NP$ KYPHOSIS_NP 176_CD patients_NNS with_IN Scheuermann's_NP$ kyphosis_NN , even_RB with_IN severe_JJ clinical_JJ deformity_NN and_CC kyphosis_NN of_IN more_AP than_IN 50_CD degrees_NNS , can_MD be_BE successfully_RB treated_VBN with_IN the_ATI CTLSO_NP Sachs_NP et_&FW al_APS have_HV shown_VBN generally_RB good_JJ results_NNS using_VBG the_ATI Milwaukee_NP brace_NN for_IN patients_NNS with_IN moderate-to- severe_NN Scheuermann's_NP$ kyphosis_NN Bradford_NP et_&FW al_APS described_VBN 75_CD patients_NNS with_IN Scheuermann's_NP$ kyphosis_NN who_WPR were_BED treated_VBN with_IN the_ATI Milwaukee_NP brace_NN , noting_VBG a_AT 40%_NP improvement_NN in_IN the_ATI degree_NN of_IN kyphotic_JJ deformity_NN , with_IN 73_CD of_IN the_ATI 75_CD patients_NNS showing_VBG some_DTI degree_NN of_IN improvement.=20_CD 177_CD unsuccessful_JJ treatment_NN (_( failure_NN to_TO reduce_VB the_ATI kyphosis_NN to_TO less_AP than_IN 45_CD degrees_NNS )_) was_BEDZ more_QL likely_RB in_IN patients_NNS with_IN (_( 1_CD1 )_) vertebral_JJ wedging_VBG greater_JJR than_IN 10_CD degrees_NNS in_IN more_AP than_IN one_CD1 vertebra_NN , (_( 2_CD )_) initial_JJ kyphosis_NN greater_JJR than_IN 65_CD degrees_NNS , and_CC (_( 3_CD )_) initiation_NN of_IN treatment_NN after_IN the_ATI iliac_JJ epiphyses_NNS had_HVD closed_VBN in_IN another_DT study_NN , patients_NNS treated_VBN with_IN a_AT modified_VBN CTLSO_NP saw_VBD significant_JJ initial_JJ improvement_NN in_IN kyphosis_NN over_IN 18_CD months_NNS , only_RB to_TO experience_VB an_AT average_JJ 15_CD degrees_NNS loss_NN of_IN correction_NN during_IN the_ATI next_AP 18_CD months_NNS after_IN weaning_JJ from_IN the_ATI brace_NN to_TO maintain_VB correction_NN , it_PP3 has_HVZ been_BEN suggested_VBN that_CS the_ATI brace_NN be_BE worn_VBN until_IN there_EX is_BEZ improvement_NN in_IN vertebral_JJ wedging_VBG to_IN roughly_RB 5_CD degrees_NNS bracing_JJ for_IN longer_RBR than_IN 18_CD months_NNS is_BEZ necessary_JJ to_TO achieve_VB this_DT improvement_NN in_IN most_QL cases_NNS 178_CD the_ATI treatment_NN of_IN patients_NNS with_IN postural_JJ kyphosis_NN (_( supple_JJ , nonstructural_JJ kyphosis_NN that_WPR is_BEZ usually_RB easily_RB correctable_JJ early_JJ on_IN )_) is_BEZ similar_JJ to_TO that_CS of_IN patients_NNS with_IN Scheuermann's_NP$ kyphosis_NN in_IN young_JJ , preadolescent_NN children_NNS with_IN supple_JJ kyphosis_NN , exercises_NNS may_MD be_BE sufficient_JJ to_IN correct_JJ the_ATI deformity_NN if_CS progression_NN of_IN the_ATI kyphosis_NN is_BEZ seen_VBN or_CC if_CS the_ATI patient_NN develops_VBZ roentgenographic_JJ changes_NNS secondary_JJ to_IN prolonged_JJ kyphosis_NN , bracing_JJ may_MD be_BE instituted_VBD to_IN correct_JJ the_ATI kyphotic_JJ deformity_NN 179_CD CONCLUSIONS_NP 180_CD modern_JJ brace_NN treatment_NN has_HVZ proven_VBN effective_JJ in_IN controlling_VBG spinal_JJ deformities_NNS in_IN skeletally_RB immature_JJ patients_NNS when_WRB curvature_NN is_BEZ identified_VBN early_JJ (_( scoliosis_NN of_IN less_AP than_IN 40_CD degrees_NNS ; kyphosis_NN of_IN less_AP than_IN 60_CD degrees_NNS )_) , a_AT high_JJ rate_NN of_IN success_NN can_MD be_BE anticipated_VBN when_WRB braces_NNS are_BER worn_VBN as_IN directed_VBN 181_CD patient_NN compliance_NN has_HVZ been_BEN improved_VBN by_IN the_ATI increasing_JJ popularity_NN of_IN underarm_JJ bracing_JJ and_CC part-time_JJB bracing_JJ results_NNS of_IN studies_NNS on_IN underarm_JJ bracing_JJ and_CC part-time_JJB bracing_JJ suggest_VB that_CS these_DTS modalities_NNS are_BER as_QL effective_JJ as_CS full-time_JJB bracing_JJ with_IN the_ATI CTLSO_NP , the_ATI gold_NN standard_NN for_IN nonoperative_JJ treatment_NN the_ATI use_NN of_IN newer_JJR bracing_JJ methods_NNS such_IN as_IN the_ATI Charleston_NP nighttime_NN bending_NN brace_NN have_HV not_XNOT been_BEN fully_RB assessed_VBN yet_RB but_CC show_VB promise_NN for_IN treating_VBG patients_NNS on_IN a_AT part-time_JJB basis_NN 182_CD *figure_NN 1_CD1 the_ATI Risser_NP stages_NNS of_IN iliac_JJ apophyseal_JJ ossification_NN reflect_VB the_ATI patient's_NN$ degree_NN of_IN skeletal_JJ maturity_NN the_ATI apophysis_NN first_OD appears_VBZ as_IN a_AT small_JJ area_NN of_IN ossification_NN over_IN the_ATI lateral_JJ aspect_NN of_IN the_ATI iliac_JJ margin_NN , usually_RB around_IN 14_CD years_NNS of_IN age_NN in_IN girls_NNS and_CC 15_CD years_NNS of_IN age_NN in_IN boys_NNS ossification_NN progresses_VBZ from_IN the_ATI lateral_JJ to_IN the_ATI medial_JJ aspect_NN as_IN the_ATI patient_NN matures_NNS (_( stages_NNS 1_CD1 through_IN 4_CD )_) , ending_VBG with_IN complete_JJ fusion_NN of_IN the_ATI apophysis_NN with_IN the_ATI crest_NN at_IN skeletal_JJ maturity_NN (_( stage_NN 5_CD )_) Spinal_NP growth_NN is_BEZ usually_RB complete_JJ at_IN Risser_NP stage_NN 4_CD , and_CC all_ABN growth_NN at_IN Risser_NP stage_NN 5_CD *_* 183_CD *figure_NN 2_CD the_ATI classic_JJ Milwaukee_NP brace_NN consists_VBZ of_IN a_AT lower_JJR pelvic_JJ girdle_NN contoured_VBN to_TO grip_NN the_ATI pelvis_NN and_CC control_NN pelvic_JJ rotation_NN , anterior_JJ and_CC posterior_JJ uprights_NNS from_IN which_WDTR thoracic_JJ pads_NNS and_CC straps_NNS are_BER suspended_VBN , and_CC an_AT upper_JJB cervical_JJ collar_NN with_IN a_AT chin_NN rest_NN and_CC occipital_JJ pads_NNS lumbar_NN (_( lower_JJR arrow_NN )_) and_CC thoracic_JJ (_( middle_JJB arrow_NN )_) pads_NNS provide_VB direct_JJ pressure_NN over_IN the_ATI convexities_NNS of_IN curvature_NN , serving_VBG to_TO passively_VB correct_JJ the_ATI deformity_NN pressure_NN of_IN the_ATI occiput_NN against_IN the_ATI occipital_JJ pads_NNS (_( upper_JJB arrow_NN )_) generates_NNS longitudinal_JJ distraction_NN forces_NNS along_IN the_ATI axis_NN of_IN the_ATI spine_NN , serving_VBG to_TO actively_RB correct_JJ curvature_NN through_IN the_ATI traction_NN *_* 184_CD *figure_NN 3_CD left_VBN , Polyethylene_NP underarm_NN brace_NN for_IN the_ATI treatment_NN of_IN scoliosis_NN this_DT one-piece_NN , molded_JJ orthosis_NN is_BEZ semirigid_JJ , allowing_VBG the_ATI patient_NN to_TO enter_VB from_IN behind_RP posterior_JJ Velcro_NP straps_NNS provide_VB a_AT snug_JJ closure_NN , while_CS pads_NNS mounted_VBN to_IN the_ATI wall_NN of_IN the_ATI shell_NN (_( arrow_NN ) _) provide_VB passive_JJ correction_NN of_IN curvature_NN this_DT brace_NN is_BEZ suitable_JJ for_IN correction_NN of_IN curvature_NN with_IN the_ATI thoracic_JJ apex_NN of_IN the_ATI curve_NN below_IN the_ATI T-7_NP level_NN Right_NP , Lyon_NP underarm_NN orthosis_NN this_DT rigid_JJ acrylic_JJ brace_NN hinges_NNS in_IN the_ATI back_RP and_CC latches_NNS in_IN the_ATI front_JJB to_TO provide_VB support_NN for_IN thoracic_JJ and_CC lumbar_JJ curvature_NN the_ATI pelvic_JJ mold_NN controls_NNS lordosis_NN , as_CS in_IN the_ATI Milwaukee_NP brace_NN , and_CC scoliotic_JJ curvature_NN is_BEZ passively_RB corrected_VBN with_IN mounted_JJ pads_NNS , as_CS in_IN the_ATI polyethylene_NN brace_NN (_( arrows_NNS )_) 185_CD *figure_NN 4_CD scoliotic_JJ correction_NN with_IN an_AT underarm_NN orthosis_NN left_VBN , Roentgenogram_NP of_IN a_AT patient_NN who_WPR presented_VBD at_IN the_ATI age_NN of_IN 15_CD years_NNS with_IN marked_JJ thoracic_JJ and_CC moderate_JJ lumbar_NN curvature_NN as_IN the_ATI patient_NN was_BEDZ skeletally_RB immature_JJ , the_ATI risk_NN for_IN progression_NN was_BEDZ significant_JJ she_PP3A was_BEDZ , however_RB , still_RB treatable_JJ with_IN bracing_JJ and_CC not_XNOT indicated_VBN for_IN surgical_JJ correction_NN right_JJ , Roentgenogram_NP shows_VBZ excellent_JJ correction_NN 1_CD1 year_NN later_RBR with_IN a_AT polyethylene_NN underarm_NN orthosis_NN markers_NNS show_VB the_ATI position_NN of_IN the_ATI pads_NNS she_PP3A is_BEZ wearing_VBG the_ATI brace_NN approximately_RB 19_CD h_d_NN , with_IN time_NN out_RP for_IN bathing_VBG and_CC sports_NNS , and_CC will_MD begin_VB weaning_JJ from_IN the_ATI brace_NN in_IN approximately_RB 6_CD months_NNS her_PP$ anticipated_VBD final_JJ curvature_NN is_BEZ still_RB likely_JJ to_IN approximate_JJ that_CS with_IN which_WDTR she_PP3A presented_VBD JPSYCE_NP (_( 152_CD )_) 1_CD1 synopsis_NN of_IN the_ATI Clinical_NP Practice_NP Guidelines_NNS for_IN Diagnosis_NP and_CC Treatment_NP of_IN Depression_NP in_IN Primary_NP Care_NP 2_CD a_AT depressed_JJ (_( sad_JJ )_) mood_NN is_BEZ a_AT normal_JJ reaction_NN to_IN disappointments_NNS or_CC losses_NNS this_DT reaction_NN is_BEZ distinguished_JJ from_IN major_JJ depressive_JJ disorder_NN , however_RB , which_WDTR is_BEZ a_AT serious_JJ medical_JJ illness_NN with_IN major_JJ public_JJ health_NN consequences_NNS about_RB 15%_CD of_IN the_ATI general_JJ public_JJ will_MD suffer_VB from_IN major_JJ depressive_JJ disorder_NN at_IN some_DTI time_NN in_IN their_PP$ lives_NNS , but_CC the_ATI disorder_NN will_MD be_BE accurately_RB diagnosed_VBN and_CC treated_VBN in_IN fewer_AP than_IN one_CD1 third_OD of_IN these_DTS persons_NNS depression_NN is_BEZ often_RB viewed_VBN by_IN patients_NNS and_CC the_ATI lay_VBD public_JJ as_IN evidence_NN of_IN a_AT character_NN defect_NN or_CC inadequate_JJ willpower_NN ; thus_RB , those_DTS persons_NNS with_IN major_JJ depressive_JJ disorder_NN must_MD endure_VB the_ATI additional_JJ burden_NN of_IN having_HVG an_AT illness_NN that_CS society_NN views_NNS as_IN the_ATI reflection_NN of_IN an_AT inherent_JJ weakness_NN or_CC a_AT fault_NN 3_CD DIAGNOSIS_NP 4_CD major_JJ depressive_JJ disorder_NN is_BEZ characterized_VBN by_IN one_CD1 or_CC more_QL episodes_NNS of_IN major_JJ depression_NN major_JJ depressive_JJ disorder_NN is_BEZ a_AT syndrome_NN or_CC specific_JJ constellation_NN of_IN signs_NNS and_CC symptoms_NNS that_CS are_BER not_XNOT normal_JJ reactions_NNS to_TO life's_NN$ stresses_NNS a_AT sad_JJ or_CC depressed_JJ mood_NN is_BEZ only_RB one_CD1 of_IN the_ATI several_AP signs_NNS and_CC symptoms_NNS of_IN a_AT major_JJ depressive_JJ disorder_NN episode_NN in_IN fact_NN , clinicians_NNS may_MD note_VB a_AT predominant_JJ mood_NN of_IN apathy_NN , irritability_NN , or_CC even_RB anxiety_NN rather_RB than_IN or_CC in_IN addition_NN to_IN sadness_NN the_ATI patient's_NN$ interest_NN or_CC capacity_NN for_IN pleasure_NN or_CC enjoyment_NN is_BEZ often_RB markedly_RB reduced_VBN not_XNOT all_ABN clinically_RB depressed_JJ patients_NNS appear_VB sad_JJ ; many_AP sad_JJ patients_NNS are_BER not_XNOT depressed_JJ furthermore_RB , the_ATI leading_JJ complaints_NNS of_IN many_AP patients_NNS with_IN major_JJ depressive_JJ disorder_NN are_BER pain_NN , other_AP somatic_JJ complaints_NNS , or_CC anxiety_NN rather_RB than_IN a_AT sad_JJ mood.=20_CD 5_CD according_IN to_IN the_ATI Diagnostic_NP and_CC Statistical_NP Manual_NP of_IN Mental_NP Disorders_NP , Revised_NP Third_NP Edition_NN (_( Ref._NP 6_CD )_) , at_RB least_RB five_CD of_IN the_ATI following_JJ symptoms_NNS during_IN the_ATI same_AP period_NN are_BER the_ATI diagnostic_JJ criteria_NNS for_IN major_JJ depressive_JJ disorder_NN : a_AT depressed_JJ mood_NN (_( sometimes_RB irritability_NN in_IN children_NNS and_CC adolescents_NNS )_) for_IN most_AP of_IN the_ATI day_NN , nearly_RB every_AT day_NN ; markedly_RB diminished_JJ interest_NN or_CC pleasure_NN in_IN almost_RB all_ABN activities_NNS for_IN most_AP of_IN the_ATI day_NN , nearly_RB every_AT day_NN (_( as_CS indicated_VBN by_IN either_DTX a_AT subjective_JJ account_NN or_CC the_ATI observation_NN of_IN apathy_NN by_IN others_APS most_AP of_IN the_ATI time_NN )_) ; a_AT significant_JJ weight_NN loss_NN or_CC gain_VB ; insomnia_NN or_CC hypersomnia_NN ; psychomotor_NN agitation_NN or_CC retardation_NN ; fatigue_NN (_( loss_NN of_IN energy_NN )_) ; feelings_NNS of_IN worthlessness_NN (_( guilt_NN )_) ; impaired_VBN concentration_NN (_( indecisiveness_NN )_) ; and_CC recurrent_JJ thoughts_NNS of_IN death_NN or_CC suicide_NN at_RB least_RB the_ATI depressed_JJ mood_NN or_CC the_ATI loss_NN of_IN interest_NN or_CC pleasure_NN must_MD be_BE present_JJ the_ATI symptoms_NNS are_BER present_JJ most_AP of_IN the_ATI day_NN , nearly_RB daily_JJ , for_IN at_RB least_RB 2_CD weeks_NNS (_( Goodwin_NP and_CC Jamison_NP (_( Ref._NP 7_CD )_) provide_VB an_AT excellent_JJ review_NN of_IN issues_NNS of_IN diagnosis_NN and_CC treatment_NN )_) 6_CD figure_NN 1_CD1 shows_VBZ the_ATI diagnostic_JJ decisions_NNS needed_VBN to_TO arrive_VB at_IN a_AT differential_JJ diagnosis_NN of_IN the_ATI primary_JJ mood_NN disorders_NNS , including_IN major_JJ depressive_JJ disorder_NN either_DTX a_AT mood_NN disturbance_NN or_CC a_AT reduction_NN in_IN interest_NN or_CC in_IN the_ATI capacity_NN for_IN pleasure_NN must_MD be_BE present_JJ inquiry_NN about_IN prior_RB manic_JJ episodes_NNS is_BEZ essential_JJ , as_IN antidepressants_NP can_MD trigger_VB mania_NN in_IN patients_NNS with_IN bipolar_NN disorder_NN (_( episodes_NNS of_IN major_JJ depression_NN interspersed_VBN with_IN episodes_NNS of_IN mania_NN or_CC hypomania_NN )_) 7_CD clinical_JJ clues_NNS that_WPR raise_VB the_ATI likelihood_NN of_IN major_JJ depressive_JJ disorder_NN include_VB : 8_CD complaints_NNS of_IN pain_NN (_( eg_NN , headaches_NNS , backaches_NNS , and_CC abdominal_JJ pain_NN )_) ; 9_CD symptoms_NNS of_IN fatigue_NN , malaise_NN , irritability_NN , or_CC sadness_NN during_IN the_ATI postpartum_NN period_NN ; 10_CD prior_RB episodes_NNS of_IN depression_NN ; 11_CD a_AT personal_JJ or_CC family_NN history_NN of_IN attempted_VBD suicide_NN ; 12_CD a_AT family_NN history_NN of_IN major_JJ depressive_JJ disorder_NN or_CC bipolar_NN disorder_NN ; 13_CD concurrent_JJ substance_NN abuse_NN ; and_CC 14_CD the_ATI presence_NN of_IN other_AP general_JJ medical_JJ disorders_NNS 15_CD recent_JJ stressful_JJ events_NNS and_CC the_ATI lack_NN of_IN social_JJ supports_VBZ may_MD also_RB contribute_VB to_IN developing_VBG or_CC maintaining_VBG depressive_JJ episodes_NNS many_AP patients_NNS are_BER aware_JJ of_IN only_RB some_DTI symptoms_NNS and_CC may_MD minimize_VB their_PP$ disability_NN interviewing_NN an_AT important_JJ other_AP person_NN can_MD be_BE extremely_RB valuable_JJ in_IN obtaining_VBG an_AT accurate_JJ picture_NN of_IN the_ATI patient's_NN$ symptoms_NNS , degree_NN of_IN disability_NN , and_CC prior_RB course_RB of_IN illness_NN 16_CD a_AT normal_JJ grief_NN reaction_NN following_JJ the_ATI death_NN of_IN a_AT loved_VBD one_CD1 persists_VBZ for_IN several_AP months_NNS but_CC usually_RB improves_VBZ steadily_RB without_IN specific_JJ treatment_NN although_CS they_PP3AS are_BER unpleasant_JJ , grief_NN reactions_NNS typically_RB cause_NN time-limited_JJ , modest_JJ impairment_NN in_IN work_NN or_CC other_AP functions_NNS most_AP grief_NN reactions_NNS never_RB meet_VB the_ATI full_JJ criteria_NNS for_IN a_AT major_JJ depressive_JJ episode_NN (_( Ref._NP 1,7_CD )_) if_CS a_AT patient_NN meets_VBZ the_ATI criteria_NNS for_IN major_JJ depressive_JJ disorder_NN (_( Figure_NP 1_CD1 )_) 2_CD months_NNS after_IN the_ATI loss_NN , major_JJ depressive_JJ disorder_NN is_BEZ diagnosed_VBN and_CC treatment_NN is_BEZ indicated_VBN , as_CS these_DTS individuals_NNS are_BER very_QL likely_JJ to_TO still_VB be_BE in_IN a_AT major_JJ depressive_JJ episode_NN 1_CD1 year_NN later_RBR (_( Ref._NP 8_CD )_) 17_CD certain_JJ medications_NNS may_MD cause_VB depression_NN current_JJ evidence_NN clearly_RB implicates_NNS only_RB reserpine_JJ , glucocorticoids_NNS , and_CC anabolic_JJ steroids_NNS with_IN the_ATI de_&FW novo_JJ development_NN of_IN depression_NN as_IN a_AT common_JJ side_NN effect_NN of_IN using_VBG these_DTS medications_NNS many_AP other_AP medications_NNS can_MD cause_VB , less_QL commonly_RB , idiosyncratic_JJ reactions_NNS in_IN some_DTI individuals_NNS , including_IN depressive_JJ symptoms_NNS usually_RB , depressive_JJ symptoms_NNS begin_VB within_IN days_NNS to_IN weeks_NNS of_IN first_OD using_VBG the_ATI medication_NN 18_CD perhaps_RB the_ATI most_AP important_JJ recommendation_NN is_BEZ to_TO not_XNOT _** explain_VB away_RP _** major_JJ depressive_JJ episodes_NNS by_IN the_ATI presence_NN of_IN untoward_JJ life_NN events_NNS or_CC general_JJ medical_JJ illnesses_NNS both_ABX explanations_NNS , in_IN fact_NN , are_BER risk_NN factors_NNS for_IN major_JJ depressive_JJ episodes_NNS careful_JJ reviews_NNS of_IN the_ATI literature_NN suggest_VB that_CS only_RB 20%_NP to_TO 25%_NN of_IN patients_NNS with_IN various_JJ general_JJ medical_JJ illnesses_NNS (_( eg_NN , stroke_NN , diabetes_NN , myocardial_JJ infarction_NN , and_CC cancer_NN )_) (_( Ref._NP 1_CD1 )_) develop_VB major_JJ depressive_JJ disorder_NN and_CC , when_WRB present_JJ , it_PP3 appears_VBZ to_TO worsen_VB the_ATI morbidity_NN associated_VBN with_IN the_ATI general_JJ medical_JJ illness_NN (_( Ref._NP 1,5_CD )_) 19_CD 19_CD the_ATI critical_JJ steps_NNS in_IN detecting_JJ and_CC managing_JJ depressive_JJ conditions_NNS as_CS provided_VBN by_IN the_ATI Agency_NP for_IN Health_NPT Care_NP Policy_NP and_CC Research_NP (_( Ref._NP 1_CD1 )_) are_BER as_IN follows_VBZ : (_( 1_CD1 )_) maintain_VB a_AT high_JJ index_NN of_IN suspicion_NN and_CC evaluate_VB the_ATI risk_NN factors_NNS ; (_( 2_CD )_) detect_VB depressive_JJ symptoms_NNS with_IN a_AT clinical_JJ interview_NN and_or_CC a_AT self-reported_JJ questionnaire_NN ; (_( 3_CD )_) define_VB the_ATI mood_NN syndrome_NN (_( with_IN clinical_JJ history_NN and_CC interview_NN provided_VBN by_IN the_ATI patient_NN and_CC , if_CS needed_VBN , by_IN a_AT spouse_NN or_CC a_AT significant_JJ other_AP person_NN )_) ; (_( 4_CD )_) define_VB potential_JJ known_JJ causes_NNS of_IN mood_NN syndrome_NN (_( eg_NN , medical_JJ causes_NNS , medications_NNS , substance_NN abuse_NN , and_CC other_AP causal_JJ psychiatric_JJ disorders_NNS )_) ; (_( 5_CD )_) treat_VB potential_JJ causes_NNS ; (_( 6_CD )_) reevaluate_VB the_ATI condition_NN for_IN mood_NN syndromes_NNS ; and_CC (_( 7_CD )_) if_CS the_ATI mood_NN syndrome_NN is_BEZ still_RB present_JJ , treat_VB it_PP3 as_IN a_AT primary_JJ mood_NN disorder_NN (_( Ref._NP 1_CD1 )_) 20_CD TREATMENT_NP 21_CD the_ATI effectiveness_NN of_IN any_DTI treatment_NN is_BEZ highly_RB determined_VBN by_IN patient_NN adherence_NN adherence_NN has_HVZ been_BEN shown_VBN , empirically_RB , to_TO be_BE increased_VBN with_IN the_ATI education_NN of_IN the_ATI depressed_JJ patients_NNS (_( Ref._NP 2_CD )_) the_ATI guidelines_NNS recommend_VB that_CS patients_NNS be_BE told_VBN the_ATI diagnosis_NN , prognosis_NN , and_CC treatment_NN options_NNS , including_IN costs_NNS , duration_NN , and_CC potential_JJ side_NN effects_NNS the_ATI following_JJ are_BER the_ATI essential_JJ elements_NNS of_IN patient_NN and_CC family_NN education_NN in_IN the_ATI clinical_JJ management_NN of_IN major_JJ depressive_JJ disorder_NN 22_CD major_JJ depressive_JJ disorder_NN is_BEZ diagnosed_VBN based_VBN on_IN specific_JJ signs_NNS and_CC symptoms_NNS if_CS the_ATI signs_NNS and_CC symptoms_NNS are_BER present_JJ , they_PP3AS should_MD not_XNOT be_BE explained_VBN away_RP by_IN current_JJ life_NN stresses_NNS or_CC other_AP medical_JJ conditions_NNS 23_CD depression_NN is_BEZ a_AT major_JJ illness_NN , not_XNOT a_AT character_NN defect_NN or_CC weakness_NN 24_CD recovery_NN is_BEZ the_ATI rule_NN , not_XNOT the_ATI exception_NN 25_CD treatments_NNS are_BER effective_JJ , and_CC there_EX are_BER many_AP treatment_NN options_NNS an_AT effective_JJ treatment_NN can_MD be_BE found_VBN for_IN nearly_RB all_ABN patients_NNS 26_CD since_IN practitioner_NN optimism_NN is_BEZ therapeutic_JJ , it_PP3 is_BEZ important_JJ to_TO convey_VB a_AT sense_NN of_IN hope_NN for_IN full_JJ recovery_NN 27_CD primary_JJ care_NN practitioners_NNS can_MD treat_VB most_QL depressions_NNS successfully_RB 28_CD the_ATI aim_NN of_IN treatment_NN is_BEZ complete_JJ remission_NN of_IN symptoms_NNS , not_XNOT just_RB getting_VBG better_JJR , but_CC staying_VBG well_RB 29_CD the_ATI risk_NN of_IN recurrence_NN is_BEZ significant_JJ , at_IN 50%_NP after_IN one_CD1 episode_NN , 70%_NP after_IN two_CD episodes_NNS , and_CC 90%_NP after_IN three_CD episodes_NNS 30_CD the_ATI patient_NN and_CC the_ATI family_NN should_MD be_BE alert_JJ to_IN early_JJ signs_NNS and_CC symptoms_NNS of_IN recurrence_NN and_CC seek_VB treatment_NN early_JJ if_CS depression_NN returns_VBZ 31_CD all_ABN depressed_JJ patients_NNS should_MD be_BE assessed_VBN for_IN their_PP$ risk_NN for_IN suicide_NN by_IN direct_JJ questioning_NN about_IN suicidal_JJ thinking_NN and_CC impulses_NNS and_CC personal_JJ history_NN of_IN suicide_NN attempts_NNS patients_NNS are_BER reassured_VBN by_IN questions_NNS about_IN suicidal_JJ thoughts_NNS and_CC by_IN education_NN that_CS suicidal_JJ thinking_NN is_BEZ a_AT common_JJ symptom_NN of_IN the_ATI depression_NN itself_PPL and_CC not_XNOT a_AT sign_NN that_CS the_ATI patient_NN is_BEZ _** crazy_JJ _** the_ATI risk_NN factors_NNS associated_VBN with_IN death_NN by_IN suicide_NN include_VB hopelessness_NN , personal_JJ substance_NN abuse_NN , physical_JJ illnesses_NNS , being_BEG male_JJ , the_ATI presence_NN of_IN psychotic_NC symptoms_NNS , a_AT family_NN history_NN of_IN substance_NN abuse_NN , being_BEG white_JJ , depression_NN , advanced_JJ age_NN , and_CC living_VBG alone_JJ the_ATI presence_NN of_IN significant_JJ current_JJ substance_NN abuse_NN or_CC psychosis_NN makes_VBZ hospitalization_NN a_AT consideration_NN 32_CD treatment_NN of_IN depression_NN consists_VBZ of_IN three_CD phases_NNS (_( Figure_NP 2_CD )_) acute_JJ treatment_NN (_( 6_CD to_IN 12_CD weeks_NNS )_) aims_NNS at_IN remission_NN of_IN symptoms_NNS continuation_NN treatment_NN (_( 4_CD to_IN 9_CD months_NNS )_) aims_NNS at_IN prevention_NN of_IN relapse_NN the_ATI evidence_NN is_BEZ rather_RB clear_JJ that_CS continuation-phase_NN medication_NN (_( at_IN the_ATI full_JJ dosage_NN )_) is_BEZ indicated_VBN there_EX is_BEZ evidence_NN to_TO suggest_VB that_CS continuation-phase_NN psychotherapy_NN may_MD be_BE helpful_JJ for_IN selected_JJ individuals_NNS who_WPR respond_VB to_TO psychotherapy_NN alone_RB in_IN the_ATI acute- treatment_NN phase_NN maintenance_NN treatment_NN aims_NNS at_IN prevention_NN of_IN recurrence_NN in_IN patients_NNS with_IN prior_RB episodes_NNS there_EX is_BEZ strong_JJ evidence_NN for_IN the_ATI efficacy_NN of_IN maintenance- phase_NN medication_NN treatment_NN , but_CC far_RB less_QL evidence_NN for_IN the_ATI efficacy_NN of_IN maintenance-phase_NN psychotherapy_NN alone_JJ 33_CD figure_NN 3_CD presents_VBZ a_AT flow_NN diagram_NN for_IN the_ATI acute- phase_JJ treatment_NN of_IN depression_NN these_DTS principles_NNS apply_VB whether_CS psychotherapy_NN , antidepressants_NNS , or_CC these_DTS therapies_NNS in_IN combination_NN are_BER chosen_VBN as_IN acute-phase_NN treatment_NN essential_JJ features_NNS of_IN this_DT plan_NN include_VB regular_JJ monitoring_VBG of_IN the_ATI patient's_NN$ symptoms_NNS and_CC changes_NNS in_IN the_ATI treatment_NN plan_NN if_CS the_ATI patient's_NN$ response_NN is_BEZ not_XNOT timely_JJ 34_CD the_ATI advantage_NN of_IN such_ABL algorithms_NNS (_( simplicity_NN )_) has_HVZ within_IN it_PP3 an_AT inherent_JJ disadvantage_NN (_( generalizability_NN )_) for_IN example_NN , in_IN the_ATI more_QL severely_RB ill_JJ or_CC impulsive_JJ patients_NNS or_CC in_IN those_DTS with_IN substantial_JJ hopelessness_NN or_CC prior_RB poor_JJ adherence_NN to_TO either_DTX treatment_NN with_IN medication_NN or_CC psychotherapy_NN , the_ATI monitoring_NN of_IN response_NN should_MD occur_VB at_RB least_RB once_RB a_AT week_NN or_CC even_RB more_QL often_RB similarly_RB , a_AT switch_NN in_IN plan_NN may_MD be_BE needed_VBN before_IN 6_CD weeks_NNS if_CS there_EX is_BEZ no_ATI response_NN and_CC the_ATI patient_NN is_BEZ severely_RB ill_JJ 35_CD conversely_RB , for_IN patients_NNS who_WPR ultimately_RB respond_VB fully_RB to_TO either_DTX formal_JJ psychotherapy_NN , medication_NN treatment_NN , or_CC their_PP$ combination_NN , it_PP3 is_BEZ common_JJ to_TO see_VB at_RB least_RB a_AT partial_JJ response_NN by_IN week_NN 6_CD thus_RB , week_NN 6_CD presents_VBZ a_AT choice_NN point_NN for_IN either_DTX continuing_VBG treatment_NN protocol_NN unchanged_JJ (_( or_CC adjusting_VBG the_ATI dosage_NN of_IN medication_NN )_) or_CC (_( for_IN nonresponders_NNS )_) augmenting_VBG or_CC switching_NN treatments_NNS 36_CD a_AT partial_JJ response_NN by_IN week_NN 12_CD presents_VBZ several_AP options_NNS if_CS psychotherapy_NN alone_JJ was_BEDZ the_ATI initial_JJ treatment_NN , the_ATI addition_NN of_IN medication_NN is_BEZ indicated_VBN if_CS the_ATI treatment_NN has_HVZ been_BEN medication_NN , the_ATI addition_NN of_IN psychotherapy_NN may_MD be_BE useful_JJ , especially_RB if_CS the_ATI residual_JJ symptoms_NNS are_BER largely_RB cognitive_JJ (_( eg_NN , low_JJ self- esteem_NN )_) if_CS the_ATI initial_JJ treatment_NN was_BEDZ medication_NN , but_CC the_ATI residual_JJ symptoms_NNS are_BER largely_RB vegetative_JJ , then_RN either_DTX a_AT switch_NN to_IN another_DT medication_NN or_CC augmentation_NN with_IN a_AT second_OD medication_NN are_BER options_NNS with_IN evidence_NN for_IN efficacy_NN 37_CD a_AT consultation_NN or_CC referral_NN is_BEZ an_AT option_NN at_IN any_DTI time_NN in_IN the_ATI diagnosis_NN and_CC treatment_NN of_IN outpatients_NNS with_IN major_JJ depressive_JJ disorder_NN conversely_RB , a_AT substantial_JJ number_NN of_IN uncomplicated_JJ cases_NNS of_IN major_JJ depressive_JJ disorder_NN can_MD be_BE effectively_RB treated_VBN in_IN PC_NPT settings_NNS the_ATI available_JJ results_NNS of_IN randomized_VBN , controlled_JJ trials_NNS indicate_VB that_CS symptoms_NNS in_IN approximately_RB 50%_NP of_IN patients_NNS will_MD remit_VB with_IN an_AT initial_JJ medication_NN trial_NN , and_CC that_CS symptoms_NNS in_IN another_DT 25%_NN will_MD remit_VB with_IN a_AT second_OD (_( different_JJ class_NN )_) medication_NN for_IN time-limited_JJ psychotherapy_NN alone_JJ , again_RB symptoms_NNS in_IN approximately_RB 50%_NP of_IN patients_NNS will_MD remit_VB during_IN a_AT single_JJ treatment_NN trial_NN whether_CS a_AT second_OD psychotherapy_NN trial_NN would_MD be_BE effective_JJ if_CS the_ATI first_OD is_BEZ not_XNOT has_HVZ not_XNOT been_BEN studied_VBN therefore_RB , medication_NN is_BEZ indicated_VBN if_CS psychotherapy_NN fails_VBZ whether_CS treatment_NN with_IN psychotherapy_NN or_CC medication_NN produces_VBZ a_AT symptomatic_JJ response_NN , it_PP3 is_BEZ clear_JJ that_CS normalization_NN of_IN psychosocial_JJ function_NN often_RB follows_VBZ , albeit_CS from_IN weeks_NNS to_IN some_DTI months_NNS later_RBR (_( Ref._NP 2_CD )_) 38_CD PSYCHOTHERAPY_NP 39_CD randomized_VBN , controlled_JJ trials_NNS have_HV established_VBN that_CS several_AP forms_NNS of_IN time-limited_JJ psychotherapy_NN (_( eg_NN , cognitive_JJ , interpersonal_JJ , or_CC behavioral_JJ )_) are_BER more_QL effective_JJ in_IN reducing_VBG symptoms_NNS than_IN being_BEG assigned_VBN to_IN a_AT wait-listed_JJ control_NN comparison_NN in_IN the_ATI treatment_NN of_IN less_QL severe_JJ , nonpsychotic_JJ forms_NNS of_IN major_JJ depressive_JJ disorder_NN in_IN the_ATI studies_NNS conducted_VBN to_TO date_VB , which_WDTR have_HV largely_RB included_VBN less_QL severely_RB ill_JJ , depressed_JJ outpatients_NNS , medication_NN alone_JJ and_CC time-limited_JJ psychotherapy_NN alone_JJ have_HV equal_JJ efficacy_NN in_IN the_ATI acute-treatment_NN phase_NN brief_JJ dynamic_JJ therapy_NN has_HVZ not_XNOT been_BEN tested_VBN against_IN a_AT waiting_VBG list_NN and_CC at_IN present_NN appears_VBZ to_TO be_BE less_QL effective_JJ than_IN the_ATI previously_RB mentioned_VBN time-limited_JJ psychotherapies_NNS that_CS are_BER designed_VBN specifically_RB for_IN depression_NN other_AP types_NNS of_IN psychotherapy_NN (_( eg_NN , marital_JJ , supportive_JJ , and_CC problem_NN solving_VBG )_) may_MD well_RB be_BE helpful_JJ in_IN the_ATI treatment_NN of_IN major_JJ depressive_JJ disorder_NN and_CC are_BER commonly_RB used_VBN however_RB , they_PP3AS have_HV not_XNOT been_BEN sufficiently_RB evaluated_VBN in_IN randomized_VBN , controlled_JJ trials_NNS to_TO establish_VB their_PP$ efficacy_NN with_IN scientific_JJ certainty_NN thus_RB , of_IN the_ATI many_AP therapies_NNS available_JJ , it_PP3 is_BEZ logical_JJ to_TO recommend_VB those_DTS that_CS have_HV been_BEN better_JJR evaluated_VBN for_IN efficacy_NN before_CS those_DTS that_CS have_HV been_BEN less_QL well_RB studied_VBN 40_CD considerations_NNS for_IN acute-phase_NN treatment_NN with_IN time-limited_JJ psychotherapy_NN alone_JJ for_IN symptom_NN relief_NN include_VB : 41_CD less_AP severe_JJ depressions_NNS ; 42_CD less_AP recurrent_JJ , chronic_JJ , or_CC disabling_JJ depressions_NNS ; 43_CD prior_RB response_NN to_TO psychotherapy_NN ; 44_CD incomplete_JJ response_NN to_IN treatment_NN with_IN medication_NN alone_JJ ; 45_CD chronic_JJ psychosocial_JJ problems_NNS ; 46_CD the_ATI availability_NN of_IN a_AT trained_VBN , competent_JJ therapist_NN ; and_CC 47_CD patient_NN preference_NN 48_CD time-limited_JJ treatment_NN with_IN psychotherapies_NNS aimed_VBN at_IN depression_NN or_CC with_IN medications_NNS are_BER clearly_RB an_AT equivalent_JJ option_NN in_IN less_QL severely_RB depressed_JJ patients_NNS patient_NN preference_NN may_MD also_RB play_VB a_AT substantial_JJ role_NN in_IN the_ATI treatment_NN selection_NN for_IN such_ABL cases_NNS in_IN addition_NN to_TO symptom_NN relief_NN , psychotherapy_NN may_MD be_BE useful_JJ in_IN increasing_JJ adherence_NN or_CC remediating_VBG the_ATI secondary_JJ consequences_NNS of_IN depression_NN (_( eg_NN , marital_JJ discord_NN , occupational_JJ difficulties_NNS , and_CC low_JJ self-esteem_NN )_) 49_CD furthermore_RB , it_PP3 is_BEZ clear_JJ from_IN randomized_VBN , controlled_JJ trials_NNS that_CS a_AT significant_JJ number_NN (_( 15%_CD to_IN 30%_NP )_) of_IN patients_NNS with_IN less_QL severe_JJ forms_NNS of_IN major_JJ depressive_JJ disorder_NN obtain_VB substantial_JJ symptom_NN relief_NN with_IN time_NN , support_NN , and_CC reassurance_NN therefore_RB , when_WRB clinically_RB safe_JJ , more_AP than_IN one_CD1 visit_NN for_IN evaluation_NN (_( extended_JJ evaluation_NN )_) can_MD help_VB to_TO identify_VB those_DTS patients_NNS for_IN whom_WPOR formal_JJ treatment_NN (_( whether_CS with_IN medication_NN or_CC psychotherapy_NN )_) is_BEZ more_QL clearly_RB indicated.=20_CD 50_CD conversely_RB , full_JJ remission_NN rather_RB than_IN simple_JJ improvement_NN is_BEZ the_ATI objective_NN of_IN acute-phase_NN treatment_NN those_DTS patients_NNS who_WPR improve_VB but_CC are_BER still_RB symptomatic_JJ after_IN an_AT extended_JJ evaluation_NN should_MD receive_VB formal_JJ treatment_NN (_( with_IN psychotherapy_NN or_CC medication_NN )_) in_IN addition_NN , even_CS if_CS the_ATI depressive_JJ symptoms_NNS remit_VB with_IN several_AP visits_NNS for_IN evaluation_NN and_or_CC support_NN , symptoms_NNS often_RB return_NN , so_CS that_CS monitoring_VBG these_DTS patients_NNS is_BEZ useful_JJ to_TO detect_VB early_JJ relapse_NN or_CC subsequent_JJ recurrence_NN 51_CD TREATMENT_NP SELECTION_NP 52_CD medication_NN 53_CD acute-phase_JJ treatment_NN of_IN depression_NN in_IN the_ATI PC_NPT setting_NN includes_VBZ medication_NN , psychotherapy_NN , or_CC both_ABX many_AP randomized_VBN , controlled_JJ trials_NNS indicate_VB that_CS over_IN 50%_NP of_IN depressed_JJ outpatients_NNS who_WPR begin_VB a_AT medication_NN treatment_NN will_MD experience_VB marked_JJ improvement_NN or_CC a_AT complete_JJ remission_NN of_IN their_PP$ depressive_JJ symptoms_NNS with_IN a_AT single_JJ antidepressant_NN this_DT rate_NN of_IN marked_JJ improvement_NN or_CC remission_NN compares_VBZ with_IN a_AT 25%_NN to_IN 30%_NP response_NN to_TO placebo_NN considerations_NNS for_IN acute-phase_NN treatment_NN with_IN medication_NN are_BER : 54_CD more_AP severe_JJ symptoms_NNS ; 55_CD recurrent_JJ episodes_NNS (_( two_CD prior_RB episodes_NNS indicate_VB treatment_NN with_IN medication_NN )_) ; 56_CD family_NN history_NN of_IN depression_NN ; 57_CD prior_RB response_NN to_IN treatment_NN with_IN medication_NN ; 58_CD incomplete_JJ response_NN to_TO psychotherapy_NN alone_JJ ; 59_CD the_ATI availability_NN of_IN a_AT trained_VBN , competent_JJ physician_NN ; and_CC 60_CD patient_NN preference_NN 61_CD 61_CD it_PP3 is_BEZ useful_JJ to_TO become_VB familiar_JJ with_IN one_CD1 drug_NN with_IN minimal_JJ side_NN effects_NNS from_IN each_DT of_IN several_AP major_JJ classes_NNS of_IN antidepressants_NNS although_CS many_AP patients_NNS will_MD respond_VB to_IN an_AT adequate_JJ trial_NN of_IN the_ATI first_OD drug_NN , those_DTS who_WPR do_DO not_XNOT are_BER likely_JJ to_TO respond_VB to_IN an_AT alternate_JJ drug_NN from_IN a_AT different_JJ class_NN (_( Figure_NP 4_CD )_) 62_CD medications_NNS are_BER selected_VBN based_VBN on_IN their_PP$ short-_NN and_CC long-term_JJB side_NN effects_NNS , the_ATI patient's_NN$ history_NN of_IN response_NN or_CC nonresponse_NN , consideration_NN of_IN possible_JJ drug_NN interactions_NNS , and_CC the_ATI presence_NN of_IN other_AP psychiatric_JJ and_CC general_JJ medical_JJ conditions_NNS 63_CD inadequate_JJ response_NN to_IN tricyclic_JJ antidepressants_NNS is_BEZ often_RB due_JJ to_TO inadequate_JJ dosing_NN , perhaps_RB because_CS of_IN side_NN effects_NNS encountered_VBN the_ATI secondary_JJ amines_NNS (_( eg_NN , desipramine_NN and_CC nortriptyline_NN )_) have_HV equal_JJ efficacy_NN but_CC fewer_AP side_NN effects_NNS than_IN amitriptyline_NN , imipramine_NN , or_CC doxepin_NN Sometimes_NP serum_NN drug_NN levels_NNS (_( for_IN selected_JJ antidepressants_NNS )_) are_BER useful_JJ (_( eg_NN , inadequate_JJ response_NN , potential_JJ serious_JJ drug_NN interactions_NNS , or_CC associated_VBN general_JJ medical_JJ conditions_NNS that_WPR affect_VB drug_NN absorption_NN metabolism_NN or_CC excretion_NN or_CC that_WPR require_VB the_ATI administration_NN of_IN the_ATI lowest_JJT effective_JJ dosages_NNS )_) minimal_JJ therapeutic_JJ serum_NN levels_NNS have_HV been_BEN fairly_RB well_RB documented_VBN for_IN amitriptyline_NN , desipramine_NN , imipramine_NN , and_CC nortriptyline_NN a_AT therapeutic_JJ window_NN has_HVZ been_BEN defined_VBN for_IN nortriptyline_NN 64_CD elderly_JJ patients_NNS often_RB require_VB lower_JJR dosages_NNS of_IN medication_NN , and_CC dosage_NN increments_NNS should_MD be_BE made_VBN more_QL slowly_RB elderly_JJ patients_NNS are_BER also_RB at_IN higher_JJR risk_NN of_IN other_AP general_JJ medical_JJ disorders_NNS or_CC are_BER more_QL likely_JJ to_TO be_BE taking_VBG nonpsychotropic_JJ medications_NNS that_DT can_MD cause_VB depression_NN Therefore_NP , a_AT particularly_RB careful_JJ history_NN and_CC general_JJ medical_JJ evaluation_NN are_BER important_JJ before_CS selecting_VBG treatment_NN for_IN these_DTS patients_NNS 65_CD antidepressants_NNS without_IN antimanic_JJ medications_NNS (_( eg_NN , lithium_NN ) _) are_BER to_TO be_BE avoided_VBN in_IN patients_NNS with_IN bipolar_NN disorder_NN in_IN the_ATI depressed_JJ phase_NN , since_CS there_EX is_BEZ a_AT substantial_JJ risk_NN for_IN inducing_VBG mania_NN with_IN antidepressants_NNS (_( this_DT may_MD even_RB occur_VB when_WRB the_ATI patient_NN is_BEZ taking_VBG lithium_NN )_) therefore_RB , psychiatric_JJ consultation_NN can_MD be_BE valuable_JJ in_IN cases_NNS of_IN suspected_VBD bipolar_NN disorder_NN , before_CS medication_NN is_BEZ prescribed_VBN 66_CD combination_NN Treatment_NP With_NP Medication_NN and_CC Psychotherapy_NP 67_CD combination_NN treatment_NN with_IN medication_NN and_CC formal_JJ psychotherapy_NN , based_VBN on_IN some_DTI very_QL modest_JJ data_NNS and_CC substantial_JJ clinical_JJ consensus_NN , is_BEZ a_AT consideration_NN in_IN various_JJ situations_NNS , including_IN : 68_CD recurrent_JJ major_JJ depressive_JJ episodes_NNS with_IN poor_JJ interepisode_NN recovery_NN ; 69_CD incomplete_JJ therapeutic_JJ response_NN to_TO either_DTX medication_NN or_CC psychotherapy_NN ; 70_CD patient_NN preference_NN ; and_CC 71_CD evidence_NN of_IN a_AT significant_JJ personality_NN disorder_NN , usually_RB indicated_VBN by_IN prior_RB poor_JJ interepisode_NN recovery_NN , partial_JJ response_NN to_TO medication_NN , marked_JJ adherence_NN problems_NNS , maladaptive_JJ interpersonal_JJ relationships_NNS , multiple_JJ suicide_NN attempts_NNS , and_CC chronic_JJ somatization_NN (_( multiple_JJ , medically_RB unexplained_JJ physical_JJ symptoms_NNS )_) 72_CD CONTINUATION_NP TREATMENT_NP 73_CD once_RB patients_NNS have_HV responded_VBN to_TO acute-phase_VB treatment_NN , continuation_NN treatment_NN is_BEZ indicated_VBN to_TO prevent_VB the_ATI return_NN of_IN the_ATI most_QL recent_JJ episode_NN Continuing_NP the_ATI medication_NN is_BEZ always_RB called_VBN for_IN if_CS the_ATI acute-phase_NN treatment_NN included_VBN medication_NN the_ATI dosage_NN is_BEZ the_ATI same_AP as_CS that_CS used_VBN in_IN acute- phase_NN treatment_NN visits_NNS to_TO determine_VB the_ATI efficacy_NN of_IN medication_NN can_MD be_BE extended_VBN to_IN once_RB every_AT 2_CD to_IN 3_CD months_NNS for_IN most_QL patients.=20_CD 74_CD if_CS psychotherapy_NN alone_JJ constituted_VBD acute-phase_NN treatment_NN , the_ATI patient's_NN$ depressive_JJ symptoms_NNS remit_VB , and_CC psychosocial_JJ function_NN is_BEZ restored_VBN , it_PP3 is_BEZ unclear_JJ (_( ie_NN , largely_RB unstudied_JJ )_) as_CS to_TO whether_CS or_CC not_XNOT psychotherapy_NN is_BEZ needed_VBN as_IN a_AT continuation_NN treatment_NN however_RB , results_VBZ of_IN two_CD uncontrolled_JJ , nonrandomized_JJ studies_NNS (_( Ref._NP 9,10_CD )_) are_BER consistent_JJ with_IN the_ATI notion_NN that_CS continuation_NN psychotherapy_NN may_MD reduce_VB the_ATI relapse_NN rate_NN in_IN those_DTS patients_NNS who_WPR respond_VB to_TO acute-phase_VB psychotherapy_NN 75_CD if_CS combined_JJ acute-phase_NN treatment_NN was_BEDZ used_VBN , we_PP1AS believe_VB that_CS psychotherapy_NN can_MD be_BE discontinued_VBN if_CS the_ATI patient_NN is_BEZ in_IN remission_NN and_CC if_CS psychosocial_JJ function_NN has_HVZ been_BEN restored_VBN , although_CS this_DT recommendation_NN rests_VBZ solely_RB on_IN clinical_JJ experience_NN 76_CD 76_CD while_CS some_DTI naturalistic_JJ follow-up_NN studies_NNS suggest_VB a_AT lower_JJR recurrence_NN rate_NN for_IN those_DTS patients_NNS who_WPR respond_VB acutely_RB to_IN cognitive_JJ therapy_NN alone_JJ (_( or_CC in_IN combination_NN with_IN medication_NN )_) once_RB treatment_NN is_BEZ discontinued_VBN , other_AP studies_NNS have_HV failed_VBN to_TO confirm_VB these_DTS findings_NNS these_DTS presently_RB mixed_JJ results_NNS could_MD indicate_VB a_AT specific_JJ effect_NN of_IN the_ATI therapy_NN or_CC , from_IN a_AT selection_NN of_IN cases_NNS with_IN a_AT naturally_RB better_JJR prognosis_NN , a_AT capacity_NN of_IN certain_JJ patients_NNS to_TO respond_VB acutely_RB to_IN psychotherapy_NN to_TO date_NN , the_ATI hypothetical_JJ benefit_NN of_IN preventing_VBG recurrence_NN with_IN acute-phase_NN psychotherapy_NN alone_JJ has_HVZ not_XNOT been_BEN established_VBN , and_CC further_JJB research_NN is_BEZ indicated_VBN 77_CD MAINTENANCE_NP TREATMENT_NP 78_CD maintenance_NN treatment_NN with_IN medication_NN should_MD be_BE considered_VBN for_IN selected_JJ patients_NNS after_IN acute-_NN and_CC continuation-phase_NN treatment_NN with_IN medication_NN the_ATI goal_NN of_IN maintenance_NN treatment_NN is_BEZ the_ATI prevention_NN of_IN the_ATI recurrence_NN of_IN a_AT new_JJ episode_NN of_IN major_JJ depression_NN patients_NNS who_WPR are_BER at_IN high_JJ risk_NN of_IN recurrence_NN should_MD be_BE maintained_VBN for_IN 1_CD1 or_CC more_QL years_NNS on_IN medication_NN treatment_NN at_IN the_ATI same_AP dosage_NN that_CS was_BEDZ effective_JJ in_IN the_ATI acute-phase_NN treatment_NN considerations_NNS for_IN maintenance_NN medication_NN as_CS provided_VBN by_IN the_ATI Depression_NPT Guideline_NP Panel_NP (_( Ref._NP 2_CD )_) include_VB three_CD or_CC more_QL episodes_NNS of_IN major_JJ depressive_JJ disorder_NN or_CC two_CD episodes_NNS of_IN major_JJ depressive_JJ disorder_NN in_IN combination_NN with_IN a_AT positive_JJ , clear-cut_JJ history_NN in_IN one_CD1 or_CC more_QL first-degree_JJB relatives_NNS (_( a_AT family_NN history_NN )_) of_IN bipolar_NN disorder_NN ; a_AT history_NN of_IN recurrence_NN within_IN 1_CD1 year_NN after_IN previously_RB effective_JJ treatment_NN with_IN medication_NN was_BEDZ discontinued_VBN ; a_AT family_NN history_NN (_( as_CS defined_VBN above_IN )_) of_IN recurrent_JJ major_JJ depressive_JJ disorder_NN ; early_JJ onset_NN (_( before_IN age_NN 20_CD years_NNS )_) of_IN the_ATI first_OD episode_NN ; and_CC having_HVG severe_JJ , sudden_JJ or_CC life-threatening_NN symptoms_NNS in_IN both_ABX episodes_NNS in_IN the_ATI past_JJB 3_CD years_NNS 79_CD the_ATI efficacy_NN of_IN maintenance_NN treatment_NN in_IN preventing_VBG a_AT future_NN episode_NN of_IN depression_NN has_HVZ been_BEN demonstrated_VBN only_RB with_IN medications_NNS maintenance_NN psychotherapy_NN , given_VBN at_RB least_RB monthly_JJ , does_DOZ not_XNOT appear_VB to_TO prevent_VB recurrence_NN (_( Ref._NP 11,12_CD )_) , although_CS one_CD1 study_NN (_( Ref._NP 11_CD )_) suggests_VBZ that_CS it_PP3 may_MD help_VB to_TO delay_VB the_ATI onset_NN of_IN the_ATI next_AP episode_NN in_IN recurrent_JJ major_JJ depressive_JJ disorders_NNS consequently_RB , maintenance_NN psychotherapy_NN can_MD be_BE useful_JJ for_IN women_NNS who_WPR want_VB to_TO become_VB pregnant_JJ and_CC bear_VB a_AT child_NN in_IN a_AT drug-free_NN condition_NN or_CC for_IN other_AP patients_NNS who_WPR must_MD be_BE medication_NN free_JJ for_IN limited_JJ time_NN periods_NNS 80_CD MAJOR_NPT DEPRESSIVE_NPT DISORDER_NPT ASSOCIATED_NPT WITH_NPT OTHER_NP CONDITIONS_NP 81_CD the_ATI algorithm_NN in_IN Figure_NP 4_CD indicates_VBZ the_ATI treatment_NN priorities_NNS when_WRB major_JJ depressive_JJ disorder_NN is_BEZ associated_VBN with_IN another_DT psychiatric_JJ condition_NN for_IN example_NN , a_AT depressed_JJ patient_NN with_IN alcohol_NN dependence_NN should_MD first_OD discontinue_VB alcohol_NN use_NN for_IN several_AP weeks_NNS if_CS the_ATI major_JJ depressive_JJ disorder_NN persists_VBZ , it_PP3 should_MD be_BE treated_VBN this_DT principle_NN has_HVZ several_AP exceptions_NNS : 82_CD when_WRB generalized_JJ anxiety_NN disorder_NN coexists_NNS with_IN major_JJ depressive_JJ disorder_NN , treatment_NN should_MD be_BE directed_VBN toward_IN the_ATI major_JJ depressive_JJ disorder_NN first_OD 83_CD if_CS panic_NN disorder_NN is_BEZ present_JJ only_RB during_IN major_JJ depressive_JJ episodes_NNS , the_ATI major_JJ depressive_JJ disorder_NN is_BEZ treated_VBN first_OD 84_NN if_CS panic_NN disorder_NN and_CC major_JJ depressive_JJ disorder_NN are_BER both_ABX present_JJ and_CC the_ATI panic_NN disorder_NN has_HVZ been_BEN present_JJ without_IN episodes_NNS of_IN major_JJ depression_NN in_IN the_ATI past_NN , the_ATI clinician_NN must_MD judge_VB by_IN family_NN history_NN , the_ATI level_NN of_IN current_JJ disability_NN attributable_JJ to_IN each_DT condition_NN , or_CC prior_RB course_RB of_IN illness_NN which_WDTR is_BEZ the_ATI most_QL significant_JJ condition_NN and_CC treat_VB that_CS condition_NN first_OD (_( some_DTI medications_NNS have_HV proven_VBN effective_JJ for_IN both_ABX disorders_NNS and_CC , therefore_RB , may_MD be_BE preferred_VBN in_IN such_ABL situations_NNS )_) 85_CD if_CS a_AT personality_NN disorder_NN is_BEZ suspected_VBN , the_ATI major_JJ depressive_JJ disorder_NN is_BEZ treated_VBN first_OD whenever_WRB feasible_JJ 86_CD general_JJ medical_JJ conditions_NNS that_CS are_BER associated_VBN with_IN depressive_JJ symptoms_NNS include_VB autoimmune_NN , neurologic_JJ , metabolic_JJ , infectious_JJ , oncologic_JJ , and_CC endocrine_NN disorders_NNS , among_IN others_APS in_IN such_ABL cases_NNS , the_ATI practitioner_NN should_MD consider_VB the_ATI following_JJ four_CD possibilities_NNS : (_( 1_CD1 )_) if_CS the_ATI depression_NN is_BEZ biologically_RB caused_VBN by_IN the_ATI general_JJ medical_JJ disorder_NN (_( eg_NN , hypothyroidism_NN )_) , treatment_NN of_IN the_ATI medical_JJ disorder_NN often_RB resolves_VBZ the_ATI depression_NN ; (_( 2_CD )_) if_CS the_ATI patient_NN has_HVZ a_AT situational_JJ adjustment_NN reaction_NN to_IN the_ATI diagnosis_NN , prognosis_NN , or_CC disability_NN , then_RN counseling_VBG , advice_NN , and_CC support_NN with_IN clear_JJ information_NN provided_VBN by_IN the_ATI family_NN physician_NN is_BEZ recommended_VBN ; (_( 3_CD )_) if_CS the_ATI patient_NN is_BEZ taking_VBG a_AT medication_NN for_IN the_ATI general_JJ medical_JJ condition_NN that_WPR is_BEZ causing_VBG the_ATI depressive_JJ symptoms_NNS or_CC even_RB a_AT major_JJ depressive_JJ disorder_NN , then_RN a_AT change_NN in_IN medication_NN is_BEZ the_ATI preferred_VBN first_OD step_NN ; and_CC (_( 4_CD )_) if_CS the_ATI patient_NN has_HVZ a_AT major_JJ depressive_JJ disorder_NN , either_DTX precipitated_VBN biologically_RB or_CC psychologically_RB by_IN the_ATI general_JJ medical_JJ disorder_NN or_CC co-occurring_NN by_IN chance_NN , then_RN specific_JJ treatment_NN for_IN the_ATI clinical_JJ depression_NN is_BEZ indicated.=20_CD 87_CD similarly_RB , if_CS major_JJ depressive_JJ disorder_NN is_BEZ still_RB present_JJ in_IN the_ATI first_OD three_CD cases_NNS after_IN the_ATI above_IN initial_JJ steps_NNS are_BER followed_VBN , specific_JJ treatment_NN for_IN the_ATI major_JJ depressive_JJ disorder_NN is_BEZ recommended_VBN in_IN these_DTS cases_NNS , persistent_JJ major_JJ depressive_JJ disorder_NN should_MD be_BE treated_VBN first_OD , followed_VBN by_IN optimal_JJ treatment_NN of_IN the_ATI nondepressive_JJ condition_NN (_( Figure_NP 5_CD )_) That_NP is_BEZ , when_WRB the_ATI general_JJ medical_JJ condition_NN is_BEZ complicated_VBN by_IN major_JJ depressive_JJ disorder_NN , the_ATI depression_NN becomes_VBZ the_ATI treatment_NN objective_JJ 88_CD CONSULTATION_NPT OR_NP REFERRAL_NP 89_CD a_AT consultation_NN or_CC referral_NN is_BEZ a_AT consideration_NN at_IN any_DTI time_NN during_IN the_ATI diagnosis_NN of_IN major_JJ depressive_JJ disorder_NN and_CC the_ATI treatment_NN of_IN the_ATI depressed_JJ patient_NN instances_NNS may_MD include_VB one_CD1 or_CC more_AP of_IN the_ATI following_JJ : 90_CD the_ATI patient_NN fails_VBZ to_TO respond_VB fully_RB within_IN three_CD treatment_NN trials_NNS 91_CD the_ATI patient_NN is_BEZ actively_RB suicidal_JJ 92_CD the_ATI patient_NN is_BEZ suffering_VBG from_IN a_AT very_QL severe_JJ , psychotic_NC , or_CC chronic_JJ depression_NN 93_CD the_ATI patient's_NN$ symptoms_NNS suggest_VB a_AT complex_JJ psychiatric_JJ or_CC general_JJ medical_JJ diagnosis_NN 94_CD the_ATI patient_NN shows_VBZ persistent_JJ psychosocial_JJ problems_NNS 95_CD formal_JJ psychotherapy_NN is_BEZ a_AT consideration_NN 96_CD specialized_JJ treatment_NN , such_IN as_IN electroconvulsive_JJ therapy_NN and_CC light_NN therapy_NN , are_BER a_AT consideration_NN 97_CD the_ATI patient_NN requests_NNS a_AT second_OD opinion_NN 98_NN medical_JJ , Metabolic_NP , and_CC Psychological_NP Effects_NNS of_IN Weight_NP Cycling_NP 99_CD weight_NN cycling_VBG refers_VBZ to_IN the_ATI phenomenon_NN of_IN repeatedly_RB losing_VBG and_CC regaining_VBG weight_NN this_DT common_JJ experience_NN of_IN many_AP dieters_NNS leaves_NNS patients_NNS and_CC health_NN care_NN professionals_NNS frustrated_JJ and_CC disappointed_JJ thus_RB , significant_JJ interest_NN was_BEDZ generated_VBN when_WRB a_AT study_NN with_IN animals_NNS reported_VBN that_CS weight_NN cycling_VBG may_MD impede_VB subsequent_JJ weight_NN loss_NN and_CC promote_VB rapid_JJ regain_VB yo-yo_NN dieting_VBG became_VBD the_ATI colloquial_JJ term_NN for_IN this_DT process_NN 100_CD there_EX is_BEZ now_RN a_AT burgeoning_VBG scientific_JJ literature_NN on_IN weight_NN cycling_NN The_NP Diet_NP and_CC Health_NP report_NN of_IN the_ATI National_NP Academy_NP of_IN Sciences_NP noted_VBD the_ATI possible_JJ deleterious_JJ effects_NNS of_IN weight_NN cycling_VBG , and_CC the_ATI Surgeon_NP General's_NPT$ Report_NP on_IN Nutrition_NN and_CC Health_NP recommended_VBD that_CS _** the_ATI health_NN consequences_NNS of_IN repeated_JJ cycles_NNS of_IN weight_NN loss_NN and_CC gain_VB _** be_BE given_VBN _** special_JJ priority_NN _** the_ATI topic_NN has_HVZ been_BEN the_ATI subject_NN of_IN reviews_NNS and_CC editorials_NNS , and_CC a_AT poll_NN of_IN obesity_NN experts_NNS found_VBN that_CS genetics_NNS , physical_JJ inactivity_NN , weight_NN cycling_VBG , and_CC depression_NN were_BED listed_VBN as_IN the_ATI key_NN causes_NNS of_IN obesity_NN 101_CD national_JJ surveys_NNS show_VB that_CS 40%_NP of_IN women_NNS and_CC 20%_NP of_IN men_NNS are_BER dieting_VBG at_IN any_DTI one_CD1 time_NN ; 37%_CD of_IN men_NNS and_CC 52%_NN of_IN women_NNS feel_VB they_PP3AS are_BER overweight_NN Weight_NP loss_NN has_HVZ long_JJ been_BEN considered_VBN a_AT means_NNS of_IN promoting_VBG health_NN , but_CC since_CS so_QL many_AP people_NNS regain_VB the_ATI weight_NN , millions_CDS of_IN individuals_NNS could_MD be_BE damaging_JJ their_PP$ health_NN if_CS weight_NN cycling_VBG has_HVZ deleterious_JJ effects_NNS on_IN medical_JJ or_CC psychosocial_JJ factors_NNS 102_CD THE_NP PHENOMENON_NP 103_CD because_CS dieting_VBG is_BEZ so_QL common_JJ and_CC relapse_NN is_BEZ a_AT likely_JJ outcome_NN , it_PP3 is_BEZ logical_JJ to_TO assume_VB that_CS weight_NN cycling_VBG is_BEZ highly_RB prevalent_JJ just_RB how_WRB much_AP individuals_NNS gain_VB and_CC lose_VB can_MD only_RB be_BE inferred_VBN from_IN incomplete_JJ data_NNS Even_NP the_ATI most_QL detailed_JJ studies_NNS of_IN weight_NN change_NN only_RB offer_VB weights_NNS separated_VBN by_IN months_NNS or_CC years_NNS 104_CD 7_CD over_IN the_ATI first_OD 14_CD years_NNS of_IN the_ATI Framingham_NP Study_NP , the_ATI SD_NN of_IN body_NN mass_NN index_NN for_IN men_NNS and_CC women_NNS was_BEDZ 5.7%_NN and_CC 6.7%_NN , respectively_RB in_IN men_NNS in_IN the_ATI Multiple_NPT Risk_NP Factor_NP Intervention_NN Trial_NP , the_ATI SD_NN of_IN weight_NN was_BEDZ 2.9_CD kg_NNU over_IN the_ATI 6_CD to_IN 7_CD years_NNS of_IN the_ATI trial_NN weights_NNS were_BED measured_VBN every_AT 2_CD years_NNS in_IN the_ATI Framingham_NP Study_NP and_CC once_RB or_CC three_CD times_NNS per_NNU year_NN in_IN the_ATI Multiple_NP Risk_NP Factor_NP Intervention_NN Trial_NP study_NN , so_QL total_JJ fluctuation_NN between_IN intervals_NNS is_BEZ unknown_JJ weight_NN variability_NN is_BEZ not_XNOT identical_JJ to_IN a_AT measure_NN of_IN repeated_JJ cycles_NNS of_IN weight_NN loss_NN and_CC regain_VB , but_CC has_HVZ been_BEN used_VBN as_IN an_AT analogue_NN since_CS cycling_VBG is_BEZ not_XNOT possible_JJ to_IN document_NN in_IN many_AP instances_NNS 105_CD a_AT study_NN (_( S._NP a._RB Everson_NP , PhD_NP , K._NP a._RB Matthews_NP , PhD_NP , unpublished_JJ data_NNS )_) tracked_JJ weight_NN in_IN a_AT 6.5-year_JJ longitudinal_JJ study_NN of_IN blood_NN pressure_NN in_IN 153_CD middle-aged_JJ adults_NNS and_CC assessed_VBN weight_NN cycling_VBG at_IN the_ATI end_NN of_IN the_ATI study_NN with_IN a_AT questionnaire_NN developed_VBN previously_RB the_ATI sum_NN of_IN all_ABN weight_NN gains_NNS and_CC losses_NNS , respectively_RB , averaged_VBD 10.3_CD kg_NNU and_CC 10.5_CD kg_NNU for_IN men_NNS and_CC 14.1_CD kg_NNU and_CC 12.4_CD kg_NNU for_IN women_NNS the_ATI total_JJ weight_NN gain_NN for_IN men_NNS was_BEDZ 12%_CD and_CC loss_NN was_BEDZ 12%_CD of_IN initial_JJ body_NN weight_NN , but_CC for_IN women_NNS gain_VB and_CC loss_NN were_BED 21%_CD and_CC 19%_CD , respectively_RB a_AT study_NN tracking_VBG 332_CD individuals_NNS who_WPR were_BED 20%_NP or_CC more_QL overweight_JJ found_VBN that_CS the_ATI vast_JJ majority_NN either_DTX lost_VBN or_CC gained_VBN significant_JJ amounts_NNS of_IN weight_NN 106_CD WEIGHT_NP CYCLING_NP , WEIGHT_NP CHANGE_NP , AND_NP METABOLISM_NP 107_CD weight_NN Loss_NN on_IN Successive_NP Diets_NP 108_CD Blackburn_NP et_&FW al_APS published_VBN the_ATI first_OD test_NN in_IN humans_NNS of_IN the_ATI cycling_NN hypothesis_NN (_( successive_JJ cycles_NNS would_MD inhibit_VB weight_NN loss_NN )_) in_IN a_AT study_NN of_IN 43_CD individuals_NNS who_WPR lost_JJ weight_NN on_IN a_AT very-low-calorie_NN diet_NN as_CS outpatients_NNS , regained_VBD weight_NN , and_CC then_RN underwent_VB the_ATI same_AP treatment_NN Consistent_NP with_IN the_ATI hypothesis_NN , subjects_NNS lost_VBN significantly_RB less_QL weight_NN (_( 0.15_CD kg_d_NN )_) on_IN the_ATI second_OD diet_NN than_CS on_IN the_ATI first_OD (_( 0.19_CD kg_d_NN )_) poorer_JJR compliance_NN on_IN a_AT second_OD diet_NN , in_IN lieu_NN of_IN , or_CC in_IN addition_NN to_TO , adaptive_JJ metabolic_JJ changes_NNS , might_MD explain_VB these_DTS results.=20_CD 109_CD Smith_NP and_CC Wing_NP measured_JJ compliance_NN across_IN two_CD bouts_NNS of_IN a_AT very-low-calorie_NN diet_NN , and_CC reported_VBN dramatic_JJ declines_VBZ during_IN the_ATI second_OD diet_NN in_IN attendance_NN at_IN sessions_NNS and_CC dietary_JJ compliance_NN Blackburn_NP et_&FW al_APS addressed_VBN the_ATI compliance_NN issue_NN by_IN examining_VBG 14_CD individuals_NNS who_WPR had_HVD taken_VBN part_NN in_IN several_AP trials_NNS of_IN a_AT supplemented_VBN fast_RB , but_CC had_HVD done_VBN so_CS as_CS inpatients_NNS on_IN a_AT metabolic_JJ unit_NN under_IN these_DTS controlled_JJ circumstances_NNS , where_WRB compliance_NN was_BEDZ consistent_JJ , weight_NN loss_NN was_BEDZ still_RB significantly_RB less_AP on_IN a_AT second_OD diet_NN compared_VBN with_IN the_ATI first_OD 110_CD several_AP subsequent_JJ studies_NNS with_IN outpatient_NN samples_NNS failed_VBN to_TO find_VB differences_NNS in_IN the_ATI rate_NN of_IN weight_NN loss_NN over_IN successive_JJ diets_NNS all_ABN used_VBN different_JJ definitions_NNS of_IN weight_NN cycling_VBG , and_CC several_AP had_HVD small_JJ sample_NN sizes_NNS , but_CC two_CD studies_NNS had_HVD substantial_JJ samples_NNS 111_CD the_ATI animal_NN literature_NN is_BEZ similar_JJ to_IN the_ATI human_JJ literature_NN in_IN that_DT some_DTI studies_NNS show_VB slowing_NN of_IN weight_NN loss_NN , while_CS other_AP studies_NNS do_DO not_XNOT It_NP is_BEZ tempting_JJ to_TO dismiss_VB the_ATI studies_NNS showing_NN a_AT cycling_VBG effect_NN because_CS there_EX are_BER studies_NNS to_IN the_ATI contrary_NN yet_RB , it_PP3 is_BEZ possible_JJ that_CS an_AT effect_NN occurs_VBZ in_IN susceptible_JJ individuals_NNS or_CC under_IN certain_JJ dietary_JJ conditions_NNS , or_CC that_CS there_EX are_BER critical_JJ periods_NNS of_IN vulnerability_NN the_ATI question_NN of_IN whether_CS the_ATI effect_NN exists_VBZ or_CC not_XNOT might_MD yield_VB to_IN the_ATI broader_JJR question_NN of_IN whether_CS weight_NN cycling_VBG affects_VBZ particular_JJ individuals_NNS under_IN specific_JJ circumstances_NNS 112_CD weight_NN Cycling_NP and_CC Metabolic_NP Rate_NP 113_CD to_TO examine_VB if_CS metabolic_JJ rate_NN is_BEZ a_AT mechanism_NN by_IN which_WDTR cycling_VBG alters_VBZ the_ATI rate_NN of_IN weight_NN loss_NN and_CC regain_VB , several_AP studies_NNS were_BED conducted_VBN with_IN wrestlers_NNS , a_AT group_NN known_VBN for_IN rapid_JJ , frequent_JJ , and_CC severe_JJ cycles_NNS Steen_NP et_&FW al_APS compared_VBN the_ATI resting_NN energy_NN expenditure_NN (_( REE_NP )_) of_IN elite_NN adolescent_JJ wrestlers_NNS with_IN a_AT history_NN of_IN weight_NN cycling_VBG to_IN REE_NP in_IN noncycling_VBG wrestlers_NNS the_ATI REE_NP was_BEDZ 14%_CD lower_JJR in_IN the_ATI cycling_NN than_CS in_IN the_ATI noncycling_NN subjects_NNS , after_IN accounting_NN for_IN age_NN , body_NN composition_NN , and_CC wrestling_VBG record.=20_CD 114_CD several_AP subsequent_JJ studies_NNS failed_VBN to_TO associate_VB weight_NN cycling_VBG with_IN lowered_VBD metabolic_JJ rate_NN in_IN wrestlers_NNS the_ATI evidence_NN for_IN changes_NNS in_IN metabolism_NN in_IN dieters_NNS also_RB appears_VBZ mixed_JJ while_CS nonobese_JJ female_JJ cyclic_JJ dieters_NNS appear_VB to_TO have_HV lower_JJR relative_JJ REE_NP and_CC exercise_NN energy_NN expenditure_NN than_IN do_DO nondieting_VBG control_NN subjects_NNS , studies_VBZ with_IN obese_JJ individuals_NNS show_VB no_ATI association_NN of_IN cycling_VBG history_NN with_IN metabolic_JJ rate_NN Jebb_NP et_&FW al_APS followed_VBN up_RP 11_CD obese_JJ women_NNS through_IN three_CD consecutive_JJ cycles_NNS of_IN 2_CD weeks'_NNS$ dieting_VBG followed_VBN by_IN 4_CD weeks_NNS of_IN nonrestricted_VBN eating_VBG and_CC found_VBN no_ATI evidence_NN of_IN progressive_JJ decreases_VBZ in_IN REE_NP 115_CD WEIGHT_NPT CYCLING_NPT BEHAVIOR_NPT AND_NPT PSYCHOLOGICAL_NP FACTORS_NP 116_CD a_AT small_JJ number_NN of_IN studies_NNS have_HV been_BEN done_VBN on_IN weight_NN cycling_VBG and_CC psychological_JJ adjustment_NN and_CC eating_VBG behavior_NN , but_CC the_ATI results_NNS thus_RB far_RB are_BER consistent_JJ foreyt_NN et_&FW al_APS found_VBN no_ATI differences_NNS in_IN psychopathology_NN between_IN obese_JJ and_CC nonobese_JJ individuals_NNS , but_CC individuals_NNS with_IN a_AT history_NN of_IN weight_NN cycling_VBG showed_VBD significantly_RB greater_JJR pathologic_JJ findings_NNS than_IN those_DTS with_IN stable_JJ weights_NNS , independent_NN of_IN weight_NN Everson_NP and_CC Matthews_NP reported_VBN that_CS lower_JJR levels_NNS of_IN life_NN satisfaction_NN were_BED related_VBN to_TO increased_JJ weight_NN cycling_VBG in_IN females_NNS but_CC not_XNOT in_IN males_NNS (_( unpublished_JJ data_NNS )_) 117_CD a_AT study_NN with_IN a_AT large_JJ sample_NN of_IN runners_NNS found_VBN that_CS a_AT history_NN of_IN weight_NN cycling_VBG was_BEDZ associated_VBN with_IN higher_JJR levels_NNS of_IN disturbed_VBN eating_VBG practices_NNS (_( indicative_NN of_IN bulimia_NN nervosa_NN )_) 118_CD binge_NN eating_VBG in_IN overweight_NN persons_NNS has_HVZ been_BEN recognized_VBN as_IN a_AT special_JJ pattern_NN of_IN behavior_NN associated_VBN with_IN increased_JJ psychopathology_NN and_CC poor_JJ prognosis_NN in_IN weight_NN loss_NN programs_NNS repeated_VBN or_CC chronic_JJ dieting_NN may_MD predispose_VB an_AT individual_JJ to_IN disordered_JJ eating_NN , including_IN binge_NN eating_NN In_NP one_CD1 study_NN , restrained_VBN eating_VBG (_( dieting_VBG )_) was_BEDZ a_AT stronger_JJR predictor_NN of_IN weight_NN fluctuation_NN than_IN was_BEDZ body_NN weight_NN itself_PPL a_AT study_NN of_IN obese_JJ individuals_NNS in_IN treatment_NN showed_VBD no_ATI relationship_NN between_IN reports_NNS of_IN previous_JJ weight_NN fluctuation_NN and_CC binge_NN eating_NN a_AT large_JJ multisite_NN trial_NN , however_RB , found_VBD that_CS obese_JJ binge_NN eaters_NNS were_BED more_QL likely_JJ than_IN nonbinge_NN eaters_NNS to_TO have_HV a_AT history_NN of_IN weight_NN cycling_NN 119_CD WEIGHT_NPT CYCLING_NPT AND_NP MORTALITY_NP 120_CD several_AP studies_NNS have_HV considered_VBN the_ATI relationship_NN between_IN weight_NN variability_NN and_CC mortality_NN a_AT study_NN of_IN male_JJ employees_NNS of_IN the_ATI Western_NP Electric_NP Company_NP found_VBD that_CS a_AT single_JJ cycle_NN of_IN weight_NN gain_NN and_CC loss_NN (_( difference_NN in_IN self-reported_JJ weights_NNS in_IN 5-year_NN intervals_NNS )_) was_BEDZ associated_VBN with_IN risk_NN of_IN death_NN from_IN coronary_JJ heart_NN disease_NN (_( CHD_NP )_) but_CC not_XNOT with_IN all- cause_NN mortality_NN data_NNS from_IN the_ATI Harvard_NP Alumni_NP Study_NP documented_VBN that_CS weight_NN gain_NN and_CC weight_NN loss_NN were_BED associated_VBN with_IN increased_VBN mortality_NN from_IN all_ABN causes_NNS and_CC from_IN CHD_NP those_DTS losing_VBG or_CC gaining_VBG more_QL weight_NN reported_VBN greater_JJR total_JJ lifetime_NN weight_NN loss_NN , which_WDTR may_MD indicate_VB weight_NN cycling_NN 121_CD data_NNS from_IN the_ATI Gothenburg_NP (_( Sweden_NP )_) Prospective_NP Studies_NP found_VBD an_AT association_NN of_IN weight_NN variability_NN with_IN CHD_NP in_IN men_NNS and_CC with_IN total_JJ mortality_NN in_IN both_ABX men_NNS and_CC women_NNS in_IN a_AT study_NN of_IN 3130_CD subjects_NNS from_IN the_ATI Framingham_NP (_( Mass_NP )_) Heart_NP Study_NP , Lissner_NP et_&FW al_APS calculated_VBN the_ATI coefficient_NN of_IN variation_NN (_( SD_mean_NP )_) of_IN eight_CD weights_NNS collected_VBN over_IN the_ATI first_OD 14_CD years_NNS of_IN the_ATI study_NN plus_IN recalled_VBD weight_NN at_IN age_NN 25_CD years_NNS weight_NN , slope_NN of_IN weight_NN , smoking_VBG , physical_JJ activity_NN , serum_NN cholesterol_NN level_NN , systolic_JJ blood_NN pressure_NN , and_CC glucose_NN tolerance_NN were_BED included_VBN as_IN covariates_NNS to_TO avoid_VB bias_NN created_VBN by_IN antecedent_JJ disease_NN influencing_VBG weight_NN variability_NN , only_RB end_NN points_NNS occurring_VBG 4_CD or_CC more_QL years_NNS after_IN the_ATI last_AP weight_NN were_BED included_VBN weight_NN variability_NN was_BEDZ associated_VBN with_IN total_JJ mortality_NN in_IN both_ABX men_NNS and_CC women_NNS , with_IN CHD_NP mortality_NN in_IN men_NNS , and_CC with_IN CHD_NP morbidity_NN in_IN women_NNS 122_CD Blair_NP et_&FW al_APS investigated_VBN weight_NN variability_NN in_IN 10594_CD men_NNS at_IN high_JJ risk_NN for_IN CHD_NP in_IN the_ATI Multiple_NPT Risk_NP Factor_NP Intervention_NN Trial_NP over_IN the_ATI 6_CD to_IN 7_CD years_NNS of_IN the_ATI trial_NN , six_CD to_IN seven_CD weights_NNS were_BED available_JJ for_IN subjects_NNS receiving_VBG no_ATI intervention_NN , and_CC 18_CD to_IN 21_CD weights_NNS were_BED available_JJ for_IN subjects_NNS receiving_VBG lifestyle_NN intervention_NN to_TO reduce_VB risk_NN for_IN heart_NN disease_NN intrapersonal_JJ SD_NN of_IN weight_NN was_BEDZ calculated_VBN for_IN each_DT subject_NN Morbidity_NP and_CC mortality_NN were_BED evaluated_VBN at_IN a_AT follow- up_NN 9_CD to_IN 12_CD years_NNS after_IN the_ATI trial_NN began_VBD death_NN rates_NNS per_NNU 1000_CD person_NN years_NNS of_IN follow-up_NN by_IN quartiles_NNS one_CD1 to_IN four_CD of_IN ISD_NP were_BED 6.72_NN , 6.62_NN , 8.19_CD , and_CC 9.14_CD , respectively_RB increased_JJ weight_NN fluctuation_NN was_BEDZ associated_VBN with_IN 50%_NP to_TO 60%_NP increased_JJ risk_NN for_IN all-cause_NN , cardiovascular_NN disease_NN , and_CC CHD_NP mortality_NN in_IN subjects_NNS with_IN at_RB least_RB one_CD1 complete_JJ weight_NN cycle_NN , the_ATI relative_JJ risk_NN for_IN all-cause_NN mortality_NN was_BEDZ 1.55_CD compared_VBN with_IN subjects_NNS with_IN stable_JJ weights_NNS Blair_NP and_CC Paffenbarger_NP reported_VBD that_CS weight_NN variability_NN was_BEDZ associated_VBN with_IN CHD_NP , hypertension_NN , and_CC diabetes_NN in_IN 12025_CD college_NN alumni_NN followed_VBN up_RP for_IN approximately_RB 30_CD years_NNS 123_CD two_CD smaller_JJR studies_NNS failed_VBN to_TO find_VB a_AT relationship_NN between_IN weight_NN variability_NN and_CC health_NN one_CD1 study_NN used_JJ data_NNS from_IN 846_NN men_NNS in_IN the_ATI Baltimore_NP (_( Md_NP )_) Longitudinal_NP Study_NP of_IN Aging_NP , which_WDTR had_HVD three_CD to_IN 16_CD weights_NNS measured_VBN over_IN 2_CD to_IN 27_CD years_NNS using_VBG variability_NN around_IN a_AT time-dependent_NN regression_NN slope_NN to_TO express_VB weight_NN fluctuation_NN , the_ATI authors_NNS found_VBD no_ATI relationship_NN of_IN variability_NN with_IN CHD_NP or_CC all-cause_NN mortality_NN using_VBG three_CD weights_NNS in_IN 928_NN males_NNS and_CC females_NNS in_IN the_ATI Charleston_NP (_( SC_NP )_) Heart_NP Study_NP , no_ATI association_NN was_BEDZ found_VBN between_IN variability_NN and_CC all-cause_NN mortality_NN using_VBG the_ATI coefficient_NN of_IN variation_NN as_IN the_ATI measure_NN of_IN weight_NN fluctuation_NN 124_CD WEIGHT_NPT CYCLING_NP AS_NP A_ZZ RISK_NP FACTOR_NP 125_CD relationships_NNS between_IN weight_NN variability_NN and_CC cardiovascular_NN disease_NN and_CC CHD_NP mortality_NN are_BER fairly_RB consistent_JJ , hold_VB true_JJ for_IN males_NNS and_CC females_NNS , and_CC reflect_VB relative_JJ risks_NNS for_IN high_JJ levels_NNS of_IN fluctuation_NN of_IN 1.25_CD to_IN 2.0_CD across_IN studies_NNS existing_JJ studies_NNS differ_VB in_IN their_PP$ methods_NNS ; the_ATI determinants_NNS of_IN weight_NN variability_NN are_BER not_XNOT specified_VBN and_CC may_MD not_XNOT be_BE due_JJ to_IN dieting_VBG and_CC regaining_VBG , and_CC therefore_RB more_QL research_NN is_BEZ needed_VBN before_CS weight_NN cycling_VBG itself_PPL could_MD be_BE declared_VBN a_AT distinct_JJ risk_NN factor_NN 126_CD one_CD1 problem_NN is_BEZ that_CS existing_JJ data_NNS sets_NNS were_BED not_XNOT designed_VBN to_TO examine_VB weight_NN cycling_NN recorded_JJ weights_NNS are_BER separated_VBN by_IN months_NNS or_CC even_RB years_NNS , so_QL little_JJ is_BEZ known_VBN about_IN weight_NN fluctuation_NN between_IN assessments_NNS the_ATI hope_NN that_CS periodic_JJ weights_NNS are_BER representative_NN of_IN total_JJ fluctuation_NN is_BEZ supported_VBN by_IN the_ATI similar_JJ findings_NNS from_IN the_ATI special_JJ intervention_NN and_CC usual_JJ care_NN subjects_NNS in_IN the_ATI Multiple_NPT Risk_NP Factor_NP Intervention_NN Trial_NP population_NN , where_WRB weights_NNS were_BED obtained_VBN three_CD times_NNS vs_IN once_RB per_NNU year_NN Still_NP , more_QL frequent_JJ weights_NNS will_MD be_BE needed_VBN to_TO ensure_VB that_CS total_JJ variability_NN is_BEZ captured_VBN or_CC to_TO validate_VB the_ATI use_NN of_IN less_QL frequent_JJ weights_NNS 127_CD other_AP important_JJ questions_NNS remain_VB one_CD1 is_BEZ the_ATI extent_NN to_TO which_WDTR indexes_NNS of_IN weight_NN variability_NN reflect_VB attempts_NNS to_TO lose_VB weight_NN Individuals_NNS lose_VB and_CC gain_VB weight_NN for_IN reasons_NNS other_AP than_IN dieting_VBG (_( disease_NN , mood_NN disorders_NNS , altered_JJ exercise_NN )_) because_CS the_ATI available_JJ studies_NNS did_DOD not_XNOT monitor_NN why_WRB weight_NN loss_NN occurred_VBD , it_PP3 is_BEZ not_XNOT possible_JJ to_TO attribute_VB the_ATI changes_NNS to_IN dieting_NN 128_CD two_CD studies_NNS suggest_VB that_CS weight_NN variability_NN is_BEZ highly_RB correlated_VBN with_IN self-reports_NNS of_IN dieting_NN in_IN the_ATI Gothenburg_NP study_NN , variability_NN was_BEDZ positively_RB correlated_VBN with_IN a_AT history_NN of_IN dieting_NN using_VBG data_NNS from_IN the_ATI National_NP Health_NP and_CC Nutrition_NN Examination_NN Survey_NP , Williamson_NP reported_VBD that_CS individuals_NNS who_WPR reported_VBD being_BEG on_IN a_AT diet_NN at_IN the_ATI baseline_NN assessment_NN had_HVD much_RB greater_JJR percentage_NN changes_NNS in_IN body_NN weight_NN over_IN 10_CD years_NNS future_NN studies_NNS should_MD distinguish_VB reasons_NNS for_IN weight_NN change_NN before_CS asserting_VBG that_CS dieting_VBG is_BEZ a_AT risk_NN factor_NN 129_CD another_DT pressing_VBG issue_NN involves_VBZ the_ATI methods_NNS used_VBN to_TO express_VB and_CC analyze_NN data_NNS on_IN weight_NN change_NN existing_JJ studies_NNS on_IN weight_NN fluctuation_NN and_CC health_NN have_HV used_VBN different_JJ methods_NNS wing_NN and_CC Cutter_NP et_&FW al_APS have_HV shown_VBN that_CS each_DT method_NN creates_VBZ a_AT different_JJ picture_NN of_IN weight_NN variability_NN one_CD1 method_NN might_MD be_BE sensitive_JJ to_IN the_ATI number_NN of_IN times_NNS an_AT individual_JJ changes_NNS weight_NN , while_CS another_DT is_BEZ more_QL influenced_VBN by_IN the_ATI magnitude_NN or_CC direction_NN of_IN the_ATI changes_NNS an_AT individual_JJ might_MD lose_VB 22.5_VB kg_NNU and_CC then_RN regain_VB , while_CS another_DT might_MD lose_VB only_RB 2.25_CD kg_NNU and_CC regain_VB , but_CC do_DO so_QL 10_CD times_NNS studies_NNS to_TO date_VB have_HV not_XNOT separated_VBN different_JJ patterns_NNS of_IN variability_NN 130_CD MECHANISMS_NPT LINKING_NPT WEIGHT_NP VARIABILITY_NP (_( OR_NP CYCLING_NP )_) TO_NP HEALTH_NP : CARDIOVASCULAR_NPT RISK_NP FACTORS_NP 131_CD two_CD studies_NNS using_VBG retrospective_JJ reports_NNS (_( one_CD1 by_IN Everson_NP and_CC Matthews_NP , unpublished_JJ data_NNS )_) and_CC two_CD using_VBG recorded_JJ weights_NNS found_VBD no_ATI associations_NNS between_IN cycling_VBG history_NN and_CC blood_NN pressure_NN another_DT study_NN found_VBN that_CS obese_JJ patients_NNS with_IN a_AT history_NN of_IN weight_NN cycling_VBG had_HVD smaller_JJR reductions_NNS in_IN systolic_JJ and_CC diastolic_JJ blood_NN pressure_NN in_IN response_NN to_IN a_AT very-low-calorie_NN diet_NN than_IN did_DOD noncycling_VBG obese_JJ patients_NNS one_CD1 study_NN with_IN rats_NNS found_VBN sustained_JJ hypertension_NN in_IN cycled_VBD animals_NNS ; two_CD studies_NNS did_DOD not_XNOT , but_CC one_CD1 of_IN these_DTS found_VBN that_WPR cycled_VBD animals_NNS were_BED more_QL responsive_JJ to_IN the_ATI pressor_JJ effects_NNS of_IN an_AT alpha- adrenergic_JJ agonist_NN .=20_CD 132_CD data_NNS at_IN present_NN do_DO not_XNOT allow_VB us_PP1OS to_TO determine_VB whether_CS there_EX is_BEZ a_AT clear_JJ link_NN between_IN weight_NN cycling_VBG and_CC blood_NN pressure_NN the_ATI finding_NN that_CS cycled_VBD animals_NNS may_MD show_VB elevated_VBD blood_NN pressure_NN when_WRB challenged_VBN should_MD be_BE addressed_VBN in_IN humans_NNS with_IN studies_NNS examining_VBG challenges_VBZ such_ABL as_CS increased_VBN dietary_JJ sodium_NN , stress_NN , and_CC weight_NN change_NN 133_CD relatively_RB little_JJ work_NN has_HVZ been_BEN done_VBN on_IN cholesterol_NN , but_CC evidence_NN thus_RB far_RB suggests_VBZ no_ATI link_NN between_IN weight_NN fluctuation_NN and_CC levels_NNS of_IN serum_NN cholesterol_NN several_AP studies_NNS have_HV found_VBN no_ATI relationship_NN between_IN weight_NN cycling_VBG and_CC fasting_NN glucose_NN values_NNS or_CC between_IN metabolic_JJ control_NN and_CC need_NN for_IN hypoglycemic_JJ medication_NN in_IN diabetics_NNS in_IN contrast_NN , a_AT large_JJ longitudinal_JJ study_NN of_IN aging_VBG found_VBN that_CS weight_NN variability_NN over_IN time_NN was_BEDZ associated_VBN with_IN greater_JJR decreases_VBZ in_IN glucose_NN tolerance_NN in_IN another_DT longitudinal_JJ study_NN with_IN 2000_CD adults_NNS , weight_NN fluctuation_NN between_IN the_ATI ages_NNS of_IN 40_CD and_CC 60_CD years_NNS was_BEDZ associated_VBN with_IN a_AT significantly_RB increased_JJ rate_NN of_IN diabetes_NN (_( relative_JJ risk_NN , 1.7_CD )_) 134_CD BODY_NPT COMPOSITION_NPT AND_NPT FAT_NP DISTRIBUTION_NP 135_CD both_ABX lean_JJ and_CC fat_JJ tissue_NN are_BER lost_VBN when_WRB an_AT individual_JJ loses_VBZ weight_NN , but_CC little_JJ is_BEZ known_VBN about_IN weight_NN regain_VB if_CS more_AP body_NN fat_NN is_BEZ regained_VBN than_IN is_BEZ lost_VBN originally_RB , successive_JJ cycles_NNS of_IN loss_NN and_CC regain_VB would_MD lead_VB to_IN altered_JJ body_NN composition_NN with_IN one_CD1 exception_NN , studies_NNS have_HV shown_VBN no_ATI differences_NNS in_IN body_NN composition_NN in_IN individuals_NNS considered_JJ cyclers_NNS and_CC noncyclers_NNS 136_CD studies_NNS on_IN body_NN fat_NN distribution_NN create_VB a_AT different_JJ picture_NN Calculating_NP the_ATI waist-hip_NN ratio_NN (_( WHR_NP )_) is_BEZ the_ATI most_QL common_JJ method_NN of_IN evaluating_VBG fat_NN distribution_NN , with_IN a_AT higher_JJR ratio_NN indicative_NN of_IN greater_JJR risk_NN of_IN CHD_NP while_CS there_EX are_BER some_DTI reports_NNS of_IN no_ATI differences_NNS in_IN WHR_NP between_IN individuals_NNS who_WPR were_BED or_CC were_BED not_XNOT classified_VBN as_IN weight_NN cyclers_NNS , based_VBN on_IN reports_NNS of_IN past_NN dieting_VBG , other_AP studies_NNS with_IN a_AT better_JJR measure_NN of_IN cycling_VBG suggest_VB the_ATI possibility_NN of_IN fat_NN redistribution.=20_CD 137_CD Rodin_NP et_&FW al_APS studied_VBN premenopausal_JJ women_NNS and_CC found_VBN that_CS WHR_NP was_BEDZ associated_VBN with_IN a_AT higher_JJR degree_NN of_IN weight_NN cycling_VBG , that_CS a_AT significant_JJ association_NN of_IN WHR_NP with_IN body_NN mass_NN index_NN was_BEDZ true_JJ only_RB of_IN weight_NN cyclers_NNS , and_CC that_CS the_ATI number_NN of_IN pregnancies_NNS was_BEDZ associated_VBN with_IN a_AT higher_JJR WHR_NP a_AT longitudinal_JJ study_NN of_IN middle-aged_JJ individuals_NNS found_VBN that_CS cycling_VBG was_BEDZ associated_VBN with_IN an_AT increased_VBN WHR_NP in_IN women_NNS but_CC not_XNOT in_IN men_NNS (_( Everson_NP and_CC Matthews_NP , unpublished_JJ data_NNS )_) in_IN a_AT longitudinal_JJ study_NN of_IN aging_VBG in_IN men_NNS , weight_NN fluctuation_NN was_BEDZ associated_VBN with_IN increased_JJ ratio_NN of_IN subscapular_NN to_IN triceps_NNS skinfolds_NNS but_CC not_XNOT with_IN WHR_NP 138_CD PREFERENCE_NPT FOR_NPT DIETARY_NP FAT_NP 139_CD several_AP studies_NNS with_IN animals_NNS found_VBN that_CS rats_NNS cycled_VBD through_IN bouts_NNS of_IN loss_NN and_CC regain_VB increased_VBN the_ATI percent_NNU of_IN calorie_NN intake_NN from_IN dietary_JJ fat_NN when_WRB given_VBN free_JJ choice_NN of_IN fat_NN , carbohydrate_NN , and_CC protein_NN little_JJ work_NN has_HVZ been_BEN done_VBN with_IN humans_NNS Jeffery_NP et_&FW al_APS found_VBN no_ATI relationship_NN of_IN fat_NN intake_NN to_IN cycling_VBG history_NN in_IN obese_JJ men_NNS and_CC women_NNS prior_RB to_IN a_AT weight_NN loss_NN program_NN two_CD studies_NNS by_IN Drewnowski_NP and_CC colleagues_NNS , however_RB , found_VBD that_CS obese_JJ weight_NN cyclers_NNS had_HVD elevated_VBD preferences_NNS for_IN both_ABX sugar_NN and_CC fat_NN compared_VBN with_IN obese_JJ individuals_NNS with_IN stable_JJ weight_NN 140_CD PERIODS_NPT OF_NP VULNERABILITY_NP 141_CD it_PP3 is_BEZ possible_JJ that_CS weight_NN cycling_VBG during_IN critical_JJ periods_NNS could_MD lead_VB to_IN increased_JJ risk_NN or_CC , similarly_RB , that_CS the_ATI vulnerability_NN created_VBN by_IN a_AT history_NN of_IN weight_NN cycling_VBG could_MD be_BE expressed_VBN during_IN critical_JJ periods_NNS For_NP example_NN , Keys_NNS et_&FW al_APS speculated_VBD that_CS irreversible_JJ atherogenesis_NN occurs_VBZ during_IN bouts_NNS of_IN weight_NN gain_NN and_CC that_CS this_DT is_BEZ not_XNOT offset_VB by_IN benefits_NNS incurred_VBN during_IN weight_NN loss_NN if_CS true_JJ , weight_NN cycling_VBG might_MD increase_VB risk_NN because_CS of_IN increased_JJ exposure_NN to_IN periods_NNS of_IN weight_NN gain_NN This_NN is_BEZ speculative_JJ , however_RB , because_CS the_ATI issue_NN has_HVZ not_XNOT been_BEN studied_VBN 142_CD pregnancy_NN may_MD represent_VB a_AT period_NN of_IN vulnerability_NN Rossner_NP found_VBD in_IN a_AT sample_NN of_IN severely_RB obese_JJ women_NNS that_CS pregnancy-related_JJ weight_NN gain_NN contributed_VBN significantly_RB to_IN their_PP$ weight_NN problems_NNS the_ATI findings_NNS of_IN Rodin_NP at_IN el_&FW that_CS both_ABX weight_NN cycling_VBG and_CC number_NN of_IN pregnancies_NNS are_BER related_VBN to_IN WHR_NP suggest_VB that_CS pregnancy_NN may_MD be_BE a_AT form_NN of_IN weight_NN cycling_VBG that_DT could_MD affect_VB risk_VB through_IN both_ABX weight_NN and_CC body_NN fat_NN distribution_NN 143_CD CONCLUSIONS_NP 144_CD the_ATI study_NN of_IN weight_NN cycling_VBG has_HVZ matured_VBN to_IN the_ATI point_NN where_WRB numerous_JJ reports_NNS exist_VB using_VBG human_JJ and_CC animal_JJ models_NNS , and_CC direct_JJ tests_NNS have_HV been_BEN made_VBN of_IN hypotheses_NNS regarding_IN weight_NN cycling_VBG , health_NN , and_CC metabolism_NN Given_NP that_CS work_NN on_IN the_ATI topic_NN began_VBD in_IN the_ATI middle_JJB 1980s_CD , the_ATI substantial_JJ literature_NN that_CS now_RN exists_VBZ is_BEZ testimony_NN to_IN the_ATI importance_NN of_IN the_ATI topic_NN and_CC the_ATI broad_JJ interest_NN it_PP3 has_HVZ generated_VBN despite_IN this_DT interest_NN , little_JJ is_BEZ known_VBN about_IN the_ATI natural_JJ history_NN of_IN weight_NN variability_NN in_IN the_ATI general_JJ population_NN 145_CD the_ATI hypothesis_NN that_CS the_ATI body_NN adapts_VBZ to_IN cycles_NNS of_IN loss_NN and_CC regain_VB by_IN becoming_VBG metabolically_RB efficient_JJ has_HVZ been_BEN found_VBN in_IN some_DTI , but_CC not_XNOT most_QL , studies_NNS it_PP3 is_BEZ possible_JJ that_CS metabolism_NN is_BEZ affected_VBN by_IN cycling_VBG under_IN certain_JJ dietary_JJ conditions_NNS or_CC in_IN susceptible_JJ individuals_NNS 146_CD weight_NN cycling_VBG appears_VBZ linked_VBN to_IN increased_JJ psychopathology_NN , lower_JJR life_NN satisfaction_NN , more_QL disturbed_VBN eating_VBG in_IN general_JJ , and_CC perhaps_RB increased_JJ risk_NN for_IN binge_NN eating_NN prospective_JJ studies_NNS will_MD be_BE needed_VBN to_TO determine_VB whether_CS cycling_VBG causes_NNS these_DTS problems_NNS , whether_CS these_DTS problems_NNS lead_NN to_IN dieting_VBG and_CC regain_VB , or_CC whether_CS cycling_VBG and_CC psychological_JJ problems_NNS are_BER correlated_VBN but_CC not_XNOT related_VBN in_IN a_AT causal_JJ fashion_NN 147_CD the_ATI bulk_NN of_IN epidemiologic_JJ research_NN shows_VBZ an_AT association_NN of_IN weight_NN variability_NN with_IN important_JJ health_NN outcomes_NNS mortality_NN from_IN all_ABN causes_NNS and_CC from_IN CHD_NP is_BEZ the_ATI most_QL consistent_JJ finding_NN ; morbidity_NN from_IN CHD_NP has_HVZ also_RB been_BEN reported_VBN the_ATI relative_JJ risk_NN of_IN increased_JJ weight_NN variability_NN is_BEZ in_IN the_ATI range_NN of_IN 1.25_CD to_IN 2.00_CD , which_WDTR is_BEZ similar_JJ to_IN the_ATI risk_NN attributed_VBN to_TO obesity_NN and_CC to_TO several_AP of_IN the_ATI cardiovascular_NN risk_NN factors_NNS determining_VBG whether_CS weight_NN variability_NN is_BEZ attributable_JJ to_IN dieting_VBG and_CC regaining_VBG is_BEZ an_AT important_JJ question_NN at_IN present_NN 148_CD there_EX are_BER several_AP possible_JJ mechanisms_NNS that_CS link_NN weight_NN cycling_VBG to_TO health_NN the_ATI obvious_JJ candidates_NNS are_BER the_ATI cardiovascular_NN risk_NN factors_NNS such_ABL as_IN blood_NN pressure_NN and_CC cholesterol_NN , which_WDTR are_BER known_VBN to_TO vary_VB as_IN weight_NN changes_NNS the_ATI evidence_NN on_IN weight_NN variability_NN and_CC cardiovascular_NN risk_NN factors_NNS is_BEZ mixed_JJ , with_IN both_ABX blood_NN pressure_NN and_CC blood_NN glucose_NN control_NN being_BEG related_VBN in_IN some_DTI studies_NNS but_CC not_XNOT others_APS since_IN hypertension_NN and_CC diabetes_NN are_BER associated_VBN with_IN excess_JJ weight_NN , because_CS individuals_NNS so_QL afflicted_VBN are_BER likely_JJ to_TO diet_NN and_CC because_CS relapse_NN rates_NNS with_IN dieting_VBG are_BER high_JJ , research_NN on_IN this_DT topic_NN is_BEZ a_AT clear_JJ priority_NN 149_CD there_EX is_BEZ suggestive_JJ evidence_NN from_IN both_ABX humans_NNS and_CC animals_NNS that_CS weight_NN cycling_VBG may_MD increase_VB preference_NN for_IN dietary_JJ fat_NN , and_CC some_DTI , but_CC not_XNOT all_ABN , studies_NNS suggest_VB the_ATI possibility_NN that_CS weight_NN cycling_VBG alters_VBZ body_NN fat_NN distribution_NN other_AP possible_JJ mechanisms_NNS , such_IN as_IN a_AT stress_NN response_NN to_IN dieting_VBG and_CC an_AT effect_NN of_IN weight_NN cycling_VBG on_IN immune_JJ function_NN , have_HV not_XNOT been_BEN studied_VBN 150_CD with_IN the_ATI caution_NN that_CS little_JJ is_BEZ known_VBN about_IN periods_NNS of_IN vulnerability_NN or_CC which_WDTR individuals_NNS may_MD be_BE at_IN greatest_JJT risk_NN for_IN the_ATI untoward_JJ effects_NNS of_IN weight_NN cycling_VBG , we_PP1AS believe_VB the_ATI issue_NN deserves_VBZ direct_JJ study_NN when_WRB an_AT individual_NN is_BEZ hypertensive_JJ , hypercholesterolemic_JJ , or_CC diabetic_JJ ; when_WRB CHD_NP is_BEZ present_JJ ; or_CC when_WRB other_AP medical_JJ problems_NNS exist_VB where_WRB weight_NN and_CC diet_NN are_BER implicated_VBN , it_PP3 is_BEZ important_JJ to_TO know_VB the_ATI degree_NN to_TO which_WDTR weight_NN cycling_VBG has_HVZ negative_JJ effects_NNS this_DT is_BEZ an_AT area_NN in_IN need_NN of_IN more_QL research_NN 151_CD some_DTI questions_NNS in_IN this_DT field_NN have_HV definitive_JJ answers_NNS , but_CC most_QL do_DO not_XNOT this_DT is_BEZ due_NN in_IN part_NN to_IN differences_NNS across_IN studies_NNS in_IN the_ATI age_NN , sex_NN , and_CC weight_NN of_IN the_ATI subjects_NNS , the_ATI use_NN of_IN recorded_JJ weights_NNS vs_IN self-reported_JJ weights_NNS , the_ATI frequency_NN and_CC time_NN span_NN of_IN recorded_JJ weights_NNS , or_CC the_ATI period_NN over_IN which_WDTR individuals_NNS estimate_NN their_PP$ weight_NN variability_NN , among_IN other_AP issues_NNS greater_JJR consistency_NN in_IN methods_NNS would_MD be_BE a_AT valuable_JJ change_NN in_IN this_DT field_NN 152_CD given_VBN the_ATI number_NN of_IN people_NNS losing_VBG and_CC regaining_VBG weight_NN , and_CC the_ATI links_NNS between_IN weight_NN variability_NN , morbidity_NN , and_CC mortality_NN , weight_NN cycling_VBG should_MD be_BE a_AT research_NN priority_NN the_ATI field_NN is_BEZ sufficiently_RB new_JJ , and_CC existing_JJ results_NNS sufficiently_RB mixed_JJ , that_CS it_PP3 is_BEZ probably_RB premature_JJ to_TO urge_VB all_ABN patients_NNS to_TO stop_VB dieting_NN the_ATI prudent_JJ stance_NN is_BEZ still_RB to_TO recommend_VB that_CS overweight_NN individuals_NNS lose_VB weight_NN , but_CC what_WDT is_BEZ known_VBN about_IN weight_NN cycling_VBG makes_VBZ the_ATI issue_NN of_IN maintenance_NN even_RB more_QL consequential_JJ studies_NNS to_TO identify_VB the_ATI determinants_NNS and_CC process_NN of_IN maintenance_NN and_CC to_TO develop_VB approaches_NNS for_IN enhancing_VBG maintenance_NN are_BER vital_JJ

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