Interrelationship of Pulp and Systemic Disease

Herpesvirus infections

Herpesviruses are ubiquitous pathogens that have the ability to establish latency in the infected host.25 There are eight identified human herpesviruses: her­ pes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6, human herpesvirus 7, and human herpesvirus 8.26 Pri­

Fig 20-1 Evaluation of the presence of HIV in human dental pulp using in situ mary infections are often asymptomatic and typically hybridization histochemistry. Dental pulp tissue from an HIV-positive patient was occur during childhood. fixed, sectioned, and incubated with one of two biotinylated oligonucleotide The pathophysiology of HSV-1 viral infection is probes complementary to a region of messenger RNA specific to HIV. Sections were incubated, washed, and developed. A positive signal is visible as a dark well established. During the primary infection, the spot in the figure. (Reprinted from Glick et al'5 with permission.) virus is transported via retrograde axonal transport to regional sensory ganglia (typically the trigeminal ganglia), where it establishes latency.27 During the latent phase, the virus exists in a quiescent immuno­ Several oral lesions have been shown to occur logically shielded state. However, shedding of HSV in association with HIV-induced immunosuppres­ has been demonstrated in the saliva of asympto­ sion.9-11 The most strongly associated lesions in matic healthy adults. Although the clinical relevance adult patients are mucosa! and include candidia­ of this finding remains to be determined, it reinforces sis (erythematous and pseudomembranous), hairy the need for strict adherence to infection-control leukoplakia, Kaposi sarcoma, non-Hodgkin lym­ procedures in the dental office to minimize the risk phoma, and periodontal disease (linear gingival of occupational exposure.26 erythema, necrotizing ulcerative gingivitis, and nec­ Clinically apparent recurrent infections are esti­ rotizing ulcerative periodontitis).12 For pediatric pa­ mated to occur in 15% to 40% of individuals har­ tients, the most strongly associated lesions are can­ boring latent HSV-1.28 Well-documented triggers didiasis (erythematous, pseudomembranous, and associated with HSV recurrence include sunlight, angular cheilitis), herpes simplex infection, linear trauma, menstruation, fever, immunosuppression, gingival erythema, parotid enlargement, and recur­ decompression of the trigeminal nerve, and irritation rent aphthous stomatitis (minor, major, and herpeti­ by dental instruments. Three clinical forms of recur­ form). The risk of developing these lesions is inverse­ rence are recognized: (1) recurrent herpes labialis, ly related to the CD4+ counts. Thus, the presence of (2) intraoral recurrence, and (3) recurrence mimicking oral lesions may serve as good clinical markers to a primary infection. lntraoral recurrent lesions typi­ signal a loss in therapeutic efficacy of ART.13·14 cally present as a focal clustering of vesicles affect­ Although HIV has been identified in dental ing the keratinized mucosa (gingiva or hard palate). pulp15 and in periradicular lesions of pulpal origin,16 The vesicles quickly rupture and coalesce to form its direct contribution to pulpal disease remains the characteristic shallow erosion. The pain may be unknown (Fig 20-1 ). Studies to assess the caries so severe as to interfere with eating and speaking. risk in HIV-infected patients have yielded conflict­ HSV-1 infection has been proposed as a potential ing results, and it is likely that numerous factors, etiologic factor of pulpal necrosis and should be such as the patient's immune status, dietary habits, considered in the differential diagnosis of odontal­ medication profile, and salivary status, all contribute gia (see chapter 19). However, the overall impact of to caries risk.17-19 The impaired immune response HSV infection on pulpal disease remains unknown. observed in patients with low CD4+ counts does not In one study assessing 31 patients with an apical appear to be associated with an increase in endo­ abscess or cellulitis of pulpal origin, HSV was detect­ dontic complications after root canal treatment,20·21 ed (using polymerase chain reaction) in only 1 of 31 and three recent studies have confirmed that HIV­ specimens.29 In contrast, another study revealed the infected patients respond well to and benefit from presence of HSV in 15 of 50 necrotic pulps assessed indicated root canal therapy.22-24 by polymerase chain reaction.30

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Fig 20-2 Periradicular radiographs of a patient 5 months after a herpes zoster outbreak. Note the periradicular radiolucencies of the maxillary left canine (a and b) and first and second premolars (c and d). (Reprinted from Goon and Jacobsen38 with permission.)

d

The classic clinical presentation of a primary tributes to pulpal disease is unknown, with only a VZV infection is termed chickenpox. Similar to HSV, few case reports noted in the literature.38·39 Further VZV establishes latency in neuronal ganglia (cranial confounding the issue, prodromal zoster pain not nerve, dorsal root, and autonomic ganglia).31 Clinical directly involving the dental pulp may mimic pain of VZV recurrence is called zoster (or shingles). Fac­ pulpal origin.40 tors that predispose an individual to zoster include Recent reports have indicated that both CMV conditions of immunocompromise (eg, lymphoma, and EBV may play an important role in the etio­ Hodgkin disease, leukemia, or AIDS) and advanced pathogenesis of periapical pathoses.41-44 CMV estab­ age.32 Zoster usually manifests a prodrome of mild lishes latency in monocytes and T lymphocytes, and to moderate tingling, itching, burning, boring pain, EBV establishes latency in B lymphocytes. Both virus­ or numbness affecting the affected dermatome.33·34 es may upregulate the production of numerous pro­ Within 3 days, the characteristic erythematous papu­ inflammatory cytokines such as interleukin 113, inter­ lar rash develops, which quickly progresses to ves­ leukin 6, and tumor necrosis factor a. These findings icles and pustules. Constitutional signs and symp­ have led some to postulate that both CMV and EBV toms of fever, chills, malaise, and headache may also may contribute to the pathogenesis of periradicu­ be present. lar pathosis, either as a result of direct infection or Resolution typically occurs within 3 weeks and through virus-induced immune system alteration. may lead to altered pigmentation or scarring of the affected area. The most common complication of Infection during fetal and childhood zoster is postherpetic neuralgia, a condition charac­ terized by pain or hyperesthesia that persists after development clinical resolution has occurred. An estimated 50% of patients over the age of 60 years who experience Maternal rubella (German measles) zoster are at risk for postherpetic neuralgia. Maternal infection during pregnancy may directly An estimated 13% of zoster cases involve the affect the developing fetus, leading to changes that head and neck.34 Zoster of the maxillary or man­ vary from inconsequential to severe enough to result dibular branch may affect dentoalveolar structures in fetal death.45 Fortunately, it appears that the most such as the pulp and periodontal ligament, lead­ commonly encountered maternal infections cause ing to pulpal death, tooth exfoliation, internal root no significant harm to the developing fetus. The resorption, tooth neuralgia, and osteonecrosis34-37 outcome of maternal infection depends largely on (Fig 20-2). The degree to which zoster directly con- the infectious agent involved, the maternal immune

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Fig 20-3 Patient with rubella. Note the discoloration of the Fig 20-4 Enamel hypoplasia. Note the linear defect in maxillary anterior teeth. enamel formation that may occur from any of the exan­ thematous fevers (eg, rubella, measles, or chicken- pox). The position of the linear defect depends on the age of morphodif­ ferentiation of the different permanent teeth at the time of the infection.

response, and the stage of fetal development when possible to crudely estimate the age at which the the infection occurred. Commonly reported orofa­ infectious process occurred by the location of the cial defects attributed to maternal infection usually linear defect on the enamel surface of the tooth. encompass structural defects such as cleft lip and palate and various tooth malformations. One of the more commonly cited examples of a Genetic and Developmental maternal infection that adversely affects tooth devel­ opment is rubella (German measles).46-49 Potential Disorders effects on the developing teeth vary from none at all to significant changes in terms of size, shape, and color (Fig 20-3). In light of current vaccination Taurodontism protocols, maternal rubella is now a rarely observed phenomenon. Taurodontism is a developmental disturbance of teeth that results in abnormally large pulp cham­ Childhood infections bers at the expense of root length.53-55 The cause Paralleling the effects of maternal infection on the is unknown but likely involves aberration or failure fetal tooth germ, infectious processes that occur of epithelial root sheath differentiation.54 Both the during childhood may adversely affect tooth devel­ primary and permanent dentitions may be affected. opment. Once again, the high prevalence of child­ The overall prevalence of taurodontism is estimated hood illnesses weighed against the actual low occur­ to be about 3%. Most cases occur as an isolated rence of tooth defects indicates that the overall trait, but the presence of taurodontism in associa­ risk is low. The actual etiopathologic mechanisms tion with several syndromes and diseases has been leading to tooth germ damage are poorly under­ reported56-76 (Box 20-1 ). stood and may involve direct injury to the develop­ Taurodontism may affect one or more teeth; ing tooth by the infectious agent and/or metabolic most cases involve molars and, to a lesser extent, changes (eg, fever or altered calcium metabolism) premolars. The radiographic appearance is char­ associated with the infection50·51 (Fig 20-4). acteristic, revealing elongated pulp chambers and Clinical findings include quantitative defects (eg, shortened roots.65·77-79 The altered pulp chamber pits, grooves, or partial or complete loss of enamel) and canal morphology of the taurodont may com­ and qualitative defects (eg, the presence of white plicate the provision of endodontic therapy because or discolored enamel with a smooth surface and identification of the canal may be compromised and normal thickness).52 Because enamel is continuously affected teeth are more prone to manipulative frac­ elaborated during tooth development, it may be ture77·78 (Fig 20-5).

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Fig 20-5 Preop­ Synd omes a d conditions � � erative radiograph of a Box 20_1 _ I associated with taurodont1sm taurodontic mandibu­ lar right second molar. Aarskog syndrome57 Note the relatively Apert syndrome58 large pulp chamber CHARGE syndrome59 and shortened roots Down syndrome60 with distal caries. Ellis-van Creveld syndrome (chondroectodermal (Reprinted from Hayas­ dysplasia)61 hi77 with permission.) Gorlin-Goltz syndrome (focal dermal hypoplasia)62 Glycogen storage disease type 11163 Kabuki syndrome58 Klinefelter (XXY) syndromess.54.5s LADD syndrome66 Lowe syndrome67 McCune-Albright syndrome58 Menz microphthalmia syndromess Mohr syndromess Prader-Labhart-Willi syndrome68 Seckel syndrome69 Smith-Magenis syndrome 70 Thalassemia major 71 Tricho-dento-osseous syndrome72 Williams syndromess Wolf-Hirschhorn syndrome73.74 Triple-X syndrome (XXX); XXXX syndromessJs X-linked hypophosphatemic rickets (XLH)76

Fig 20-6 Clinical presentation (a) and radiograph (b) of a dens in dente. (Courtesy of Dr Yoav Shiloah, San Antonio, TX.)

Dens in dente (dens invaginatus) and affected by dens in dente are classified into three types: Type 1 is an enamel-lined, relatively minor dens evaginatus defect; type 2 is an enamel-lined blind sac that invades the root; and type 3 invades the root and There are several examples of developmental dis­ has a secondary foramen. The prevalence has been orders of morphodifferentiation of teeth. Dens in reported to be between 0.04% and 10.0%.80 dente (dens invaginatus) and dens evaginatus are There are several points of clinical significance in two of the more common disorders of morphodiffer­ the dens in dente tooth. First, there is an increased entiation that have pulpal implications. The reader risk of bacteria-induced pulpal necrosis, and prophy­ is encouraged to review oral pathology textbooks lactic placement of sealants may be indicated.80-84 for a complete discussion of other disorders of mor­ Second, nonsurgical root canal treatment is difficult phodifferentiation (eg, gemination, fusion, concres­ because the anatomical complexity makes both tis­ cence, and dilacerations)_:>-s sue debridement and complete obturation extreme­ Dens in dente is a developmental disorder in ly challenging. Suggested treatment approaches which a portion of the crown undergoes an invagina­ include the use of ultrasonic files, calcium hydroxide tion prior to calcification. This is thought to involve dressings, and obturation with a thermoplasticized an infolding of the dental papilla during develop­ gutta-percha technique. ment and may occur because of altered tissue pres­ Dens evaginatus is a localized outgrowth of sures, trauma, infection, or localized discrepancies in ameloblasts that appears clinically as a globule of cellular hyperplasia (eg, apically directed prolifera­ enamel and may be reminiscent of an accessory tion of ameloblasts). Dens in dente is characterized cusp. The most commonly affected teeth are pre­ by a deep infolding of enamel and dentin and often molars or molars. The prevalence is higher among involves maxillary lateral incisors80-83 (Fig 20-6). Teeth Asians (about 15%) than among Caucasians.5 The

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Fig 20-7 Clinical and radiographic views of dens evagi­ natus in an 11-year-old boy. (a) Clinical view of external anatomy. (b) Preoperative radiograph. Note the extensive periradicular radiolucency, complex root canal systems, and immature apex. The sinus tract is traced with a gutta-percha cone. (c) Postoperative view illustrating the use of Collatape (Sulzer Dental) and mineral trioxide aggregate (MTA) as an internal barrier and final obturation with thermoplasticized gutta-percha. (Courtesy of Dr Neil Begley, Sequim, WA, and Dr William Schindler, San Antonio, TX.)

Fig 20-8 Type II DI in an 18-year-old man. Note the Fig 20-9 Periradicular radiographs of a patient with type I DI. (a) Preoperative radiograph. Note yellow-brown shade of the anterior teeth and the blue-gray the reduced size of the pulp chamber, canal orifices, and canal systems in the first premolar as well as shade of the posterior teeth. (Reprinted from Huber90 with the presence of overextended gutta-percha and apical periodontitis. (b) One-year follow-up after root­ permission.) end resection and MT A retrofill of the first premolar.

outgrowth is postulated to arise from proliferation common dental genetic disease in humans, affecting and elongation of a portion of the inner enamel epi­ an estimated 1 in 6,000 to 8,000 people.87·92 thelium and associated dental papilla into the stel­ The clinical findings of all types of DI are similar late reticulum of the developing enamel organ.85·86 and characteristic. The teeth manifest an amber­ The resultant extension contains enamel, dentin, brown to blue-gray hue, an opalescent sheen, crack­ and pulp. The clinical significance of this disorder is ing or loss of enamel, and attrition8B-91·98 (Fig 20-8). that the relatively narrow shelf of enamel, once pen­ Radiographic findings for DI types I and II include a etrated, often results in pulpal exposure (Fig 20-7). bulbous crown structure, cervical constriction, short roots, and obliteration of the pulp chamber (Fig 20-9). For DI type Ill, the radiographic features are similar, Dentinogenesis imperfecta except that the pulp chambers appear normal or enlarged (shell teeth), and periradicular radiolucen­ Dentinogenesis imperfecta (DI) can occur either as cies are frequently present. The notable clinical an isolated finding or in association with osteogene­ similarities between DI types II and Ill, along with a sis imperfecta.87-93 Three types of DI are recognized. similar condition called dentin dysplasia type II, has DI type I is associated with osteogenesis imperfecta prompted some to speculate that these disorders and likely represents the dental manifestation of the represent phenotypic variations of a single disor­ underlying type I collagen defect. DI types II and Ill der.91·94 Both the primary and permanent dentitions are attributed to mutations affecting the dentin sia­ may be affected. lophosphoprotein (OSPP') gene.87·92·94 DSPP encodes The altered tooth structure associated with DI may two tooth matrix proteins (dentin sialoprotein and compromise the success of endodontic therapy.99 dentin phosphoprotein) that are involved with den­ Pulpal obliteration may compromise access, canal tinogenesis.92·%-97 Recent studies have demonstrated identification, and chemomechanical debridement. that DI types II and Ill occur as a consequence of The presence of extensive shelling may increase the altered dentin sialoprotein and phosphoprotein pro­ risk of spontaneous or manipulative enamel frac­ duction.89·91·96 DI type II is considered to be the most ture. The altered, and at times difficult to identify,

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II ftjtjtjfJ•lmProven genes for amelogenesis imperfecta* Gene Inheritance pattern Phenotypic findings

Amelogenin (AMELXJ X-linked Distinctive vertical banding pattern on enamel of affected females

Enamelin (ENAM) Autosomal dominant Hypoplastic (thin) enamel Mild pitting Horizontal lines in the affected enamel. especially in the cervical third

Distal-less homeobox Autosomal dominant Enamel hypoplasia 3 (OLX3)t Taurodontism

Enamelysin (MMP20) Autosomal recessive Pigmented agar-brown discoloration Rough, mottled enamel Enamel fracturing Decreased radiopacity of enamel

Kallikrein 4 (KLK4) Autosomal recessive Pigmented yellow-brown discoloration Hot/cold sensitivity Chewing sensitivity Enamel fracturing Decreased radiopacity of enamel

*Data from Ng and Messer. 101 'Phenotype considered a variation of the trichodento-osseous syndrome.

root canals may compromise the success of surgical calcifications (14%) was significantly greater than that endodontic treatment. observed in controls.107 The presence of pulp calci­ fication was highly associated with the autosomal­ recessive hypoplastic form of Al. Amelogenesis imperfecta Although the patient with Al may present sig­ nificant restorative and esthetic challenges for the Amelogenesis imperfecta (Al) comprises a hetero­ dental practitioner, there is no Al-specific reason to genous group of heritable developmental disorders withhold indicated endodontic therapy. that affect both the primary and permanent denti­ tions in the absence of a generalized syndrome.100-105 Al is estimated to occur in 1:14,000 patients in the Osteoclastic diseases United States, and autosomal-dominant, autosomal­ recessive, and X-linked patterns of inheritance have Osteoclasts, which are essential for normal tooth been described.102 To date, four confirmed genes eruption, are highly specialized cells derived from for Al have been described, but others remain to hematopoietic cell precursors in the bone mar­ be identified and mapped101 (Table 20-1). A univer­ row and peripheral blood.10a-112 Osteoclast forma­ sally accepted nosology to describe the phenotypic tion requires the presence of two essential factors diversity of Al does not exist, but most cases are found in bone marrow stromal cells and osteoblasts: clinically described as either hypoplastic, hypocalci­ macrophage colony-stimulating factor and receptor fied, or hypomatured.101·102·106 activator of nuclear factor KB ligand (RANKL).109·113·114 In addition to the universal enamel impairment Binding of RANKL with the osteoclastic recep­ observed in Al, other anomalies, such as delayed or tor activator of nuclear factor KB (RANK) leads to failed eruption, crown resorption, and pulp calcifica­ increased nuclear factor KB (NFKB) signaling and tion, have been reported.107 However, the extreme upregulation of genes required for osteoclast differ­ phenotypic diversity observed in Al compromises entiation and activity. Another defined modulator in comparative studies, of which there are few. In one the RANK/RANKL system is osteoprotegerin (OPG), study of 22 patients from nine unrelated families which is a soluble decoy receptor that competes with various forms of Al, the presence of crown with RANK for the RANKL binding site. resorption (41%), delayed eruption (27%), and pulp

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It appears that most processes affecting bone nerve impingement, the disease may adversely alter resorption and tooth eruption act through mod­ the bone density, mass, and structure of the auditory ulation of the balance of RANKL and OPG108-112 complex to contribute to hearing compromise. for RANK. Disease states that result in reduced Numerous dental abnormalities, such as malocclu­ osteoclastic activity (eg, osteopetrosis, cleidocranial sion, hypercementosis, tooth mobility, root resorp­ dysplasia, and pyknodysostosis) commonly exhibit tion, pulp calcification, osteomyelitis, poorly fitting phenotypic delay or failure of tooth eruption, while prostheses, and excessive postsurgical bleeding, disease states that result in increased osteoclastic have been associated with PDB.122·123 However, these activity (eg, Paget disease of bone [PDB] and juve­ findings are largely based on anecdotal case reports, nile Paget disease) manifest accelerated tooth loss. and their true prevalence is unknown. In a cross­ sectional survey of 292 patients with PDB, 93% of Paget disease of bone (osteitis deformans) those with maxillomandibular involvement related PDB is a heterogenous, focal, progressive bone dis­ having dental problems, compared to only 10% of ease characterized by active bone turnover.114·115 The those with skull or other distant bone involvement.122 risk of developing PDB increases with age, affect­ However, compared to controls, the patients with ing an estimated 1 % of individuals over the age of dental problems reported no significant difference in 40 years in the United States.116 Men are at slightly edentulism, tooth movement, change in bite, change greater risk than women. In addition to a genetic in denture fit, periodontal disease, or need for endo­ predisposition, other yet to be defined environ­ dontic treatments. Many of the dental changes asso­ mental factors likely contribute to the disease pro­ ciated with PDB are likely explained by the dynamic cess.111.118 nature of the disease. During the osteolytic phase, Mutations affecting the sequestosome 1 gene are tooth mobility, shifting, and increased postsurgical found in up to 50% and 30% of patients with familial bleeding may occur. More mature pagetoid changes and sporadic cases of PDB, respectively.119 Sequesto­ affecting the jaws may manifest as malocclusion and/ some 1 (also known as p62) is an important scaffold or deformity and result in an increased risk of osteo­ protein in the NFKB pathway. In terms of environ­ myelitis. mental factors, some have proposed that a latent Potential radiographic changes associated with paramyxoviral infection (eg, measles, canine distem­ PDB reflect the brisk osteoclastic and osteoblastic per virus, or respiratory syncytial virus) contributes to nature of the disease.121·124 The characteristic lytic PDB, but this issue remains unresolved.113·118·120 sign of PDB affecting the skull is osteoporosis cir­ PDB may affect one (monostotic) or a few (poly­ cumscripta, whereas the characteristic sclerotic sign ostoti c) bones, and most cases are asympto­ is the cotton wool appearance. An overall mosaic matic and discovered incidentally.116·118.121 The of lytic and sclerotic findings is frequently noted. most commonly affected sites include the pelvis, Potential radiographic findings of PDB involving skull, vertebra, femur, and tibia. Affected bones the jaws include hypercementosis, thickening of the usually manifest an initial osteolytic phase, followed periodontal ligament space, root resorption, and by a mixed osteolytic/osteosclerotic phase, which pulpal obliteration.123·125-129 ultimately progresses to a disorganized osteoscle­ Hypercementosis has been reported to occur rotic phase. In reality, all three arbitrary phases of frequently in PDB, and its presence is considered PDB may exist concurrently. Common clinical signs highly suggestive of PDB.123·126·127 Large amounts and symptoms include osseous distortion or expan­ of cementum may be deposited in the apical two­ sion and mild to moderate, deep, aching bone pain. thirds of the roots, giving the tooth the appear­ Elevated serum total alkaline phosphatase levels are ance of a baseball bat (Fig 20-10). The cementum reflective of the increased bone activity and charac­ may appear to be fused with the adjacent sclerotic teristic for the disease. While osteosarcoma is a rare bone130 (Fig 20-11), resulting in ankylosis.128 In such a complication of PDB, most cases of adult osteosar­ scenario, the involved teeth will be abnormally firm. coma occur in patients with PDB.113 Lytic activity around an involved tooth may affect Skull involvement is estimated to occur in about the lamina dura to produce a widened periodontal 27% of patients and may result in hearing loss and ligament space. In contrast to primary or secondary vestibular problems in up to 89% of those affected.122 hyperparathyroidism, which manifests generalized It is postulated that, in addition to direct auditory thickening of the periodontal ligament space, in

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Fig 20-10 Ground section of a maxil­ Fig 20-11 Characteristic intraoral radiographic features of Paget disease. Note the variable appearance of the lary second premolar showing the extensive canal space, periodontal ligament space, and lamina dura. (a) Areas of radiolucency. (b) Isolated sclerosis. (c) Iso­ hypercementosis associated with Paget dis­ lated sclerosis and distal root resorption of the maxillary second molar. (d) Isolated sclerosis and hypercementosis ease. of the second premolar. (Reprinted from Barnett and Elfenbein130 with permission.)

PDB the widening is restricted to involved teeth. An Disturbances of vitamin D metabolism additional lytic change that may occur is root resorp­ tion, which may clinically manifest as mobility. Paral­ The primary regulator of calcium homeostasis and leling the concurrent mixed lytic and sclerotic pro­ subsequent bone and dentin mineralization in the cesses affecting the bone, lytic changes may affect body is bioactive vitamin D {1a,25-dihydroxyvitamin some teeth while other teeth may demonstrate 03).131-133 Numerous rachitic conditions relating to hypercementosis. specific alterations in vitamin D metabolism have The potential for pagetoid changes to affect the been identified. Both vitamin D-dependent rickets pulp has been proposed, but few reports addressing type I (VDDRI) and vitamin D-dependent rickets the issue exist.125•128•129 In one case report evaluat­ type II (VDDRll) are rare recessive disorders, while ing a mandibular third molar, internal resorption of X-linked hypophosphatemic rickets (XLH) is passed the dentin, direct apposition of cellular hard tissue as an X-linked dominant trait. The phenotypic pre­ partially occluding the coronal pulp, and dystrophic sentations of all three forms of rickets have much in calcification in the radicular region of the pulp were common, but subtle variations do exist. noted. The overall mosaic pattern observed was similar to that typically observed in the bone and Vitamin D-dependent rickets type 1 cementum.125 These potential radiographic findings VDDRI manifests as deficient 1-a-hydroxylase pro­ may interfere with endodontists' ability to establish duction, and the responsible mutation has been a proper working length, prompting some to rec­ mapped to chromosome 12.131 1-a-hydroxylase is ommend the use of an apex locator to establish the a member of the cytochrome P450 superfamily of canal length.123 enzymes and is required for normal vitamin D acti­ vation. It acts on the circulating vitamin D precur­ sor 25-hydroxyvitamin D to form bioactive vitamin 3 D.132•134 Originally believed to be restricted to the kid­ ney, 1-a-hydroxylase expression and activity occur at several extrarenal sites, including skin, lymph nodes, colon, pancreas, brain, endothelial cells, and bone.

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Prominent clinical features of VDDRI include girls. On initial examination, an abscessed primary stunted growth, skeletal abnormalities, genu val­ maxillary first molar was noted, and his teeth also gum, rachitic rosary, open fontanels, pathologic exhibited enlarged pulp chambers and thin dentin. fractures, muscle weakness, and convulsions. Com­ The abscessed tooth was extracted and submitted mon laboratory findings include hypocalcemia, for histologic assessment. The histologic findings hypophosphatemia, elevated parathyroid hormone, showed abundant interglobular dentin and a lack high alkaline phosphatase, normal levels of vitamin of a predental layer. This child did not respond to D precursors, and low levels of bioactive vitamin medical therapy, and the dental defects persisted. D. A single case report of the dental findings in a patient with VDDRI noted the presence of enamel X-linked hypophosphatemic rickets hypoplasia, large quadrangular pulp chambers, and The most prevalent form of rickets is caused by short roots.133 The administration of physiologic lev­ mutations affecting the PHEX gene (phosphate­ els of bioactive vitamin D (1a,25-dihydroxyvitamin regulating gene with homology of endopep­ D3) is the treatment of choice. Such therapy bypass­ tidases that maps to the X chromosome) and is es the deficient enzyme, thereby fostering normal termed X-linked hypophosphatemia.136 The muta­ development. tion responsible for XLH has been mapped to Xp22.2-p22.1, and the incidence is estimated at 1 in Vitamin D-dependent rickets type II 20,000 persons.70·136-138 Patients with XLH experience Mutational abnormalities mapped to chromosome impaired 1-a-hydroxylase activity, reduced phos­ 12 underlie VDDRll.131 In this scenario, the vitamin phate resorption in the kidney and intestine, hypo­ D receptor is adversely affected, resulting in end­ phosphatemia, and hyperphosphaturia. The current organ resistance to vitamin D modulation. The resul­ medical treatment of choice is the prompt institution tant defective intestinal calcium absorption leads of supplemental vitamin D and phosphate therapy. to hypocalcemia and rickets. Laboratory findings The main clinical features include severe bony include hypocalcemia, elevated parathyroid hor­ deformities, impaired growth, short stature, frontal mone levels, and hypophosphatemia. Vitamin D bossing, craniotabes, and a square-shaped head. precursor levels are normal, and bioactive vitamin D The dental findings affect both the primary and per­ levels are elevated. The elevated levels of bioactive manent dentitions and include enlarged pulp cham­ vitamin D help to distinguish VDDRI from VDDRll.131 bers, enlarged pulp horns, hypocalcified and inter­ The clinical findings of VDDRll are often severe globular dentin, short roots, taurodontism, poorly and usually apparent within a few months of birth.131 defined lamina dura, and hypoplastic alveolar ridg­ The clinical phenotype is similar to that for VDDRI. es70·133·138 (Figs 20-12 and 20-13). The severity of the However, a fairly characteristic feature of VDDRll is clinical and radiographic dental lesions is influenced sparse body hair, or a/opecia universa/is, the pres­ by the patient's age, the type of teeth (prenatal or ence of which appears to correlate well with disease postnatal odontogenesis), and whether the patient severity. Medical therapy is limited and consists of was undergoing therapy prior to the time of exami­ calcium infusion and the administration of pharma­ nation. cologic levels of precursor and bioactive vitamin D. The finding of prominent pulp horns extending Because neither of these approaches addresses the up to the dentinoenamel junction in both denti­ receptor deficiency, results have been mixed. tions is regarded by some as pathognomonic for Only a single report is available in the English XLH.137·139 These abnormalities place the XLH patient literature addressing the dental findings associated at risk for spontaneous dental abscesses, which with VDDRll.135 The authors reported on the dental occur frequently and often without any evidence of findings in three children with VDDRll. Two of the preexisting trauma or caries.70·137·138·140·141 It is likely three children, both girls, exhibited no evidence that attrition of the enamel allows bacterial entry of enamel hypoplasia but did manifest enlarged into the dentinal tubules and pulp.70·142·143 Although pulp chambers and thin dentin. Both responded endodontic treatment is clearly [ndicated in many well to medical therapy and experienced normal instances, the underlying structural defects associ­ root canal and pulp chamber development. The ated with XLH may compromise the clinician's ability other child, a boy, presented with a more severe to obtain an adequate obturation seal. phenotypic presentation of VDDRI I than the two

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Fig 20-12 (a and b) Bitewing radio­ graphs of a patient with XLH rickets. Note the enlarged pulp chambers, large root canal systems, and pulp horns that extend to the dentinoenamel junction. (Reprinted from Bender and Naidorf139 with permis­ sion.)

Fig 20-13 Ground section of a premolar from a patient with XLH rickets. The high risk of pulpal necrosis and subsequent periradicular lesions is readily apparent. The pulp horn defect appears as a tubular cleft covered only by a thin layer of hypoplastic enamel, showing the exten­ sion of the pulp horn to the dentinoenamel junction. Note the appearance of hypoplastic enamel and interglobular dentin. (Courtesy of Dr C. J. Witkop).

Hemoglobinopathies production and reduced 13-globin production results in severe anemia, an ineffective compensatory eryth­ Hemoglobinopathies are a group of hereditary ropoiesis, and iron overload. The compensatory blood disorders that affect hemoglobin. The two erythropoiesis often leads to a 15- to 30-fold expan­ most commonly cited diseases of this group are sion of the bone marrow.63•147 Iron overload under­ thalassemia and sickle cell anemia (SCA). lies most of the other characteristic manifestations, including hepatosplenomegaly, skeletal changes, Thalassemia growth retardation, increased susceptibility to infec­ Thalassemia refers to a group of clinically hetero­ tion, endocrine dysfunction, and cardiac failure. genous and common hemolytic anemias involving Medical management is multidisciplinary and reduced or absent hemoglobin production.63·144·145 centered on lifelong regular transfusions and Most cases are inherited in an autosomal-recessive chelation therapy. The primary cause of death in pattern, and an estimated 1.67% of the worldwide 13-thalassemia is cardiac failure, usually during early population carries a thalassemia trait.145 Thalasse­ adulthood, because of iron overload.145 mias vary in severity and are classified as homozy­ Orofacial manifestations of 13-thalassemia are gous (major), heterozygous (minor}, or compound frequently observed and generally a consequence heterozygous (intermedia). The most serious type of of the extensive marrow space expansion. A char­ thalassemia is the major form of 13-thalassemia, also acteristic "rodent" or "chipmunk" facies may be known as Cooley anemia.145·146 observed because of the presence of maxillary pro­ Hemoglobin consists of four protein subunits, trusion and expansion, bossing of the skull, hyper­ typically two subunits called a-globin and two telorism, and prominent cheek bones.63·146·148 Mal­ subunits called {3-globin. The HBB gene provides occlusion is commonly observed, typically marked instructions for making 13-globin. Over 200 point by overbite, flaring, increased overjet, and spac­ mutations affecting the gene have been discovered, ing of the teeth. Delayed dental development has which helps account for the variability in 13-globin­ been reported, as has a higher prevalence of tau­ chain synthesis reduction.145•147 In 13-thalassemia, rodontism. Radiographically, the jaws have been two 13-globin genes that carry a severe mutation are described as osteoporotic with coarse trabecula­ present. The imbalance between normal a-globin tion 146 (Fig 20-14).

481 www.shayanNemodar.com Interrelationship of Pulp and Systemic Disease

infection, and specific end-organ damage (eg, reti­ nopathy, nephropathy, leg ulcers, and osteomyelitis of long bones and the mandible).149 Characteristic painful episodic vaso-occlusive crises (sickle cell crises) occur in the abdomen, joints, muscles, and bones. These crises may be precipitated by dehy­ dration, acidosis, strenuous exercise, trauma, pulmo­ nary disease, or a prior vaso-occlusive event. There is no cure for SCA Medical management is multidisciplinary and targeted to relieve pain, prevent infection, prevent end-organ damage, and control complications if they occur.150 Heterozygous carriers generally do not manifest significant clinical Fig 20-14 Periradicular radio­ Fig 20-15 Periradicular radio­ disease. graph from a patient with thalas­ graph from a patient with sickle cell semia. anemia. Head and neck manifestations of SCA, such as marrow hyperplasia, osteoporosis, bone infarction, osteonecrosis, and osteomyelitis, are observed in 79% to 100% of SCA patients.151 The risk that osteo­ myelitis will affect the jaws of patients with SCA is 200 times that found in healthy controls.152 Radio­ paque lesions, commonly observed in the posterior body of the mandible, are believed to represent a sclerotic response to a prior osseous infarction.151 A spectrum of neuropathic manifestations may Sickle cell anemia occur as a consequence of vaso-occlusive events. SCA represents the most common form of a Examples include asymptomatic pulpal necrosis, group of sickling disorders that affect hemo­ symptomatic pulpitis without evident radiographic globin.149 It is a recessive disorder estimated to affect involvement, vague jaw pain or paresthesia, and 1 in 500 African Americans. Approximately 13% of referred odontalgia.151·153-155 When feasible, endo­ African Americans are heterozygous carriers of the dontic treatment is preferred over extraction to SCA trait. SCA is caused by a single point muta­ reduce the risk of osteomyelitis. All dental care tion at the sixth codon, which leads to the substi­ should be performed in close consultation with the tution of valine for glutamic acid in the 13 chain of managing physician. If surgery is necessary, surgical hemoglobin.150 When deoxygenated, affected hemo­ manipulation and trauma should be minimized.156 globin undergoes polymerization, which causes the red blood cell to change into the characteristic sickle Other inherited disorders affecting the shape.151 For those individuals with SCA, more than 70% of circulating hemoglobin is affected, whereas oral cavity for those with SCA trait, less than 45% of circulating hemoglobin is affected.151 Gaucher disease The sickle red cell is more fragile than a healthy Gaucher disease, the most commonly occurring red cell and cannot deform as it attempts to move lysosomal storage disorder, is a recessively inher­ through the capillaries. As a consequence, the affect­ ited deficiency of the enzyme acid-13-glucosidase.157·158 ed red cell life span is reduced from the normal 120 Acid-13-glucosidase breaks down the glycolipid glu­ days to a range of 10 to 30 days, and compensatory cocerebroside to yield glucose and ceramide. Insuf­ marrow hyperplasia is characteristic (Fig 20-15). The ficient enzyme availability leads to accumulation of disruption of blood flows leads to vascular occlu­ glycolipid throughout the reticuloendothelial system, sions, hemorrhages, infarctions, and ischemic necrosis particularly in macrophages. Gaucher disease is clas­ affecting a variety of body tissues and organs.149·151 sically divided into three types, based on the presence Clinical manifestations of SCA include chronic or absence and rate of progression of neurologic hemolytic anemia, pallor, increased susceptibility to manifestations.158·159 Type I Gaucher disease is the

482 www.shayanNemodar.com Genetic and Developmental Disorders

Fig 20-16 Radiographic presentation of Gaucher disease. (a and b) Uniform bilat­ eral periapical radiolucency of the mandibular second premolars and first molars. (c) Twenty-year follow-up revealing evidence of periapical root resorption on the second premolar and first molar. The resorption only occurs in the apical portion of the roots. (d) Twenty-year follow-up of the contralateral side reveals less periapical root resorption. (Reprinted from Bender and Bender163 with permission.)

II m�CEJ•EllDental observations in 11 patients with Gaucher disease (type 1) Mandibular Maxillary Sclerotic Hemorrhagic Radiologic root radiolucency radiolucency Osteopenia changes Biopsy diathesis resorption

+ + + +

+ + +

+ + + + +

+ 0 + + +

+ + + +

+ 0 + + 0

+ 0 + + 0 +

+ 0 + 0 + +

+ 0 + +a +a

+ + + + + 0 +b

+ 0 + 0 + 0 0

+, present;-, absent; 0, not mentioned; +a, autopsy; +b, histologic resorption. (Reprinted from Bender and Bender'" with permission.)

most frequently occurring genetic disorder affecting of the femur is considered a pathognomonic sign for Ashkenazi Jews, among whom the carrier rate is about Gaucher disease.161•162 1 in 15.158 Most patients with Gaucher disease respond In a small survey, radiographic involvement of the well to the administration of recombinant acid­ jaws, consisting of enlarged marrow spaces, cortical 9 �-glucosidase (enzyme replacement therapy).15s.15 thinning, endosteal scalloping, external root resorp­ The clinical manifestations of Gaucher disease vary tion, or radiolucencies of the jaws, were noted in 25 of greatly, ranging from death in utero to inconsequen­ 28 patients studied.162 Involvement of the mandibular tial. Common signs and symptoms include hepato­ body and the premolar and first molar region of the splenomegaly, thrombocytopenia, and anemia. mandible has also been noted163 (Fig 20-16). Bender Skeletal manifestations affect an estimated 75% of and Bender163 reported on the dynamic nature of patients and include osteopenia, lytic lesions, path­ Gaucher disease, following 11 affected patients over ologic fracture, deformity, chronic and acute bone a period of 13 to 60 years (Table 20-2). They noted pain, bone infarcts, and osteonecrosis.157·160·161 An lesion enlargement and temporary bone regenera­ Erlenmeyer flask-like appearance of the distal head tion that occurred after local curettage, tooth extrac-

483 www.shayanNemodar.com Interrelationship of Pulp and Systemic Disease

II @tjtfJ•f111 Other inherited disorders affecting the oral cavity Mode of Disease inheritance Pathogenesis Clinical manifestations

Fabry disease166·167 X-linked Deficiency of lysosomal enzyme Acroparesthesias, angiokeratomas, recessive a-galactosidase hypohidrosis, corneal opacity, hearing loss, malocclusion, diastemas, mucous retention cysts

Oculocerebrorenal X-linked Deficient phosphatidylinositol 4,5- Hydrophthalmos, cataracts, mental syndrome (Lowe recessive bisphosphate-5-phosphatase retardation, renal tubular dysfunction, 9 syndrome)67.16s.16 large pulp chambers, dysplastic dentin, periodontal disease

Cyclic neutropenia 110-173 AD Cyclic production of white blood cells Increased susceptibility to infection, (21-day periodicity) progressive periodontal disease, oral ulcerations

Papi I Ion-Lefevre AR Defective cathepsin C activity Palmoplantar hyperkeratosis, severe 77 syndrome174-1 early-onset periodontitis leading to early tooth loss

Chediak-Higashi AR Defective intracellular protein traffick­ Severe immunologic defects, reduced syndrome1 1s-1so ing to and from the lysosome pigmentation, mild bleeding tendency, progressive neurologic dysfunction

22q11.2 deletion AD Deletion of approximately 30 genes on Cardiovascular defects, craniofacial syndrome (DiGeorge chromosome 22 anomalies, ear defects, immunologic syndrome)181 problems, parathyroid abnormalities, kidney abnormalities

Primary oxalosis type 11s2-1s4 AR Deficiency of alanine-glyoxylate Progressive nephrolithiasis/ aminotransferase nephrocalcinosis and eventual renal failure, extrarenal calcium deposits, slate-gray teeth, odontalgia, pulpal calcifications, root resorption

AD, autosomal dominant; AR, autosomal recessive.

tion in proximity to the lesion, or long-bone fracture. Other disorders These changes were eventually replaced by further Numerous other uncommon or rare inherited disor­ lytic destruction. While extraosseous extension of ders may manifest involvement of the oral cavity. A Gaucher lesions is considered rare, reports of extraos­ selected few are summarized in Table 20-3.74·16b--184 seous extension into masseter muscle and sphenoid sinuses have been published.160·161·164 Aside from the previously mentioned exter­ Endocrine Disorders nal root resorption, specific dental and gingival I changes associated with Gaucher disease appear to be minimal.162 However, these patients should be closely followed and should undergo regular radio­ Diabetes mellitus graphic assessment to monitor osseous involvement because they may be at increased risk for develop­ Diabetes mellitus is a serious endocrine disorder ing osteomyelitis or pathologic fracture.165 Many characterized by an absolute or relative insulin insuf­ of these patients undergo splenectomy as part of ficiency or target resistance to insulin activity. In their disease management, which may increase their the United States, an estimated 25.8 million indi­ risk of infection. Finally, the commonly observed viduals have diabetes, and an estimated 7.0 million thrombocytopenia places the patient with Gaucher are undiagnosed.185 Patients with poorly controlled disease at risk for increased postsurgical bleeding.162 diabetes manifest chronic hyperglycemia and are at

484 www.shayanNemodar.com Endocrine Disorders

increased risk for myriad complications, including tes.206 However, there have been no studies directly infection.186-189 The five classic complications of dia­ addressing the issue, and the overall complexity of betes are (1) retinopathy, (2) nephropathy, (3) neu­ diabetes would seem to confound any attempted ropathy, (4) macrovascular disease, and (5) impaired study. It is clear that any infection, including pulp­ wound healing.187,189-191 al disease, in the diabetic patient must be man­ Hyperglycemia leads to the creation and accu­ aged promptly and aggressively. As a rule, diabetic mulation of advanced glycation end-products patients under good disease control can be gener­ (AGEs), which are believed to contribute directly to ally regarded as normal patients, whereas patients the etiopathogenesis of diabetes.187·189·191-196 AGEs who are either suspected of having diabetes or impair normal homeostatic collagen turnover, lead­ whose diabetes seems under poor control should be ing to the accumulation of a more mature, less referred for medical evaluation prior to the delivery soluble collagen in the vessel wall; subsequent ves­ of dental care. Medical consultation is further rec­ sel wall thickening and reduction in lumen size; and ommended for any anticipated dental treatment, a decrease in tissue perfusion.187·189·195 AGE-altered such as extensive surgery, that can adversely impact collagen is also more prone to bind with low-density the patient's glucose control. lipoprotein to form atheromas, which contribute to large vessel disease.187 At the immunologic level, hyperglycemia results in impaired chemotaxis, Adrenal dysfunction adherence, and phagocytosis of polymorphonuclear leukocytes.187 AGE interaction with monocytes and Cortisol, a naturally occurring glucocorticoid of the macrophages results in the creation of a proinflam­ adrenocortex, and the catecholamine epinephrine are matory phenotype.187,191,193.197 the primary modulators of the stress response.207-210 While it is axiomatic that adequate medical con­ Cortisol stimulates peripheral fat and protein catab­ trol of diabetes is essential to the maintenance of olism to serve as substrates for the hepatic produc­ oral health, the impact of poor oral health (eg, peri­ tion of glucose.211 Well-established anti-inflammatory odontitis or periradicular abscess) on the control and immunomodulatory effects of cortisol include and progression of diabetes must be understood. preventing leukocyte migration from the circulation A two- to three-times greater rate of periodon­ into the extravascular space, reducing the accumula­ tal disease has been observed in individuals with tion of monocytes and granulocytes at inflammatory diabetes. This is understandable, given the fact sites, and suppressing the production of numerous that the typical area of the susceptible periodon­ cytokines and other proinflammatory mediators. tium is roughly the size of the palm.198 Such a large Cortisol also acts in a permissive role to allow other inflammatory burden may negatively impact glu­ hormones such as catecholamines and angiotensin II cose control in the diabetic patient and confer an to modulate cardiac contractility, vascular tone, and increased risk of developing diabetes-related com­ blood pressure.212-214 Finally, cortisol provides nega­ plications.188-191,194, 197-199 tive feedback to the hypothalamus and the anterior Although there are few studies addressing the pituitary gland (hypothalamic-pituitary-adrenal [HPA] relationship between diabetes and pulpal disease, axis) in regulating corticotropin-releasing hormone logical points of intersection to consider would and adrenocorticotropin-releasing hormone.207·210·215 include diabetes-induced microvascular, neuropathic, Conditions of insufficient cortisol production, and inflammatory changes. It appears that diabetic regardless of the etiology, are termed Addison dis­ patients in need of endodontic treatment are more ease. 216 Most cases of glucocorticoid deficiency likely to present with larger periradicular lesions, har­ develop insidiously, presenting with nonspecific bor more virulent pathogens, experience periopera­ signs and symptoms such as lethargy, anorexia, tive symptoms, and experience a higher incidence of nausea, weight loss, and hypoglycemia. These therapeutic failure than control patients.186·200-205 patients are typically prescribed empirical replace­ The increased risk of infection and potential poor ment glucocorticoid therapy.217 Conditions of wound healing observed in the diabetic patient has endogenous cortisol excess are termed Cushing led some to advocate the administration of antimi­ syndrome.211·218·219 However, the most frequent cause crobial prophylaxis prior to dental treatment, partic­ of glucocorticoid excess is iatrogenic. The clinical ularly in the individual with poorly controlled diabe- findings of cortisol excess correspond directly to the

485 www.shayanNemodar.com Interrelationship of Pulp and Systemic Disease

Fig 20-17 Comparison of predentin thickness in teeth collected from a healthy patient (a) and a patient who was chronically treated with gluco­ corticoids, suffering from renal failure, and under­ going dialysis (b). The predentin is about four times wider in the healthy patient than it is in the chronically ill patient (hematoxylin-eosin stain). (Reprinted from Wysocki et al224 with permission.)

-

...... -

severity and duration of glucocorticoid excess and it appears that the risk of an Addisonian crisis dur­ include truncal obesity, violaceous striae of the skin, ing an outpatient dental procedure is low or very buffalo hump, facial fullness (moon facies), facial low.217·23° Consequently, patients need only to take plethora, acne, hirsutism, easy bruising, muscle wast­ their usual daily glucocorticoid dose on the day of ing, and myopathy. the procedure. If moderate or major surgical stress is There are no disease-specific oral manifestations anticipated under general anesthesia and the patient of Addison disease. Some individuals manifest a has documented or presumed HPA axis suppression, patchy brown (bronzing) pigmentation of the face then appropriate stress doses of perioperative ste­ (with superimposed areas of vitiligo}, the buccal roids are indicated. mucosa, the tongue, and, less frequently, the lips and gingivae. Head and neck manifestations of Cushing syndrome include facial plethora, moon face, hirsutism, and acne. Affected children may I Cancer exhibit delayed or arrested dental development paralleling the overall growth retardation that may occur with glucocorticoid excess.220·221 Chronic expo­ There are few reports of malignancies affecting the sure to excess glucocorticoid appears to stimulate dental pulp. The risk that a primary malignancy will odontoblast-like cells within the dental pulp, result­ arise from pulpal tissue appears to be extremely ing in narrowing of the dental pulp chamber or com­ remote.231 In reviewing the dental literature pub­ plete pulpal obliteration222-224 (Fig 20-17). lished over a 100-year span (1870 to 1970), Stanley129 Patients with Addison disease are inherently reported fewer than 20 case reports of pulpal cancer. unable to produce sufficient levels of adrenocorti­ Furthermore, if a primary pulpal malignancy were to cotropic hormone or cortisol to meet physiologic develop, the enclosed nature of the pulp chamber demand. Similarly, chronic exogenous glucocorticoid increases the likelihood that the tumor growth will exposure can suppress the HPA axis, and therefore adversely interrupt the pulpal vascular network, result­ patients on chronic glucocorticoid therapy may not ing in self-strangulation. A more likely, albeit still rare, be able to produce sufficient levels of adrenocorti­ scenario occurs when the pulp or periradicular area is cotropic hormone and cortisol to meet physiologic infiltrated by a hematologic malignancy or is the tar­ demand.211·225--227 The concern in clinical practice is get of a solid tumor metastasis.232-251 that, for either situation, an overwhelming stressor Regardless of the specific malignancy involved, (surgery, sepsis, or fever) may precipitate an Addi­ the presenting signs and symptoms are often non­ sonian crisis (adrenal insufficiency with hypotension specific and mimic routine inflammatory pulpal or and shock).22&-230 Accordingly, supplemental gluco­ periodontal disease.235•237•238·243·244 Thus, the pres­ corticoids ("stress dose" steroids) are recommend­ ence of findings such as odontalgia, percussion ed perioperatively for patients with documented or sensitivity, periradicular radiolucencies, and gingival presumed HPA axis suppression when they are to inflammation and swelling often raise little suspicion. undergo a stressful medical procedure. Fortunately, However, the presence of more worrisome findings,

486 www.shayanNemodar.com References

such as altered sensation (eg, anesthesia or par­ esthesia), asymmetric widening of the periodontal ligament space, loss or thinning of the lamina dura, and moth-eaten or ill- defined radiolucencies, war­ rant increased suspicion (Fig 20-18). Finally, a prior history of malignant disease, especially of the breast, lung, adrenal glands, kidney, prostate, thyroid, and colon, should raise the clinician's suspicion of a malignancy even more.252,253 Therapeutic interventions to treat cancer may adversely affect structures of the head and neck, including the dental pulp.254-261 Probably the most frequently incurred therapy-induced damage affect­ Fig 20-18 (a and b) Periradicular radiographs of a 13-year-old patient with ing adult patients occurs as a consequence of head acute monocytic leukemia. Note the uniform widening of the periodontal liga­ and neck irradiation therapy. Potential signs and ment space. symptoms associated with head and neck irradiation include mucositis, irreversible salivary gland impair­ ment, taste aberration, radiation caries, and osteo­ References radionecrosis.256 While developed teeth appear to I be fairly resistant to the effects of irradiation, it has

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Garcia RI, Henshaw MM, Krall EA. Relationship between periodontal Tissue Res 2005;321:391-400. health and systemic health. Periodontol 2000 2001;25:21-36. 223. Huang GT, Shagramanova K, Chan SW. Formation of odontoblast-like 195. Miley DD, Terezhalmy GT. The patient with diabetes mellitus: Etiology, cells from cultured human dental pulp cells on dentin in vitro. J Endod epidemiology, principles of medical management, oral disease burden, and 2006;32: 1066-1073. principles of dental management. Quintessence Int 2005;36:779-795. 224. Wysocki GP, Valey TD, Ulan RA. Predentin changes in patients with chronic 196. Sampathkumar R, Balasubramanyam M, Rema M, Premanand C, Mohan renal failure. Oral Surg Oral Med Oral Pathol 1983;56:167-173. V. A novel advanced glycation index and its association with diabetes and 225. Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative microangiopathy. Metabolism 2005;54: 1002-1007. glucocorticoid coverage. A reassessment 42 years after emergence of a 197. Grossi SG, Skrepcinski FB, Decaro T, Zambon JJ, Cummins D, Genco RJ. problem. Ann Surg 1994;219:416-425. Response to periodontal therapy in diabetics and smokers. J Periodontol 226. Schiff RL, Welsh GA. Perioperative evaluation and management of 1996;67: 1094-1102. the patient with endocrine dysfunction. Med Clin North Am 2003;87: 198. Mealey BL, Rose LF. Diabetes mellitus and inflammatory periodontal dis­ 175-192. eases. Curr Opin Endocrinol Diabetes Obes 2008; 15:135 -141. 227. Schlaghecke R, Kornely E, Santen RT, Ridderskamp P. The effect of long­ 199. Chandu A, Macisaac RJ, Smith AC, Bach LA. Diabetic ketoacidosis sec­ term glucocorticoid therapy on pituitary-adrenal responses to exogenous ondary to dento-alveolar infection. Int J Oral Maxillofac Surg 2002;31: corticotropin-releasing hormone. N Engl J Med 1992;326:226-230. 57-59. 228. Graham GW, Unger BP, Coursin DB. Perioperative management of select­ 200. Bender IB. Diabetes mellitus and the dental pulp. J Endod 2003;29: ed endocrine disorders. Int Anesthesiol Clin 2000;38:31-67. 383-389. 229. Kehlet H, Binder C. Adrenocortical function and clinical course during 201. Britto LR, Katz J, Guelmann M, Heft M. Periradicular radiographic assess­ and after surgery in unsupplemented glucocorticoid-treated patients. ment in diabetic and control individuals. Oral Surg Oral Med Oral Pathol 1973;45: 1043-1048. Oral Radiol Endod 2003;96:449-452.

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230. Miller CS, Little JW, Falace DA. Supplemental corticosteroids for dental 246. Selden H, Mannhoff D, Hatges N, Michel R. Metastatic carcinoma patients with adrenal insufficiency. Reconsideration of the problem. J Am to the mandible that mimicked pulpal/periodontal disease. J Endod Dent Assoc 2001;132:1570-1579. 1998;24:267-270. 231. Neuhaus K. Teeth: Malignant neoplasms in the dental pulp? Lancet Oncol 247. Shankar S. Dental pulp metastases and pan-osseous mandibular involve­ 2007;8:75-78. ment with mammary adenocarcinoma. Br J Oral Maxillofac Surg 232. Ahmad S, Roberts GJ, Lucas VS, Barrett AW, Harkness W. Metastatic 1984;22:455-461. infiltration of the dental pulp by medulloblastoma. J Oral Pathol Med 248. Svoboda W, Aaron G, Albano E. North American Burkitt's lymphoma pre­ 2002;31:244 -245. senting with intraoral symptoms. Pediatr Dent 1991;13:52-58. 233. Baumgartner JC, Heggers JP, Harrison JW. The incidence of bacteremias 249. Thompson 10, Phillips VM, Kalan M. Metastatic squamous cell carcinoma related to endodontic procedures. I. Nonsurgical endodontics. J Endod manifesting as a periapical lesion. J Dent Assoc S Afr 1992;47:481-483. 1976;2:135-140. 250. Todd H, Langeland K. Pulpal destruction of neoplastic etiology. J Endod 234. Bavitz JB, Patterson OW, Sorensen S. Non-Hodgkin's lymphoma disguised 1987; 13:299-301. as odontogenic pain. J Am Dent Assoc 1992;1 23:99-100. 251. Tsui S, Wong M, Lam W. Burkitt's lymphoma presenting as mandibular 235. Bornstein MM, von Arx T, Altermatt HJ. Loss of pulp sensitivity and pain swelling-Report of a case and review of publications. Br J Oral Maxillofac as the first symptoms of a Ewing's sarcoma in the right maxillary sinus and Surg 2000;38:8-11. alveolar process: Report of a case. J Endod 2008;34:1549-1553. 252. D'Silva NJ, Summerlin DJ, Cordell KG, et al. Metastatic tumors in the jaws: A 236. Heng C, Heng J. Implications of malignant lymphoma on a periapical man­ retrospective study of 114 cases. J Am Dent Assoc 2006; 137: 1667-1672. dibular lesion. Gen Dent 1995;43:454-458. 253. Kuttan NA, Flemming DK, Dane JN, Ang DB. Metastatic lesion of the 237. Hiraki A, Nakamura S, Abe K, et al. Numb chin syndrome as an initial anterior mandible with an occult primary: A case report. Spec Care Dentist symptom of acute lymphocytic leukemia: Report of three cases. Oral Surg 2006;26:76-80. Oral Med Oral Pathol Oral Radiol Endod 1997;83:555-561. 254. Dahlliif G. Craniofacial growth in children treated for malignant disease. 238. Kanas R, Jensen J, DeBoom G. Painful, nonhealing tooth extraction socket. J Acta Odontol Scand 1998;56:378-382. Am Dent Assoc 1986; 113:441-442. 255. Hiiltta P, Hovi L, Saarinen-Pihkala UM, Peltola J, Alaluusua S. Disturbed root 239. Keyes GG, Balaban FS, Lattanzi DA. Periradicular lymphoma: Differen­ development of permanent teeth after pediatric stem cell transplantation. tiation from inflammation. Oral Surg Oral Med Oral Pathol 1988;66: Dental root development after SCT. Cancer 2005; 103: 1484-1493. 230-235. 256. Huber MA, Terezhalmy GT. The head and neck radiation oncology patient. 240. Landesberg R, Yee H, Datikashvili M, Ahmed A. Unilateral mandibular Quintessence Int 2003;34:693-717. lip anesthesia as the sole presenting symptom of Burkitt's lymphoma: 257. Kaste SC, Hopkins KP, Jones D, Crom D, Greenwald CA, Santana VM. Case report and review of the literature. J Oral Maxillofac Surg 2001;59: Dental abnormalities in children treated for acute lymphoblastic leukemia. 322-326. Leukemia 1997;11:792-796. 241. Levi PA Jr, Kim OM, Harsfield SL, Jacobson ER. Squamous cell carci­ 258. Lilly JP, Cox D, Arcuri M, Krell KV. An evaluation of root canal treatment in noma presenting as an endodontic-periodontic lesion. J Periodontol patients who have received irradiation to the mandible and maxilla. Oral 2005;76:1 798-1804. Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:224-226. 242. Maygarden S, Askin F, Burkes E, McMillan C, Sanders J. Isolated extra­ 259. Minicucci EM, Lopes LF, Crocci AJ. Dental abnormalities in children medullary relapse of acute myelogenous leukemia in a tooth. Mod Pathol after chemotherapy treatment for acute lymphoid leukemia. Leuk Res 1989;2:59-62. 2003;27:45-50. 243. Morgan L. Infiltrate of chronic lymphocytic leukemia appearing as a peri­ 260. Oguz A, Cetiner S, Karadeniz C, Alpaslan G, Alpaslan C, Pinarli G. Long­ apical radiolucent lesion. J Endod 1995;21 :475-478. term effects of chemotherapy on orodental structures in children with non­ 244. Peterson D, Gerad H, Williams L. An unusual instance of leukemic infil­ Hodgkin's lymphoma. Eur J Oral Sci 2004; 112:8-11. trate. Diagnosis and management of periapical tooth involvement. Cancer 261. Springer IN, Niehoff P, Warnke PH, et al. Radiation caries-Radiogenic 1983;51: 1716-1719. destruction of dental collagen. Oral Oncol 2005;41 :723-728. 245. Pruckmayer M, Glaser C, Marosi C, Leitha T. Mandibular pain as the lead­ 262. Kielbassa AM, Attin T, Schaller HG, Hellwig E. Endodontic therapy in a ing clinical symptom for metastatic disease: Nine cases and review of the postirradiated child: Review of the literature and report of a case. Quintes­ literature. Ann Oncol 1998;9:559-564. sence Int 1995;26:405-411.

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Page numbers followed by "f" denote figures; peripheral mechanisms of,170b, 170--171 pulpal healing affected by, 302-303 "t" tables; and "b" boxes Allogeneic bone marrow transplantation, 93-94 Streptococcus mutans, 214 Allogeneic stem cells, 95 Bacterial sinusitis, 455 A a-Adrenergic receptors, 118f Basement membrane, 73 A fibers,135--137, 148, 150f,434 Amalgam, 344 Bay cysts,3811, 381-382 Aj3 fibers,13 6--137 Ameloblasts,4, 1 7f Bead implantation assays, 6,6f Acetaminophen,193-195, 200 Amelogenesis imperfecta,477, 477t Bell stage, of tooth development, 3f,4 Acid etching Amelogenins,316 j3-Adrenergic receptors,119 description of, 48, 340 Anemia Bifidobacterium species, 215 illustration of,49f Cooley,481 Bioactive molecule-containing materials, 315-- microcirculatory effects, 126 sickle cell,464, 481-482, 482f 317 reactionary dentin stimulated by, 38 Antigen I/Ii, 221 Biofilm, plaque Actinomyces species, 214, 220, 234, 37 6f Antigen-presenting cells,80, 269 -270 antimicrobial resistance of,208 Adaptive immune responses,285 -287 Antigen-presenting dendritic cells, 277-278 bacteria in. See Bacteria,in biofilm. Adaptive immunity, 329 Anti-inflammatory cytokines,268 -269 caries formation secondary to, 211-212. See Addison disease, 485--486 Antimicrobial agents,208 also Caries. AO fibers,137, 167, 177-17 8 Apical foramen, 101,375, 3811 characteristics of, 207 Adhesion molecules, 247-248,250 Apical periodontitis definition of, 206--207 Adhesion restorations, 323, 344 definition of, 206, 222,278 disease enhancement, 208 Adhesive dentistry, 323 external root resorption and, 404-405 endodontic-periodontal infections caused by, Adhesive luting cements,323 periapical responses,277-282 379 Adhesive resin systems,312 -313 persistence of,232f extracellular matrix formation, 207 Adhesives, 312-313 pulpal responses,277 -278 formation of,209f, 209 -210 chronologic classification of,337 radiograph of, 206f illustration of,207f etch-and-rinse, 336 sy mptomatic,231 infectious, 379 self-etching, 336 treatment of,23 4-235 microcolonies in,207 Adrenal dysfunction,485--486 Apoptosis, 33,311 Bleaching Advanced glycation end-products,485 Arachidonic acid metabolites, 250--252, 254- intracoronal, 410 Afferent nerve fibers,147 255, 290--291 lasers for,367 Aging Archaea,231 Blood clotting, for root canal revascularization, biologic changes associated with,431-436 Argon laser,359 100--101,102t blood vessels affected by, 432-434 Arterioles, 109-110, 11Of, 1211, 127f Blood vessels cellular behavior affected by, 432 Arteriovenous anastomosis aging effects on, 432-434 degenerative processes induced by, 431 shunts, 111 arterioles,109 -110, 11Of, 1211, 127f dentinal sensitivity and, 177 Y-shaped, 112f capillaries,11 0--111 dentinogenesis changes,431, 438-440 Atypical odontalgia, 461-462 venules,111 disease versus, 422 Autologous stem cells,94-95, 104 Bonding. See Dentin bonding. intratubular and intertubular dentin formation Avulsion, 386 Bone morphogenetic proteins secondary to,440 Axon degeneration, 147 BMP-4,11 odontoblast changes secondary to, 427, 429- calcitonin gene-related peptide effects,63 430 B enamel knots and, 14 oral health during,421 B cells, 80,279, 283b expression of,111 overview of, 421 Bacteria function of, 77,97t oxidative stress theory of,423-424 antibacterial agents,221 odontoblast differentiation, 355 process of, 421-425 beneficial types of,214 source of,97t pulp capping considerations,441-442 in biofilm tooth development role of,10-- 11,11 f pulp testing responses to evaluate effects of, community lifestyle of, 207-208 Bone sialoprotein, 18,18t, 20, 211, 74 436-437 intercommunication among,208 -209 Bradykinin,123 ,256 pulpal changes secondary to, 425-442 quorum sensing, 208-209 Bud stage, of tooth development, 2, 3f pulpodentin complex changes secondary to, cariogenic, 213-215, 216t 334,427,440-442 coaggregation of,210 c radiographic signs of,441 endodontic infections,222 C fibers,135--137, 148-150, 434 root canal revascularization using blood clotting endodontic-periodontal diseases caused by, Calcific metamorphosis, 314 affected by, 101 377-378 Calcitonin gene-related peptide, 63, 70, 121- senescence and, 421-423 fluoride effects on metabolism by,222 123,136, 139,243-247,434,436 sensory nerves affected by, 434-436 Gram-negative, 227b Calcium hydroxide,305 telomeres,423-425, 431 Gram-positive,227b antimicrobial properties of, 308-309 Airborne particle abrasion, 367-368 microleakage of, 303, 343 caustic actions of, 308 Allergy-induced sinusitis,4 55 mutans streptococci,2 13-214 dentin adhesives vs,312 -313 Allodynia,449 nutrients for, 230 dentinal bridges created using,308-310 ,314 central mechanisms of, 171-173,172b primary intraradicular infections caused by, description of, 71,308 characteristics of,169 t, 169-170 226--228,2 27b mineral trioxide aggregate vs, 314 definition of,169 proteolytic, 377 outcomes of,310

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pulp inflammatory responses caused by, 315 Cell-rich layer of Hiihl, 28, 41 anti-inflammatory, 268--269 reactionary dentin deposition affected by, 342 Cell-rich zone, 68 functional studies of, 292-293 reparative dentin formation, 308 Cementoblasts, 282, 398 inflammatory role of, 263 resin-modified glass ionomers vs, 312 Cementodentin junction, 405 osteoclast activity inhibited by, 292 zinc oxide-eugenol vs, 318 Cementoenamel junction, 56, 353 proinflammatory, 264-268, 265f, 287-289, Calcospherites, 31, 31f, 48 Cementum, 58, 398--399 291-293 Cancer. 486-487 Central sensitization, 171-173 secretion of, 263 Candida albicans, 378 Cervical loop, 4 Cytomegalovirus, 231, 379 Cannabinoid receptors, 164 C-factor. 338--339 Cytotoxic T cells, 79, 278 Cap stage, of tooth development, 2-3, 3f Charcot-Leyden crystals, 383, 384f Capillaries, 11�111 Chediak-Higashi syndrome, 484t D Capillary filtration, 114 Chemoattractants Deafferentation, 461-462 Capillary network, 111 in leukocyte adhesion, 250 Decorin, 18t 72, 73f Capsaicin, 122, 149, 245, 462 transforming growth factor-[31, 41 Deep caries, 217f Carbohydrates, 213, 220 Chemokines, 269, 282, 287 Defensins, 270 Caries Chickenpox, 473 Demineralization antibacterial control for. 22�221 Childhood caries, 215, 343 description of, 212 bacteria associated with, 213--215, 216t, 22� Chlorhexidine gluconate, 221, 319 fluoride effects on, 221-222 221, 224 Cholesterol crystals, 382, 382f Dendritic cells, 82-84, 83f, 279-280, 283b, 400 categories of, 211-212 Chronic paroxysmal hemicrania, 457 Dens evaginatus, 475-476 cavitation caused by, 217f Chronic periapical lesions, 281 Dens in dente (dens invaginatus), 475f, 475-476 characteristics of, 325--328 Circulatory system. See Microcirculatory system, Dental epithelium, 4 childhood, 215, 343 of pulp. Dental follicle, 2, 4 deep, 217f, 332f Clotting system, 257-259 Dental follicle progenitor cells, 95 definition of, 211 Cluster headache, 457-458 Dental plaque. See Plaque. dendritic cells' response to, 85 co2 lasers, 361-362 Dental pulp constructs, 98--100, 99f, 102t dentinal, 216f, 216t, 216-218, 326, 327f-328f Coaggregation, 210 Dentin. See also Pulpodentin complex. description of, 205 Cocci, 227b, 229 acid etching of, 48, 49f diagnosis of. 218f, 218--219 Cold stimuli, for pulpal vitality testing, 179-180 apical, 59-60 diet and, 218, 220 Collagen axial, 56 ecological plaque hypothesis of, 212-213, age-related changes in, 427-428 caries-affected, 325--326, 327f-328f 213f basement membrane expression of, 14-15 carious, 324, 328 economic burden of, 206 biosynthesis of. 71-72 characteristics of, 52-53, 53t, 62 enamel, 211 characteristics of, 67 coefficients of thermal expansion, 350 etiology of, 212-215, 317 chemical composition of, 70 collagen types in, 16 fluoride for. 221-222 definition of, 70, 76 composition of, 52, 52t, 335 global prevalence of, 205--206 degradation of, 71 definition of, 48 hand instruments used to remove, 318 dentin types of, 16 depth-related changes in structure of, 5�52 immunocompetent cells' response to, 85--86 intraluminal, SH exposure of, 62 nonspecific plaque hypothesis of, 212 odontoblast synthesis of, 29 formation of, 16 nursing, 215 in pulp, 7�71 grinding of, effect on pulpal blood flow, 125f occlusal, 216t, 307f, 330f, 332f reverse transcriptase-polymerase chain reaction hereditary opalescent, 476 pathogenesis of, 212 amplification of, 9f intertubular. 32, 49, 440 prevalence of, 205 structure of, 70 intratubular. 49, 440 prevention of, 22�222 type I, 70 laser effects, 361 primary, 212, 325 type II, 70 mantle, 31, 48, 53t progression of, 327 type Ill, 70 mineralization of, 16, 3�31 progressive, 206f type V, 70 morphology of, 48--50 pulp exposure caused by, 224, 224f type VI, 70 nerve endings in, 136f pulpal responses to, 331 Collagen fibrils, 31, 7�71, 71f neuronal desensitivity, 187-190 radiographs of, 218, 218f Colony-stimulating factor. 97t noxious substance permeation in, �2 recurrent, 211-212, 218-219 Connective tissue periluminal, 49 remaining, 212 definition of, 67 peritubular. 32, 32f. 49, 52, 438 root, 211, 216t extracellular matrix, 67 permeability saliva and, 218, 220 function of, 67 cavity preparations effect, 61-62 secondary, 211, 325 Continuous capillary, 111 cementum effects, 58--59 sequelae of, 205 Convergence theory, 176-177, 448--449 dentinal thickness and, 56f smooth surface, 216t Cooley anemia, 481 depth, 54 specific plaque hypothesis of, 212 Core-binding factor a1, 12, 13f, 432 description of, 69 treatment of, 219-220, 326 Coronal leakage, 384-385 factors that affect, 56, 69 vaccine for. 221 Coronal pulp, 71f illustration of, 55f white-spot lesion presentation of, 211, 211f Coronal restoration, 385 importance of, 441 zone of destruction, 216, 217f Corticosteroids, 195 noxious substances, �2 Carious dentin, 324 Crown fracture, 304, 385 pulpal blood flow effects, 61 Cavity preparation Crown-root fracture, 385--386 restorative procedures effect, 61-62 dentin permeability effects, 61-62 Cushing syndrome, 485-486 smear layer effects, 57-59 heat production during Cusp tubular occlusion, 328 causes of, 335 fracture of, 385 types of, 54 inflammation secondary to, 170 morphogenesis of, 14, 15f uniformity of, 55, 58 immunocompetent cells' response to, 84-85 Cyclic neutropenia, 484t physical characteristics of, 52-53, 53t mechanical stimuli during, 353--355 Cyclo-oxygenases porosity of, 54-55 odontoblast disruptions caused by, 75, 341 arachidonic acid metabolites synthesized by, primary, 27, 28f, 48 pulpal injury caused by, 334--335 25�251 reactionary tertiary dentinogenesis effects, 35 inhibitors of, 194 cavity etching stimulation of, 38 thermal stimuli during, 349-353 Cyclophosphamide, 283--284 cellular signaling of, 38 CD4' T cells, 279 Cysteine cathepsins, 318, 326 definition of, 34, 78, 324 CD8' T cells, 279 Cysts, 381f, 381-382 deposition areas for, 334 Cell adhesion molecules, 248 Cytokines ethylenediaminetetraacetic acid effects, 38

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production of, 333 mechanisms of, 177-178 Enamel fracture, 385 remaining dentinal thickness effects, 37-38 neuronal desensitivity, 187-190 Enamel knots, 14, 15f restorative materials effect on formation of, neurophysiology of, 151-152 Enamel matrix derivative, 316 342-343 overview of, 185-186 Endocrine disorders remaining thickness, 37-38, 325, 334--335 prevalence of, 185-186 diabetes mellitus, 484-485 remodeling of, 30 risk factors, 185 glucocorticoid excess, 485-486 reparative, 34, 78, 308, 324 Dentinal tubules Endodontic disease resorption of, 411 aging changes, 441 periodontal disease and, 389-392, 389f-392f root anatomy of, 223 primary, 388, 392 impermeability of, 58 bacteria in, 51f Endodontic infections mechanics of, 53-54 caries infections in, 317 archaea, 231 permeability of, 56f, 56-60 cocci in, 229f characteristics of, 225b sclerotic convergence of, 49 description of, 222 description of, 327 density of, 51t, 54--56, 57f, 60, 324 extraradicular, 234 illustration of, 32f diameter of, 51t fungi that cause, 231 permeability of,56 exposed,373-374,374f microbiota associated with, 226-228, 227b, secondary, 27, 33-34, 48--49, 78, 430, 433, innervation of, 177 228f, 230--232 438--439 microleakage, 60 pathogenesis of, 222-224 secretory model of, 29-30, 32-33 permeability persistent, 225b softness of, 52 description of, 50, 54 persistent intraradicular, 225b, 232-234 tensile strength of, 52-53 sensitivity management by reductions in, primary intraradicular tertiary, 27, 34--35, 49, 49f, 78, 317, 324 186-187 characteristics of, 225b, 226 thermal properties of, 335, 349, 350t scanning electron micrograph of, 223f description of, 225-226 thickness of, 49, 325 sclerosis effects, 319, 331 geographic influences, 228-229 trauma-induced exposure of, 224 shape of,30, 31f, 31-32 microbiota associated with, 226-228, 227b, 228f, water content of, 51-52 Dentinoenamel junction, 48-50, 216 230 Dentin adhesives, 312-313 Dentinogenesis routes of, 223f Dentin bonding aging effects on, 431, 438-440 secondary intraradicular, 225b, 232-234 glass ionomers for, 312, 337-338 definition of, 430 treatment of, 234--235, 406 history of, 335 glycosaminoglycans' role in, 72 types of, 225-234 limitations of, 338-340 primary, 31-33, 430 viruses that cause, 231-232 polymerization shrinkage concerns, 338 reactionary Endodontic therapy pulp affected by, 340--341 biologic processes, 35f-36f, 35-37 microcirculatory system effects, 126 resin-based materials for, 335-337, 336f definition of, 35, 331, 333 pain continuance after resin-modified glass ionomers for, 312, 338 factors that affect, 37-38 description of, 173-174 Dentin chips, 99, 304--305 histomorphometric findings, 37-38 local anesthetics for, 195-196 Dentin dysplasia, 476 odontoblast upregulation during, 35-37 management strategies for, 199-200 Dentin matrix restorative materials that cause, 35-36 nonsteroidal anti-inflammatory drugs for, 193- composition of, 17-18 reparative 194, 199-200 growth factors in, 36 biologic processes during, 35f Endodontic-periodontal diseases lateral branches of, 30, 30f collagen fibrils in,72 anatomical relationships, 373-375 odontoblast-like cell differentiation induced definition of, 333 contributing factors by, 41 dentin bridge formation vs, 43 avulsion, 386 remodeling of, 29-30 description of, 38 coronal leakage, 384 secondary, 34 fibrodentin matrix secreted before, 39 crown fracture, 385 vesicle, 31f histologic findings, 38, 39f crown-root fracture, 385-386 Dentin matrix protein 1, 18, 18t, 20, 21f, 430 matrices secreted during, 38, 39f-40f developmental malformations, 387 Dentin phosphoproteins, 18-19, 29 odontoblast-like cell differentiation, 41-43 enamel fracture, 385 Dentin sialophosphoprotein, 8, 17-19, 310, 476 progenitor cell recruitment in, 40-41 luxation,386 Dentin sialoprotein, 18, 74, 76, 476 tertiary dentinogenesis and, 39 perforation, 386-387 Dentinal bridge secondary, 33-34 poor endodontic treatment, 384 calcium hydroxide for creating, 308-310 tertiary root fracture, 386, 390 defects, 43 cavity preparation materials that affect,35-36 trauma,385-386 formation of, 43, 71 description of,34-- 35 differential diagnosis of,388-392 vital pulp therapy and, 306-307 transforming growth factor-j31's role in, 36 etiology of Dentinal caries, 216f, 216t, 216-218 Dentinogenesis imperfecta, 16, 17f, 476f, 476- bacteria, 377-378 Dentinal fluid, 52f, 55f 477 Charcot-Leyden crystals, 383, 384f description of, SO Dentrifices, 188-189, 188t-189t cholesterol crystals, 382, 382f flow Developmental malformations, 387 foreign bodies, 380, 380f-381f evaporative, 352 Diabetes mellitus, 484-485 fungi, 376f, 378 sensitivity management by reduction of, Digastric muscle, 454f infectious biofilms, 379 186-187 DiGeorge syndrome, 285-286, 484t live pathogens, 375-379 pain perception secondary to movement of, Direct pulp capping,340 nonliving pathogens, 380--383 177 Discontinuous capillary, 111 Rushton hyaline bodies, 383, 383f Dentinal sensitivity Diversity of microbiota, 226 Russell bodies, 382f, 382-383 age and, 177 DNA chips, 22 viruses, 379 characteristics of, 177-178 Dysfunctional pain, 175 overview of, 37 3 desensitizing agents for portals of exit, 374--375 fluoride-containing medications, 189 E prognosis for, 392-393 guanethidine, 189-190 Ecological plaque hypothesis, 212-213, 213f Endogenous opioid peptides, 164 potassium-containing dentrifices, 188-189, Ectomesenchyme, 2 Endothelin 1, 123, 243 188t-189t EDTA-soluble dentin matrix protein preparation, Endothelin receptor A, 243 strontium chloride solutions, 189 342 Endothelin receptor B, 243 diagnosis of, 190--191 Eicosanoids. See Arachidonic acid metabolites. Enterococcus faecalis, 233 hydrodynamic theory of, 177-178 Elderly, 421 Eosinophils, 283b inflammation effects, 178 Embryonic stem cells, 93-94 Epidermal growth factor, 97t lasers for, 365-367 Enamel caries, 211 Episodic neuropathic pain, 458 management of, 185-190 Enamel cracks, 224 Epithelial rests of Malassez, 380

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Epitheliated granuloma, 380 Glial-derived neurotrophic factor, 137 caries-induced response, 85--86 Epstein-Barr virus, 231-232, 379, 473 Glossopharyngeal neuralgia, 4S9-460 cavity preparation and restoration effects, Erupting teeth, 142 Gl ucocorticoid excess, 48S-486 84--8S Er:YAG lasers, 362-36S Glucocorticoids, 19S dendritic cells, 82--84 Etch-and-rinse adhesives, 336 Glycosaminoglycans, 4, 67, 72 lymphocytes, 79--81 Etchants, 36 Golgi complex, 74--7S, 434 macrophages, 81--82 Etching. See Acid etching. G-protein-coupled receptors, 14S Immunodeficiencies Ethylenediaminetetraacetic acid, 36, 38, 103, Gram-negative bacteria, 227b description of, 283 342, 361 Gram-positive bacteria, 227b innate responses, 283--28S Evaporative fluid flow, 3S2 Granulocyte colony-stimulating factor, 284 specific responses, 285--287 Evolutionary theory, 422 Granulocyte-macrophage colony-stimulating factor, lmmunoglobulins, 270, 281, 426 Excimer lasers, 36S 287 Indirect pulp capping, 317-319 Excitatory amino acids, 162, 16S Growth factors Infection. See also Endodontic infections. External root resorption. See Root resorption, angiogenic, 36 in childhood development, 473--474 external. definition of, 10, 77, 97 cytochemical responses to, 139-14S Extracellular matrix in dentin matrix, 36 in fetal development, 473--474 basement membrane, 73 function of, 97t intraradicular. See lntraradicular infections. collagen. See Collagen . insulin-like, 36 structural responses to, 139-14S dentin, 9, 440 odontoblast-like cell differentiation induced Inflammation fibronectin, 73--74 by, 42 dentinal sensitivity caused by, 178 growth factors in, 42 orthodontic therapy effects, 127 heat-induced, 170--171 laser capture microdissection studies of, 9 regenerative medicine use of, 9&--98 humeral immunity in, 281-282 odontoblast secretion modulated by, 33 types of, 97t management of, 403 plaque biofilm formation of, 207 Growth-associated protein-43, 137 mediators of. See Inflammatory mediators. tooth morphogenesis role of, 14--1 S Guanethidine, 189-190 microcirculatory system effects, 127-128 Extrusive luxation, 386 Gutta-percha, 3S&--3S8 neuropeptides' role in, 243--247 prostaglandins' role in, 2S1 F H resident cells in, 282 Fabry disease, 484t Hageman factor, 2S7 response to, 16&--167 Fenestrated capillary, 111 Hartwig's epithelial root sheath, 397 restorative materials and procedures that Fermentable carbohydrates, 213, 220 Hayflick phenomenon, 423 cause, 343f Fibrillar proteins, 67 Headache root resorption induced by, 401-402 Fibrinogen, 2S7, 3S4 cluster, 4S7-4S8 Inflammatory cyst, 381f Fibroblast(s) migraine, 4SS-4S7 Inflammatory mediators connective tissue remodeling, 79 Healing arachidonic acid metabolites, 2S0--2S2, 2S4-- definition of, 78 bacteria effects on, 302-303 2SS, 290--291 functions of, 67 with cementum, 402 chemokines, 269 illustration of, 78f osseous replacement for, 402-403, 403f cytokines, 263--264, 26&--269 . See alsoCytokines. interleukin-1 effects, 264 Heat shock proteins, 33S, 432 defensins, 270 mitotic activity of, 78 Helper T cells, 79, 278, 280, 291-292 description of. 127-128, 241 morphology of, 78 Hemoglobinopathies, 481-482 drugs that block, 192-19S substance P effects, 70 Hemorrhage control, 305--306 function of, 241 Fibroblast growth factors, 10--11, 14, 97t Hereditary opalescent dentin, 476 histamine, 123, 242 Fibrodentin, 39 Herpes zoster, 460 immunoglobulins, 270 Fibronectin, 73f. 73-74 Herpesvirus, 379, 472-473, 473f maresins, 2SS Fibronectin-binding protein, 333 Heterotypic assays, Sf microcirculatory system effects, 127-128 Fluorescent antibody cell sorting, 96 Histamine, 123, 242 nerve functions affected by, 171-172 Fluoride Homeostatic regeneration, 91 neuropeptides, 243--247, 3S4 caries prevention using, 221-222 Homotypic assays, Sf nitric oxide, 261t, 261-262, 3SS dentinal sensitivity managed using, 189 Horizontal gene transfer, 208 nociceptors sensitized by, 160 Foreign bodies, 380, 380f-381f Hot stimuli, for pulpal vitality testing, 179 nucleotide-binding oligomerization domains, FOXP3+CD2S+ cells, 280 Human immunodeficiency virus, 286, 379, 471- 267-268 Fractures, 385--386 472 odontoblast production of, 242 Free radicals, 423--424 Humeral immunity, 281-282 oxygen-derived free radicals, 262-263 Fungi, 231, 376f, 378 Hydroxyapatite crystals periapical, 287-293 Fusobacterium species, 217 carbonated, 221 plasma proteases characteristics of, SO clotting system, 2S7-2S9 G formation of, 29 complement system, 2S&--2S7 G proteins, 14S nucleation of, 31 fibrinolytic systems, 2S7-2S9 Gap junctions, 7 6, 136f Hyperalgesia, 148 kinin system, 2S6 Gaucher disease, 482-484, 483f, 483t central mechanisms of, 171-173, 172b lysosomal enzymes, 260--261 Gene regulation, 422 characteristics of, 169t, 169-170 matrix metalloproteinases, 260--261 Genetic and developmental disorders definition of, 169 protease inhibitors, 261 amelogenesis imperfecta, 477 peripheral mechanisms of, 170b, 170--171 platelet-activating factor, 2S6 dens in dente, 47Sf, 475-476 Hyperesthesia, 460 protectins, 2SS dentinogenesis imperfecta, 16, 17f, 476f, 47&-- Hyperglycemia, 48S regulatory mechanisms, 168--169 477 Hyperparathyroidism, 478-479 resolvins, 2SS Gaucher disease, 482-484, 483f, 483t Hypersensitivity. See Dentinal sensitivity. root resorption, 399 hemoglobinopathies, 481-482 Hypoesthesia, 460 serotonin, 242-243 hypophosphatemic rickets, 479-481, 481f Hypophosphatemic rickets, 479-481, 481f Inflammatory pain sickle cell anemia, 481-482, 482f characteristics of, 16&--177 taurodontism, 474, 47Sf nonsteroidal anti-inflammatory drugs for, thalassemia, 481, 482f Ibuprofen, 193-194 193-- 194, 199-200 German measles, 473--47 4 Immune responses Injury-induced regeneration, 91 Glass ionomers adaptive, 285--287 Innate immunity conventional, 337, 337f innate, 283-28S adaptive immunity and, transition between, description of, 312 periapical, 277-282 329 resin-modified, 312, 338 Immunity, 277 deficiencies in, 283-28S Glia, 16S lmmunocompetent cells description of, 277

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toll-like receptors, 266--267 types of, 358-359 capillaries, 110--111 Innervation wavelengths of, 359f description of, 109 agents involved in, 138t Laser capture microdissection, 9 diagnostic uses of, 128 axonal transport, 134, 135f Laser Doppler flowmetry, 127-128 endodontic therapy effects, 126 developing teeth, 142 Lateral luxation, 386 inflammatory mediators effect,127 -128 erupting teeth, 142 Lateral periodontitis, 406 local anesthetics effect, 124-125 neuropeptide-rich fibers, 134 Leukemia, 487f lymphatic vessels, 112-114 overview of,133 -137 Leukocyte adhesion microcirculation, 114-115 parasympathetic, 138 chemotactic factors involved in, 250 orthodontic therapy effects, 126-127 peptidergic, 143-145 margination, 247 orthognathic surgery effects,127 primary teeth, 142 molecules involved in, 247-248,250 restorative procedures effect, 125--126 pulpal, 141, 1411 Leukocyte adhesion deficiency-1, 250, 283 schematic diagram of, 11Of sensory neurons, 134f, 134-135, 434 Leukocyte adhesion deficiency-2, 248, 283 transcapillary exchange, 114-115 sympathetic, 138 Leukotrienes venules, 111 lntegrins, 77, 250, 397 B., 311 Microcomputed tomography, 431 lntercellular cell adhesion molecules, 248, 250 description of, 252 Microsurgery, 437f lnterleukin-1, 264, 289 L-form bacteria, 378 Migraine, 455-457 Interleukin- la, 288 Lidocaine,196-197 Mineral trioxide aggregate, 307,313-315, 315f lnterleukin-1 f3, 287-289 Linear coefficient of thermal expansion, 350--351 Mitochondrial DNA, 423 lnterleukin-2, 268 Lipopolysaccharides, 217, 267, 281 Mitochondrial respiratory system, 423 lnterleukin-6, 268-269, 287-288, 399 Lipoteichoic acid,264, 269, 282, 329 Moire interferometry, 350 lnterleukin-8,287 Lipoxins, 252,254-255, 255 Monocytes,283b lnterleukin-11, 288, 399-400 Lipoxygenase,252, 254-255 Multiple sclerosis, 465 Internal root resorption. See Root resorption,internal. Local anesthetics Mutans streptococci, 213-214 lnterneurons, 162-163 circulatory effects, 124-125 Myelin, 146,146f Interstitial pressure intraligamentary injections of, 198 Myofascial pain, 452-454 microvascular exchange effects on,114-116 intraosseous administration of, 197-198 pulpal, 115--116 pain block using, 450 N Interstitial space,114 pain localization using, 177 Naloxone,164-165 lntertubular dentin, 32, 49, 440 pain management using, 195--198 Natural killer T cells, 280 lntracanal irrigants, 100, 235 speed of injection,197 Nd:YAG laser, 359, 365--366 lntracoronal bleaching, 410 Lowe syndrome, 484t Nerve degeneration, 147 lntraligamentary injections, of local anesthetics, Luxation, 386 Nerve fibers 198 Lymphatic vessels, 112-114 Af3,136-13 7 lntraluminal collagen, 511 Lymphocytes. See B cells; T cells. activation of, 1511 lntraradicular infections Lysosomal enzymes, 260--261 A8, 137 persistent, 225b,232 -234 antigen-presenting cells and,270 primary M chemical signaling, 138 characteristics of, 225b,226 Macrophages, 811,81 -82, 287-288 cytochemical features of, 137 description of,22 5--226 Magnetic resonance imaging,104 immunochemistry of,140f geographic influences,228-229 Major histocompatibility complex molecules, 80-- inflammation effects, 171-172 microbiota associated with, 226-228, 227b, 84, 83f, 269-270,354 odontoblasts and, 177 228f,230 Mantle dentin, 31, 48, 53t patterns of, 140f secondary,225b,232-234 Maresins, 255 pulpal interactions with, 139 lntratubular dentin, 49, 440 Margination,247 sprouting of, 141, 171,243 Ion channels,14 5--147 Masseter muscle, 454f types of, 136-137 Irreversible pulpitis, 450-451 Maternal rubella, 473-474 Nerve growth factor,97t, 136-137, 434 lrrigants, 100, 235 Matrix metalloproteinases Neuritic pain, 460-461 aging effects on, 425 Neurokinin A, 143, 243 J collagen degradation by,339 Neurons, 164 Junctional epithelium, 134-135 definition of, 30, 326 Neuropathic pain dentin remodeling, 261 continuous, 460-462 extracellular matrix degradation caused by,261 definition of, 458 K inhibitors of, 339-340 description of,174-175, 175f Kallikrein, 123 odontoblast expression by, 30 episodic, 458 Kinin system, 256 odontoblast synthesis of, 76-77 Neuropeptide Y, 119, 1201, 143, 243, 245--246, 354 Kininogens, 256 source of, 326 Neuropeptides, 122f, 143, 243-247, 354, 434 Knockout mice, for tooth development studies, tooth morphogenesis role of,15 Neuropulpal interactions 7-8, 12 Mechanoreceptors,135 agents involved in, 138b Korff fibers, 68, 71, 73 Medial pterygoid muscle, 454f schematic diagram of, 134f Medullary dorsal horn,160f, 162 Neutrophils, 262, 283b L Membrane attack complex,256 Niches, 93 Lactobacilli, 214 Membrane receptors, 145--147 Nitric oxide, 261t, 261-262, 355 Lamina phase, of tooth development, 2, 3f Mesenchymal cells, undifferentiated, 68, 79 Nociceptors Laser(s) Mesenchyme, dental central sensitization activated by,172 argon, 359 enamel knot formation regulated by,14 drugs that block release or actions of inflammatory co,, 361-362 molecules that affect, 10 mediators, 192-195 dentinal injury caused by,36 1-362 Metarterioles, 110 interneurons effect, 163, 163f dentinal sensitivity treated with, 365--367 Microarrays,22, 22f neurophysiology of, 147-153 description of, 358-359 Microbiota sensitization of, 170 Er:YAG, 362-365 definition of, 226 signal transmission pathways,16 0--166 excimer, 365 diversity of, 226 Nodes of Ranvier, 146 Nd:YAG, 359, 365--366 ecology of, 230--231 Noncollagenous proteins, 18, 18t pulpal responses, 359-361 in endodontically treated teeth,233-23 4 Nonodontogenic pain root canal use, 361 primary intraradicular infections caused by, atypical odontalgia, 461-462 ruby,361 226-228,22 7b, 228f, 230 cardiac origin of, 462-463 schematic diagram of, 359f Microcirculatory system, of pulp. See also Pulpal causes of, 451-453 soft tissue uses of, 367 blood flow. clinical features of,4 52b tooth bleaching use of, 367 arterioles,109 -110, 1101, 1211, 127f cluster headache, 457-458

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deafferentation origin of, 461-462 definition of, 111 Periapical bone loss, 288--289 glossopharyngeal neuralgia, 459-460 illustration of, 68f Periapical immune responses, 277-282 migraine, 455-457 Odontoblast process, 47, 75, 75f, 440 Periapical inflammation myofascial pain, 452-454 Odontoblastoid cells, 96 humeral immunity in, 281-282 psychogenic origin, 463--464 Odontocytes, 431 mediators of, 287-293 systemic disorders that cause, 464-465 Odontogenesis. See Tooth development. resident cells in, 282 trigeminal autonomic cephalgia, 457-458 Odontogenic pain, 191-199, 447, 451b. See also Periapical lesions trigeminal neuralgia, 458-459 Pain. chronic, 281 zoster, 473 Odontogenic toothache, 449b, 450f, 451 definition of, 277 Nonspecific plaque hypothesis, 212 Oligonucleotide arrays, 22 description of, 281 Nonsteroidal anti-inflammatory drugs, 193-194, Opioids, 196 illustration of, 376f, 380f, 384f 199-200 Opsonization, 270 immune cells in, 278--281 Notch signaling, 41, 310, 432 Orthodontics, 126-127 Periapical replacement resorption, 404 Nucleotide-binding oligomerization domains, Orthognathic surgery, 126-127 Periluminal dentin, 49 267-268 Osseous replacement, 402-403, 403f Periodontal disease Nucleus caudalis, 162-164 Osteitis deform ans. See Paget disease of bone. endodontic disease and, 389-392, 3891-392f. Nursing caries, 215 Osteocalcin, 18t See also Endodontic-periodontal diseases. Osteoclast(s), 477 primary, 388, 3891-390f, 393 0 calcified tissue resorption by, 400 Periodontal ligament-derived stem cells, 7, 7f Occlusal adjustment, for pain management, 191 extracellular protein binding, 397 Periodontitis Occlusal caries, 216t, 307f, 330f, 332f mediators that affect functioning of, 399 apical. See Apical periodontitis. Oculocerebrorenal syndrome, 484t odontoblast vs, 400 lateral, 406 Odontalgia Osteoclast-activating factor, 288 progressive, 390 atypical, 461-462 Osteoclastic diseases, 477-478 Peritubular dentin, 32, 32f, 48, 52, 440 diagnosis of, 190-191 Osteoimmunology, 400 Permeability incidence of, 185, 447 Osteonectin, 18t, 74 capillary, 127 Odontoblast Osteopontin, 18, 18t, 21, 211, 401 dentin. See Dentin, permeability. age-related changes in, 426, 429-430 Osteoprotegerin, 398, 477-478 Phospholipids, 2511 calcium transport system, 30 Oxidative stress, 423--424 Pink tooth, 412 cavity preparation effects on, 341 Oxygen-derived free radicals, 262-263 Plaque cell body of, 74-75 accumulation of, 206f characteristics of, 68 p acid production by, 214 collagen synthesis, 29 Paget disease of bone, 415, 478-479, 4791 beneficial bacteria in, 214 cultures for studying, 6, 9 Pain biofilm. See Biofilm, plaque. death of, 43 classification systems for, 452 definition of, 206 definition of, 4, 47, 76 diagnostic approach, 190-191, 465 developmental stages of, 209-210 differentiation of dysfunctional, 175 mechanical removal of, 220 bone morphogenetic proteins, 355 endogenous analgesic system activated by, Plasma cells, 283b collagen fibers in, 71 165 Plasma exudate, 305-306 core-binding factor a 1's role in, 12, 14 incidence of, 159, 185 Plasma proteases fibronectin effects, 73 inflammatory. See Inflammatory pain. clotting system, 257-259 morphologic changes, 15-16 local anesthetic blocking of, 450 complement system, 256-257 signaling interactions that influence, 10-15 myofascial, 452-454 fibrinolytic systems, 257-259 steps involved in, 15 neuritic, 460-461 kinin system, 256 studies of, 9 neuropathic lysosomal enzymes, 260-261 terminal events in, 16f, 73 continuous, 460-462 matrix metalloproteinases, 260-261 fibronectin effects on, 73 definition of, 458 protease inhibitors, 261 functions of, 76-78, 138, 355 description of, 174-175, 175f Plasticity glycosaminoglycans effect, 72 episodic, 458 embryonic stem cells, 93 Golgi complex, 74-75 nonodontogenic. See Nonodontogenic pain. trigeminal ganglion, 140-141 illustration of, 6f, 48f nonpharmacologic treatment of, 191-192 Platelet-activating factor, 256 inflammatory mediators produced by, 242 odontogenic, 191-199, 447, 451b Platelet-derived growth factor, 97t injury response of, 77-78 perception of Platelet-endothelial cell adhesion molecule, 248 innate immunity functions of, 77 drugs that block, 198--199 Polymerization shrinkage, 338--339, 341 integrins secreted by, 77 mechanisms, 159-160, 164-166 Polymorphonuclear neutrophils, 278--279, 285 junctions of, 75-76, 136f postendodontic therapy, 173-174 Porcine enamel matrix, 316 life cycle of, 399f prostaglandins' role in, 251-252 Porphyromonas species, 217 matrix metalloproteinase synthesis by, 76-77 pulpal vitality testing to diagnosis, 178--180 Postherpetic neuralgia, 473 mitochondria of, 75 referred, 176-177, 447-448, 448f-4491 Postnatal stem cells, 93-94, 98 morphology of, 15-16, 28, 68, 430 site of, 449-451 Potassium-containing dentrifices, 188t, 188--189 nerve fibers and, 177 source of, 449-451 Predentin, 16f, 47-48, 48f, 71-72, 411-412, 433, osteoclast vs, 400 transmission of 486f phenotype of, 28--29 drugs that block, 195-198 Prekallikrein, 256 predentin secretion by, 16f physiologic mechanisms, 160-166 Pressure resorption, 403--404 progenitor cells for, 40-41 treatment of Pre-trigeminal neuralgia, 458 pulp and, relationship between, 28--29 corticosteroids, 195 Prevotella species, 217 restorative materials effect on, 341-342 cyclo-oxygenase inhibitors, 194 Primary caries, 212 secondary, 78 glucocorticoids, 195 Primary dentinogenesis, 31-33, 430 secretory behavior of, 29f, 29-31, 33, 76-77 nonpharmacologic, 191-192 Primary endodontic disease, 388, 392 sensory fibers and, interactions between, 138 nonsteroidal anti-inflammatory drugs, 193- Primary hyperparathyroidism, 478-479 structure of, 74-76 194, 199-200 Primary oxalosis type I, 484t synthesis functions of, 76-77 pharmacologic, 192-199 Primary periodontal disease, 388, 3891-390!, 393 toll-like receptor 4, 102 strategies for, 199-200 Primary teeth, 142 tooth sensation role of, 138 Papillon-Lefevre syndrome, 484t Progenitor cells type I collagen in, 17f Parasympathetic nerves chemoattractants, 41 ultrastructural appearance of, 28f pulpal blood flow regulated by, 120-121 definition of, 92 Odontoblast layer tooth innervation by, 138 dental follicle, 95 characteristics of, 68--69 Peptidergic innervation, 143-145 description of, 310 Peptidoglycans, 264 mesenchymal cells, 40

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regenerative medicine use of, 92-95 Pulp core, 69 repair capacity of, 334 in reparative dentinogenesis, 40--41 Pulp proper, 69 structure of, 47-48, 48f, 324-325 Progressive periodontitis, 390 Pulp space infection Pulse oximetry, 128 Proinflammatory cytokines, 264-268, 265f, 287-289, description of, 404 291-293 external root resorption caused by, 404-408 Q Projection neurons, 163-164 prevention of. 407 Ouorum sensing, 208-209 Prostaglandins treatment of, 407-408 description of, 123, 168, 251-252, 290 Pulp stem cells R E2, 282 description of, 95--96 Radiographs Prosthetic procedures, 125--126 pulp constructs created from, 98-100, 99f, 102t aging, 441 Protease inhibitors, 15, 261 smear layer attachment of, 102, 103f apical periodontitis, 206f Protectins, 255 Pulp stones, 437-438 caries, 218, 218f Protein kinases, 164 Pulpal blood flow external root resorption, 413, 414f, 415 Proteoglycans bacterial effects, 127-128 internal root resorption, 412-413, 412f, 415 bacterial penetration prevented by, 73 calculation of, 114 Raman spectroscopy, 431 definition of, 67 dentin grinding effects on, 125f RANKL, 282, 398, 401, 477-478 in extracellular matrix, 18t histamine effects, 242 Reactionary dentin hydrophilicity of, 72 inflammatory mediators effect, 69 cavity etching stimulation of, 38 structure of, 72 measurement of, 116-117 cellular signaling of, 38 Proteolytic bacteria, 377 neuropeptides' effect on, 122f definition of, 34, 78 Pulp prosthetic procedures' effect on, 125--126 deposition areas for, 334 adhesion molecules in, 247-248, 250 regulatory mechanisms of ethylenediaminetetraacetic acid effects, 38 age-related changes in, 425--442 a-adrenergic receptors, 118f production of, 333 biology of, 21-22 endocrine factors, 123 remaining dentinal thickness effects, 37-38 blood vessels of, 432-434 metabolism, 117-118 restorative materials' effect on formation of, 342- caries-induced exposure of, 224, 224f neuronal, 118-123 343 cellular arrangement of, 68f, 68--69 neurotransmitters, 122 Reactionary dentinogenesis circulatory system of. See Microcirculatory system. paracrine factors, 123 biologic processes, 35f-36f, 35--37 clonal lines for studying, 6 parasympathetic nerves, 120-121 definition of, 35, 331, 333 collagen types in, 70-71 peptidergic afferent fibers, 121-123 factors that affect, 37-38 coronal, 711, 429f schematic diagram of, 115f, 117f histomorphometric findings, 37-38 crown fracture involving, 385 sympathetic nerves, 118-120 odontoblast upregulation during, 35--37 dendritic cells of, 82-84 trigeminal sensory nerves, 126 restorative materials that cause, 35--36 dentin bonding effects on, 340-341 restorative procedures' effect on, 125-126 Reactive oxygen species, 423 edema of. 305 sensory nerve denervation effects on, 1211 Receptor activator of nuclear factor Kf3 ligand. See elasticity of, 71 stimulation of, 61 RAN KL. exposure of, 302f, 303-305 Pulpal infection. See also Endodontic infections. Recombinant human bone morphogenetic proteins, features of, 68--69 caries. See Caries. 91, 310 innervation of, 141, 1411 protective immunity against, 282-287 Recombinant human insulin-like growth factor 1, low-compliance environment of, 69 Pulpal injury. See also Tooth injury. 97-98 mineralization of, 437 cavity preparation as cause of, 334-335 Recurrent caries, 211-212, 218-219 necrosis of, 404-405 description of, 77-78 Referred pain, 176-177, 447-448, 448f-449f nerve fibers of. See Nerve fibers. healing after, 302-303 Regeneration odontoblasts of. See Odontoblast. microleakage, 343 definition of, 92 radicular, 429f pulp capping for. See Pulp capping. history of, 91 recession of, 33 reasons for, 301 homeostatic, 91 responses of, 277-278 root resorption caused by, 402-403 injury-induced, 91 revascularization of. 407 signaling molecules contributing to, 43f Regenerative endodontics root resorption role of. 401-402 Pulpal interstitial pressure, 115--116 challenges associated with, 104b sensory innervation of. 70 Pulpal nerves delivery improvements for, 103-104 size reductions in, 438 degeneration of, 147 dental pulp constructs for, 98-100, 99f, 102t structural organization of, 68--69 sensory functions of, 148-150, 152-153 objectives of, 92 sympathetic nervous system innervation of, 118 Pulpitis outcome measurements, 104 testing responses of, for aging evaluations, immune cells in, 277-278 postnatal stem cells for, 98-99, 99f, 102t 436-437 management of, 190-199 research priorities for, 102-104 tissue engineering of, 103 opioids for, 198 root canal revascularization using blood clotting, vascular responses of, 242 pain caused by, 147, 190-199 100-101, 102t vasculature of. See Microcirculatory system. silent, 147 Regenerative medicine vitality of. See Vital pulp. Pulpodentin complex. See also Dentin; Pulp. foundations of, 92-98 Pulp capping age-related changes in, 427, 440--442 growth factors, 96-98 adhesive systems for, 312-313 caries history of, 91 in aging tissue, 441-442 defense responses to, 329-331, 330f-3311 progenitor cells, 92-95 dentin bridge formation as indication of, 43 description of. 325 stem cells. See Stem cells. dentinal bridge effects on, 306-307 injury responses to, 328-329 Regulatory T cells, 278, 280, 291 direct, 340 responses to, 328-333 Remaining caries, 212 exposure duration effects on, 303 characteristics of, 69-70, 223 Remaining dentinal thickness, 37-38, 325, 334-335, hemorrhage control before, 305--306 defense responses by, 329-331, 330f-3311 355 indirect, 317-319 definition of, 1 Remineralization materials for functions of, 91 description of, 212 calcium hydroxide. See Calcium hydroxide. injury response fluoride effects on, 222 dentin adhesives, 312-313 to caries, 328-329 Renal dystrophy, 415 description of, 305--306, 311 cavity preparation, 334 Reparative dentin, 34, 78, 308 experimental bioactive molecule-containing description of, 77-78 Reparative dentinogenesis materials, 315--317 neuroanatomical responses, 141 biologic processes during, 35f glass ionomers, 312 signaling molecules contributing to, 43f collagen fibrils in, 72 mineral trioxide aggregate, 313-315, 315f stimuli that cause, 139 definition of, 333 zinc oxide-eugenol, 318 summary of, 344-345 dentin bridge formation vs, 43 microbial leakage effects on, 310 permeability of, 324-325 description of, 38 fibrodentin matrix secreted before, 39

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histologic findings,39f pink tooth, 412, 415 overview of,91 -92 matrices secreted during,38, 39f-40f radiographic findings, 412-413, 412f, 415 periodontal ligament-derived, 7, 7f odontoblast-like cell differentiation, 41-43 treatment of,412-413 postnatal, 93--94, 98 "- progenitor cell recruitment in, 40--41 vitality testing, 415 protein expression by, 96 tertiary dentinogenesis and,39 mechanisms of, 397-401 pulp. See Pulp stem cells. Reparative tertiary dentinogenesis, 316 misdiagnoses, 415 source-based classification of, 94 Replicative senescence,423 Paget disease of bone and, 415. See a/so tooth-derived,6-7, 7f Resident cells, 282 Paget disease of bone. umbilical cord,94 Resin-based materials, 335-337,336f -337f pulpal role in, 401-402 xenogeneic,95 Resin-modified glass ionomers, 312, 338 renal dystrophy and,415 Sternocleidomastoid muscle,454f Resolvins, 255 requirements for, 401 Stratum intermedium,4 Restorative dentistry,323 resistance to,39 7-398 Streptococcus mutans, 214 Restorative materials and procedures subepithelial inflammatory, 408-410,415 Subepithelial inflammatory root resorption, bacterial microleakage, 303,343 systemic causes of, 415-416 408-410,415 calcium hydroxide . See Calcium hydroxide. Rubella,473-474, 474f Subluxation,386 dentin permeability effects,61-62 Ruby lasers, 361 Substance P,70, 121-123, 243--247,334 inflammation caused by, 343f Ruffini mechanoreceptors,135 Sulcular infection, 408-410 microcirculatory effect, 125-126 Rushton hyaline bodies,383, 383f Suppressor T cells,291 mineral trioxide aggregate, 313--315,31 Sf Russell bodies, 382f,382 -383 Sympathetic nerves odontoblast survival affected by,341 -342 pulpal blood flow regulated by, 118-120 physical properties of,349 -351 s tooth innervation by,119f, 138 reactionary dentin formation affected by,342- Saliva, 218, 220, 222 Systemic disorders 343 Scaffolds,99-100, 102 herpesvirus infections, 472-473, 473f specific heat of, 349-350 Sclerotic dentin human immunodeficiency virus, 471-472 tertiary dentinogenesis effects, 35-36 description of,327 nonodontogenic pain caused by,464-465 thermal conductivity of, 349 illustration of, 32f Paget disease, 478-479, 479f thermal diffusivity of, 350 permeability of, 56 rubella,473-474, 474f tooth-colored, 344 Secondary caries, 211 toxicity of, 303 Secondary dentin,27, 33-- 34, 48-49,78, 430,433, T zinc oxide-eugenol,318 439,440 T cells, 283b Revascularization of root canals using blood Selectins, 248 caries-induced response, 85-86 clotting,100- 101, 102t Self-etching adhesives, 336 CD4+, 279 Reverse transcriptase-polymerase chain react­ Senescence,421-423 CDS+, 279 ion, 9f Sensitivity. See Dentinal sensitivity. cytotoxic,278 Rickets Sensory fibers description of, 79-80 hypophosphatemic, 479-481,4811 injury responses of, 139 helper, 278,280, 291 vitamin D-dependent,479-480 odontoblast and,interactions between, 138 illustration of, 80f Root canals Sensory neurons, 134f, 134-135, 434 mechanism of activation, 80 accessory,37 4 Serotonin,242 -243 natural killer, 280 disinfection of, 102 Severe combined immunodeficiency,285- 286 regulatory, 278,280, 291 filling stage of, bacteria present at,232 -233 Shingles, 473 suppressor, 291 infections of. See Endodontic infections. Sickle cell anemia,464, 481-482, 482f Taurodontism,474, 475b, 475f laser therapy of, 361 Silent pulpitis,1 47 Telomeres, 423-425, 431 lateral, 374 Single-bottle adhesive systems, 336 Temporalis muscle, 454f pulp stem cell attachment to, 103f Sinus headache, 454 Temporomandibular dysfunction, 453-454 revascularization of, using blood clotting, Sinusitis, 455,460 Terminal arteriole,110 100-101,102t Small integrin-binding ligand, N-linked glyco­ Terminal capillary network,68 sodium hypochlorite-irrigated, 57f protein family,18 Tertiary dentin,27, 34-35, 49, 49f, 78,317, 324 Root caries, 211, 216t Smear layers Tertiary dentinogenesis Root dentin creation of, 57, 335 cavity preparation materials that affect, impermeability of, 58 description of, 57 35-36 mechanics of, 53--54 illustration of, 58f description of, 34-35 permeability of, 56f, 56-60 permeability effects, 58 reparative,316 Root fracture, 386,390 pulp stem cell attachment to, 102,103f transforming growth factor-fl1 's role in,36 Root perforation,386-- 387 removal of, 103,341 T halassemia,481, 482f Root resorption treatment of, 58 Thermal allodynia,449 cervical, 408 Smear plugs,57 T hermal stimuli external Smooth surface caries,216t cavity preparation, 349-353 apical periodontitis and,404-405 Sodium channels,146 laser treatment,358-366 description of,402 Sodium hypochlorite, 235 Thromboxanes,251 -252 diagnostic features of, 413,414b, 415 Somatoform pain disorder, 464 Tight-junction capillary, 111 diffuse injury,402-403 Specific plaque hypothesis,212 Tissue development stages, 94f lateral periodontitis with,406 Spirochetes, 378 T issue engineering localized injury,402 Starling forces, 114-115, 116 definition of, 92 pressure-induced,403-404 Stellate reticulum, 4 pulp, 103 pulp space infection, 404-408 Stem cells,41 scaffolds for, 99-100 radiographic findings, 413, 414f, 415 advantages of, 94-95 Toll-like receptors, 77, 102, 266f-267f, 266-267, sulcular infection, 408-410 allogeneic,95 282, 287-288,329 vitality testing,415 from apical papilla, 95 Tooth bleaching,36 7 histologic appearance of, 399f autologous, 94-95, 104 Tooth development inflammation-induced,401-402 definition of, 92 description of, 1-2 inflammatory mediators involved in,399 developmental stages of,9 4f enamel knots, 14 internal differentiation of, 7 epithelial-mesenchymalsignalinginteractions characteristics of, 411 embryonic,9 3--94 during, 10f clinical manifestations of,412 from human exfoliated deciduous teeth, 7, experimental systems for description of, 411 7f, 95 description of, 4 diagnostic features of,413, 414b, 415 isolation and identification of, 96 knockout mice, 7-8 etiology of,4 111,4 11-412 niches of,93 laser capture microdissection,9 histologic appearance of, 411 f,412 osteogenic induction of, 7f tooth organ culture systems,4-6, Sf

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transgenic mice, 7--8 transgenic mice studies of, 8 Vasoactive neuropeptides, 329 general features of, 2 Transgenic mice Vasoconstrictors, 124 stages of, 2-4, 3f development of, 7-8 Veil/one/la species, 214 Tooth injury. See also Pulpal injury. tooth development studies using, 7f, 7--8 Venular network, 111 axonal degeneration secondary to, 147 Transient receptor potential ion channels, 145 Venules, 111 classification of, 139 Transient receptor potential vanilloid 1, 462 Viruses, 231-232, 379 cytochemical responses to, 139-145 Transmigration, 248 Vital pulp delayed neural reactions to, 141 Transmitted-light photoplethysmography, 128 external root resorption prevented by main­ human teeth studies of, 141-142 Trauma tenance of, 407 ion channels, 145--147 dentin exposure caused by, 224 testing of membrane receptors, 145--147 endodontic-periodontal diseases secondary to, description of, 178-180 stimuli that cause, 139 385--386 root resorption diagnosis, 415 structural responses to, 139-145 Trephination, 191-192 Vital pulp therapy. See also Pulp capping. trigeminal nerve and ganglion plasticity, 140-141 Treponema species, 378 dentin adhesives for, 312-313 Tooth organ culture systems, 4--6, Sf Trigeminal autonomic cephalgia, 457-458 dentinal bridge effects, 306-307 Toothache, odontogenic, 449b, 450f, 451 Trigeminal ganglion description of, 301 Tooth-colored restorative materials, 344 dental nerve cell bodies, 137f mineral trioxide aggregate for, 313-315, 31Sf Tooth-derived stem cell lines, 6--7, 7f plasticity of, 140-141 resin-modified glass ionomers for, 312 Tooth-signaling molecules, 1 Trigeminal neuralgia, 458-459 Vitamin D metabolism disorders, 479-481 Transcapillary exchange, 114-115 Trigeminal sensory neurons, 162 Vitamin D-dependent rickets, 479-480 Transcription factors Trigeminovascular system, 455 Voltage-gated ion channels, 145 core-binding factor a1, 12, 13f Trigger points, 452 definition of, 10 True combined endodontic-periodontal disease, w function of, 10 391f-392f, 391-392 Wide dynamic range projection neurons, 164 Transdentinal permeability, SSf Tubular sclerosis, 219 Transforming growth factor-a, 97t Tumor necrosis factor, 264, 284 x Transforming growth factor-fl, 97t Tunnel defects, 43 Xenogeneic stem cells, 95 Transforming growth factor-[l1, 430 X-linked hypophosphatemic rickets, 479-481, 4811 chemotactic role of, 41 u etchants that solubilize, 36 Ultrasound, 333 z inflammatory role of, 269 Umbilical cord stem cells, 94 Zinc oxide-eugenol, 318 odontoblast secretion, 33 Undifferentiated mesenchymal cells, 68, 79 Zone of destruction, 216, 217f odontoblast-like cell differentiation induced by, Zone of Hohl, 96 41-42, 42f v Zone of Weil, 68, 113 production of, 293 Vascular cell adhesion molecule, 248 Zoster, 473, 473f reactionary dentinogenesis role of, 36 Vascular endothelial growth factor, 329 receptors, 38 Vasoactive intestinal peptide, 120-121, 143, 243

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