In the Name of God the Compassionate the Merciful

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The lung clinical physiology and pulmonary function tests. Chest. 1989; 65: 20 Proofs: These will be sent via E-mail, and must be duly cor- – 22. rected and returned within 48 hours. Absent authors should ar- 2 Schiebler GL, van Mierop LHS, Krovetz LJ. Diseases range for a colleague to access the E-mail and reply the proof. of the tricuspid valve. In: Moss AJ, Adams F, eds. Heart Disease in Infants, Children, and Adolescents. 2nd ed. Baltimore: Williams and Wilkins; 1988: 134 – 139. For further information please contact the Editorial Of- 3 Guyton AC. Textbook of Medical Physiology. 8th ed. fice through: Philadelphia: WB Saunders; 1996. Tele: +98-218-864-5492 Tables: Enumerate tables with Arabic numerals. They should Fax: +98-218-8656198 be self-explanatory, clearly arranged, and supplemental to the E-mail: [email protected] ; [email protected] text. Tables should provide easier understanding and not du- plicate information already included in the text or figures.

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 iii Table of Contents

Table of Contents

268 • Editorial

Hepatitis C in Iran. How Extensive of a Problem Is It? S. Merat, H. Poustchi 268

When Are Patients with Common Bile Duct Stones Referred for Surgery? M. Khatibian, S. Merat 269 271 • Original Articles

High Prevalence of Hepatitis C Infection among High Risk Groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran B. Sarkari, O. Eilami, A. Khosravani, A. Sharifi, M. Tabatabaee, M. Fara- rouei 271

Assessment and Treatment of Choledocholithiasis when Endoscopic Sphincterotomy is not Successful A. Shojaiefard, M. Esmaeilzadeh, Z. Khorgami, R. Sotoudehmanesh, A. Ghafouri 275

Reliability and Validity of the Modifiable Activity Questionnaire (MAQ) in an Iranian Urban Adult Population A. Momenan, M. Delshad, N. Sarbazi, N. Rezaei_Ghaleh, A. Ghanbarian, F. Azizi 279

Efficacy of Harm Reduction Programs among Patients of a Smoking Cessation Clinic in Tehran, Iran H. Sharifi, R. Kharaghani, H. Emami, Z. Hessami, M.R. Masjedi 283

Validity, Reliability and Factor Structure of Hepatitis B Quality of Life Questionnaire Version 1.0: Findings in a Large Sample of 320 patients A. Poorkaveh, A.H. Modabbernia, M. Ashrafi, S. Taslimi, M. Karami, M. Dalir, A. Estakhri, R. Malekzadeh, H. P. Sharifi, H. Poustchi 290

A New Technical Approach to Cancers of the Cervical Esophagus N. Nikbakhsh, F. Saidi, H. Fahimi 298

Severe Thrombocytopenia and Hemorrhagic Diathesis due to Brucel- losis H. Karsen, F. Duygu, K. Yapıcı, A. İ. Baran, H. Taskıran, İ. Binici 303

Acute Administration of Zn, Mg, and Thiamine Improves Postpartum Depression Conditions in Mice S. Nikseresht, S. Etebary, M. Karimian, F. Nabavizadeh, M. R. Zarrindast, H. R. Sadeghipour 306

Microbial Susceptibility, Virulence Factors, and Plasmid Profiles of Uropathogenic Escherichia coli Strains Isolated from Children in Jah- rom, Iran S. Farshad, R. Ranjbar, A. Japoni, M. Hosseini, M. Anvarinejad, R. Mo- hammadzadegan 312

iv Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Table of Contents

317 • Brief Report A Report of the Injuries Sustained in Iran Air Flight 277 that Crashed near Urmia, Iran A. Afshar, M. Hajyhosseinloo, A. Eftekhari, M. B. Safari, Z. Yekta 317 320 • Report Advocacy Strategies and Action Plans for Reducing Salt In- take in Iran N. Mohammadifard, S. Fahimi, A. Khosravi, H. Pouraram, S. Sajedinejad, P. Pharoah, R. Malekzadeh, N. Sarrafzadegan 320 325 • Case Reports A Rare Case of Perforated Meckel’s Diverticulum Presenting as a Gatrointestinal Stromal Tumor S. Sozen, Ö. Tuna 325

Primary Adrenal Hydatid Cyst Presenting with Arterial Hy- pertension M. Mokhtari, S. Zeraatian Nejad Davani 328

Primary Intrathoracic Biphasic Synovial Sarcoma Y.Tezcan, M. Koc, H. Kocak, Y. Kaya 331 333 • Photoclinic M. F. jarmakani, M. R. Mohebbi 335 • Excerpts from Persian Medical Literature

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 v S. Merat, H. Poustchi

Editorial Hepatitis C in Iran. How Extensive of a Problem Is It?

See the pages: 271– 274

Cite this article as: Merat S, Poustchi H. Hepatitis C in Iran. How extensive of a problem is it?. Arch Iran Med. 2012; 15(5):268.

epatitis B virus (HBV) used to be - and in many countries, similar to IL28B which predicts response to treatment or spontane- still is - the most common cause of chronic viral hepatitis. ous resolution. H Since the introduction of an effective vaccine against this virus, many countries have implemented neonatal HBV vaccina- In Iran there is a low prevalence of HCV, a low ratio of difficult- tion in their general health programs. We are beginning to observe to-treat genotypes, a high rate of spontaneous resolution, and better the effects of this vaccination in most parts of the world, including response to treatment. However, with the improvement of general Iran, where the prevalence of HBV infection is slowly declining.1,2 health awareness in Iran and the high prevalence of HCV infection On the other hand, there is no effective vaccine against hepatitis C among high-risk groups, we will soon face a large number of HCV virus (HCV). The lack of an effective vaccine and increase in intra- patients who seek treatment for which we need to be prepared. venous drug abuse, has led to a gradual increase in HCV infection in recent years.3,4 It follows that sooner or later, HCV will replace Shahin Merat MD, Hossein Poustchi MD PHD HBV as the major cause of chronic viral liver disease. Currently, in Digestive Disease Research Center, Tehran University of Medical many Western countries this already is the case. In Iran the rate of Sciences, Tehran, Iran. E-mail: [email protected] HCV infection in the general population is relatively low. Esti- mates are around 0.5%, while the latest estimates of HBV infection References are around 2.5%. Thus it would be quite a while before HCV prevalence in the general population of Iran reaches that of HBV.2,4 1. Merat S, Malekzadeh R, Rezvan H, Khatibian M. Hepatitis B in Iran. Nevertheless, in high risk populations the prevalence of HCV in- Arch Irn Med. 2000; 3: 192 – 201. fection is already alarming. In a report from Sarkari et al., pub- 2. Merat S, Rezvan H, Nouraie M, Jamali A, Assari S, Abolghasemi H, 5 et al. The prevalence of hepatitis B surface antigen and anti-hepatitis B lished in this issue of the journal, a rate of 8.6% is noted among core antibody in Iran: a population-based study. Arch Iran Med. 2009; over 2000 high-risk subjects. Other studies from Iran report rates 12(3): 225 – 231. as high as 31% in patients on chronic hemodialysis, 44.7% in thal- 3. Rezvan H, Ahmadi J, Farhadi M, Tardyan S. A preliminary study of 6 7 prevalence of HCV infection in healthy Iranian blood donors. Vox assemia patients, 72% in hemophilia patients, and up to 80% Sang. 1994; 67(suppl 2): 149. 8 among intravenous drug abusers in prisons. Numerous reports 4. Merat S, Rezvan H, Nouraie M, Jafari E, Abolghasemi H, Radmard from Iran indicate a high prevalence of HCV infection in high-risk AR, et al. Seroprevalence of hepatitis C virus: the first population- populations. How serious is the threat of HCV in Iran? based study from Iran. Int J Infect Dis. 2010; 14 (suppl 3):113 – 116. 5. Sarkari B, Eilami O, Khosravani A, Sharifi A, Tabatabaee M, Fararoee M. High prevalence of hepatitis C infection among high risk groups in Unlike HBV, there is a good chance for total eradication of Kohgiloyeh and Boyerahmad province, Southwest of Iran. Arch Iran HCVwith appropriate treatment. However this treatment is not in- Med. 2012; 15(5): 271 – 274 expensive, nor is it well-tolerated. Genotype is one of the major 6. Hassanshahi G, Arababadi MK, Assar S, Hakimi H, Karimabad MN, Abedinzadeh M, et al. Post-transfusion-transmitted hepatitis C virus factors effecting treatment and response. According to various re- infection: a study on thalassemia and hemodialysis patients in south- ports from Iran, the difficult-to-treat genotypes (1 and 4) comprise eastern Iran. Arch Virol. 2011; 156: 1111 – 1115. about 40% – 60% of our cases which is less than reports from most 7. Mosavi SA, Mansouri F, Saraei A, Sadeghei A, Merat S. [Seropreva- Western countries.9,10 Another peculiarity of Iranian HCV patients lence of hepatitis C in hemophilia patients refering to Iran Hemophilia 11 Society Center in Tehran]. Govaresh. 2011; 16: 16 – 174. is that they appear to respond better to treatment, although this 8. Mir-Nasseri MM, Mohammadkhani A, Tavakkoli H, Ansari E, Pou- better response might be partially explained by the recently de- stchi H. Incarceration is a major risk factor for blood-borne infection scribed IL28B polymorphism.12 This is fortunate as non-respond- among intravenous drug users: Incarceration and blood borne infection ers will probably require treatment with the expensive and poorly among intravenous drug users. Hepat Mon. 2011; 11: 19 – 22. 9. Zarkesh-Esfahani SH, Kardi MT, Edalati M. Hepatitis C virus geno- available protease inhibitors. type frequency in Isfahan province of Iran: a descriptive cross-sectional study. Virol J. 2010; 7: 69. It should be noted that the prevalence of HCV, as that of HBV, is 10. Samimi-Rad K, Nategh R, Malekzadeh R, Norder H, Magnius L. Mo- lecular epidemiology of hepatitis C virus in Iran as reflected by phylo- not uniform throughout the country. Differences up to 6-fold have genetic analysis of the NS5B region. J Med Virol. 2004; 74: 246 – 252. been observed. The prevalence among men is much higher than 11. Jabbari H, Bayatian A, Sharifi AH, Zaer-Rezaee H, Fakharzadeh E, women, probably in the range of 10-fold.4 Asadi R, et al. Safety and efficacy of locally manufactured pegylated in- Another feature of HCV infection in Iran is that there is probably terferon in hepatitis C patients. Arch Iran Med. 2010; 13(4): 306 – 312. 12. Mahboobi N, Behnava B, Alavian SM. IL28B SNP genotyping among a less chance for chronicity. In a recent report from Iran, up to 38% Iranian HCV-infected patients: A preliminary report. Hepat Mon. 2011; 13 of HCV infections spontaneously resolved. 11: 386 – 388. 13. Poustchi H, Esmaili S, Mohamadkhani A, Nikmahzar A, Pourshams We need studies that will evaluate host factors in Iranian patients. A, Sepanlou SG, et al. The impact of illicit drug use on spontaneous hepatitis C clearance: experience from a large cohort population study. It is conceivable that researchers may discover a genetic variation PLoS One. 2011; 6:23830.

268 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 When are patients with common bile duct stones referred for surgery?

Editorial When Are Patients With Common Bile Duct Stones Referred for Surgery?

See the pages: 275 – 278

Cite this article as: Khatibian M, Merat S. When are patients with common bile duct stones referred for surgery? Arch Iran Med. 2012; 15(5): 269 – 270.

n this issue of the journal, Shojaiefard et al. report the results On the one hand, the former will eventually need surgery to re- of surgery upon 186 patients in which endoscopic removal of move the gallbladder, even if ERCP is successful in removing the I common bile duct (CBD) stones had failed.1 CBD stones, so a second or third endoscopic attempt to remove the Endoscopic Retrograde Cholangiopancreatography (ERCP) is CBD stones might not be justified in light of the overloaded ERCP considered the standard primary treatment for CBD stones in pa- department with many emergency patientsin line. The relatively tients with previous cholecystectomy. Even in patients with gall large number of non-cholecystectomied patients refered for sur- bladders, ERCP together with cholecystectomy is a well-accepted gery in this study (76%) might be a reflection of this fact. On the method.2 Laprascopic CBD exploration is time consuming, re- other hand, subjects who have already undergone cholecystectomy quires more expertize, and is associated with increased morbid- can be spared surgery if endoscopic treatment is successful. Thus, ity including biliray strictures.Thus, surgeons often prefer to have multiple attempts at removing the CBD stones endoscopically is the CBD stones removed endoscopically either before or after well justified. cholecystectomy.3A meta-analysis on non-cholecystectomiedsub- jects with CBD stones looked at 7 trials comparing open surgery It is also frequently observed that patients with less operative risk for removing both the gallbladder and the CBD stones vs. chole- are more readily refered for surgery. cystectomy and endoscopic removalof CBD stones. The results in In patients who are poor surgical risks, ERCP without cholecys- terms of success rate, morbidity and mortality were no different tectomy might lead to less morbidity and mortality. If the CBD between the two groups. Thus, the endoscopic method (followed stones cannot be removed, even after trying mechanical lithotripsy by laparoscopic cholecystectomy), being less invasive and as suc- and ESWL, stenting of the CBD without removing the stones can cessful as surgery was recommended as the therapeutic strategy of still resolve symptoms in a majority of cases. choice for CBD stones.4 A few newer techniques have also evolved. When ERCP is not When is surgery performed to remove CBD stones? Obviously, performed before cholecystectomy, during surgery a standard one occasion is when endoscopic treatment fails. Shojaiefard et ERCP cathter can be secured in the cystic duct instead of a T-tube. al. report that among 1462 cases with CBD stones, 186 failed en- The cathter can be used to do cholangiography after surgery and doscopic treatment.1 The success rate for removal of CBD stones if a stone is found, ERCP would be successful in removing the with ERCPis 80 to 90%. Failures might be due to bile duct stric- stone in 97% withan only 1% complication rate.Transcystic stent- tures, unusual anatomy such as duodenal diverticuli, stones being ing of the CBD during cholecytectomy, or placing a guidewire via beyond the reach of wire basket, or stones being too large.5 Failure the cystic duct and using the so-called ʻrendezvouz technique’ are of cannulation of ampulla occurs in 5% of ERCPs. The success rate among other methods with promise. The ʻfacilitated ERCP’ per- is 76 and 80% at second and third attempt respectively. Although formed after such surgeries has a much higher success rate of 95% by expertise, the success rate might approach 100% on the second and results in shorter hospital stay.9 attempt.6 Needle knife sphincterotomy increases the success rate by 25%. But occasionally, blocking of the endoscopic view due to Morteza Khatibian MD, Shahin Merat MD bleeding might cause failure.6 Needle-knife fistulotomy is another Digestive Disease Research Center, Tehran university of Medical technique which might assist in difficult cases.7 In patients with Sciences, Tehran Iran. large CBD stones, mechanical lithotripsy can increase the success rate to 95%. If mechanical lithotripsy fails too, extracorporeal References: shock wave lithotripsy (ESWL) can be successful in another 80%.8 As discussed above, when initial ERCP fails, there is still a very 1. Shojaiefard AE, KhorgamiZ, SotoudehmaneshR, GhafouriA. Assess- good chance of success with repeated attempts using appropriate ment and Treatment of Choledocholithiasis when Endoscopic Sphinc- terotomy is not Successful. Arch Iran Med. 2012; 15(5): 275 – 278. techniques. Nevertheless, sometimes patients are refered for sur- 2. Adler DG, Baron TH, Davila RE, Egan J, Hirota WK, Leighton JA, et gury immediately after the first failure. al. ASGE guideline: the role of ERCP in diseases of the biliary tract and the pancreas. Gastrointest Endosc 2005; 62(1): 1 – 8. A few other factors are involved in the decision of when to give 3. Martin DJ, Vernon DR, Toouli J. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2006; 2: CD003327. up on non-surgical management. Endoscopists tend to refer pa- 4. Sikora SS. Common bile duct stones: endoscopy or surgery? Natl Med tients with simultanious gallbladder and CBD stones for surgery J India 2007; 20(1): 23 – 24. earlier than those who have already had their gallbladder removed. 5. Tyagi P, Sharma P, Sharma BC, Puri AS. Periampullary diverticula and

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 269 M.Khatibian, S.Merat

technical success of endoscopic retrograde cholangiopancreatography. Med. 2008; 11(1): 16-20. Surg Endosc. 2009; 23(6): 1342 – 1345. 8. Minami A, Hirose S, Nomoto T, Hayakawa S. Small sphincterotomy 6. Kim J, Ryu JK, Ahn DW, Park JK, Yoon WJ, Kim YT, et al. Results combined with papillary dilation with large balloon permits retrieval of repeat endoscopic retrograde cholangiopancreatography after initial of large stones without mechanical lithotripsy. World J Gastroenterol. biliary cannulation failure following needle-knife sphincterotomy. J 2007; 13(15): 2179 – 2182. Gastroenterol Hepatol. 2012; 27(3): 516 – 520. 9. Morino M, Baracchi F, Miglietta C, Furlan N, Ragona R, Garbarini 7. Khatibian M, Sotoudehmanesh R, Ali-Asgari A, Movahedi Z, Kolah- A. Preoperative endoscopic sphincterotomy versus laparoendoscopic doozan S. Needle-knife fistulotomy versus standard method for can- rendezvous in patients with gallbladder and bile duct stones. Ann Surg. nulation of common bile duct: a randomized controlled trial. Arch Iran 2006; 244(6): 889 – 893.

270 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 HCV Infection in a Southwest Area of Iran

Original Article

High Prevalence of Hepatitis C Infection among High Risk Groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran

Bahador Sarkari PhD1, Owrang Eilami MD2, Abdolmajid Khosravani PhD•2, Asghar Sharifi PhD2, Marzieh Tabatabaee MD2, Mohammad Fararouei PhD3

See the pages: 268

Abstract Background: Detection of Hepatitis C virus (HCV)-infected people in each community assists with infection prevention and control. This study aims to evaluate the prevalence of HCV infection among high risk groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran. Methods: This was a cross-sectional study conducted from 2009-2010 in Kohgiloyeh and Boyerahmad Province. High risk groups for HCV were the subjects of this study. Blood samples were taken from 2009 individuals at high risk for HCV that included inmates, injecting drug users (IDUs), health care workers, patients on maintenance hemodialysis, hemophilic patients, and those with histories of blood transfusions. Patients were residents of Yasuj, Gachsaran, and Dehdasht (3 main townships in the province). Samples were analyzed by ELISA for anti- HCV antibodies. Demographic features of participants were recorded by a questionnaire during sample collection. Data were analyzed by SPSS version 13 software. Results: Of 2009 subjects, HCV antibodies were detected in 172 (8.6%). Rate of infection was higher in males (11.4%) compared to females (3.2%). Rate of infection in inmates was 11.7% while this rate was 42.4% in IDUs, 4.2% in health care workers, and 6.1% in thalassemic patients. Significant correlation was found between HCV infection, history of imprisonment, and thalassemia. Conclusion: Results of this study have provided epidemiologic features of HCV and its risk factors in Kohgiloyeh and Boyerahmad Prov- ince, Southwest Iran. This information may assist in preventing the spread of HCV infection in this and other similar settings in the region. The findings of this study may help in improving surveillance and infection control in the community through management and monitoring of infected individuals.

Keywords: HCV, high risk group, Iran, prevalence, seroprevalence

Cite this article as: Sarkari B, Eilami O, Khosravani A, Sharifi A, Tabatabaee M, Fararouei M. High Prevalence of Hepatitis C Infection among High Risk Groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran. Arch Iran Med. 2012; 15(5): 271 – 274.

Introduction which corresponds to as many as 0.5 million chronic carriers.3 A higher seroprevalence of HCV has been reported in special groups epatitis C is a global health problem affecting more than (homeless or gypsies) in Iran.4,5 The infection is emerging mostly 170 million people worldwide.1 Hepatitis C virus (HCV) due to the problem of intravenous drug abuse and needle-sharing H is mainly transmitted parenterally or in the course of blood in this country. contamination during medical procedures. In a recent population-based study by Merat et al. male sex, history Most who acquire acute HCV infection have no symptoms or of intravenous drug abuse, and imprisonment were attributed to have a mild clinical disease. However, chronic HCV infection de- HCV infection.3 velops in 75% – 85% of those acutely infected individuals.2 HCV- Injection drug users (IDUs) constitute the largest group of persons infected people serve as a reservoir for transmission of the infec- at high risk for acquiring HCV infection in developed countries. tion to others, including health care workers. The range of HCV infection among IDUs in Iran has been reported It has been estimated that HCV accounts for 27% of cirrhosis to be 38% to 47%. 6–8 and 25% of hepatocellular carcinoma (HCC) worldwide. HCV is It is essential to assess the magnitude of HCV infection in each a leading cause of liver failure and liver transplantation in adults.2 region of Iran. This assessment will assist health authorities in im- In Iran, it has been estimated that between 0.12% – 0.89% proving surveillance and prevention of HCV infection in the com- of the general population have anti-hepatitis C virus antibodies, munity through management and monitoring of infected individuals. Authors’ Affiliations: 1Center for Basic Researches in Infectious Diseases, High-risk populations for HCV infection are individuals involved Shiraz University of Medical Sciences, Shiraz, Iran, 2Faculty of Medicine, Yasuj in activities that include possible contact with contaminated blood, 3 University of Medical Sciences, Yasuj, Iran, Faculty of Health, Yasuj University such as blood transfusions, medical or dental care, acupuncture of Medical Sciences, Yasuj, Iran. •Corresponding author and reprints: Abdolmajid Khosravani PhD, Faculty and tattooing, IDUs, prison inmates, and healthcare workers. of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran, E mail: This study aims to evaluate the epidemiologic features of HCV [email protected] and its risk factors among high risk groups in Kohgiloyeh and Accepted for publication: 7 September 2011

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 271 B. Sarkari, O. Eilami, A. Khosravani, et al.

Table 1. Demographic characteristics of participants. Features Frequency Percent Place of residence Gachsaran 803 40 Yasuj 802 39.9 Dehdasht 404 20.1 Sex Male 1231 66.4 Female 621 33.6 Marital status Single 692 39.7 Married 1047 60.3 High risk groups Inmates 616 30.6 Health care workers 212 10.5 Injecting drug users (IDUs) 158 7.8 Thalassemic 49 2.4 Other† 602 30 Age group (years) 1–20 166 9.5 21–30 691 39.6 31–40 472 27.1 > 40 415 23.8 Missing 265 - † Tattooing, history of surgery, dental care, having HCV-positive family member(s).

Table 2. High-risk groups and HCV prevalence. High-risk groups Frequency HCV-positive Percent Inmates 616 72 11.7 Health care workers 212 9 4.2 Injection drug users (IDUs) 158 67 42.2 Thalassemic 49 3 6.1 Others† 602 47 7.8 † Tattooing, history of surgery, dental practice, HIV-positive family members.

Table 3. Risk factors associated with HCV seropositivity in high risk groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran. Risk factor HCV positive HCV negative Total History of imprisonment 72 544 616 History of drug use 67 91 158 Transfusion 2 46 48 Needle stick 9 213 222 Thalassemia 3 46 49 Unprotected sex 6 12 18 Other† 47 555 602 † Tattooing, history of surgery, dental practice, having HCV-positive family members.

Boyerahmad Province, Southwest Iran, where such data are not (222 in the 3 main townships, based on the population of health currently available. care workers in each township), and thalassemic patients (49). Participation in this study was voluntary and all participants were Materials and Methods counseled about the study. Participants were requested to provide signed informed consents. Confidentiality of the details of the This descriptive cross-sectional study was conducted from 2009 participants was guaranteed. – 2010 in Kohgiloyeh and Boyerahmad Province, Iran. High risk Demographic features of participants were recorded using groups for HCV were the subjects of this study. After obtaining a questionnaire during sample collection. The questionnaire approval from the Ethics Committee of Yasuj University of contained detailed questions regarding HCV-related risk behaviors Medical Sciences, blood samples were taken from 2009 individuals such as injection of intravenous drugs, history of imprisonment, who were residents of Yasuj, Gachsaran, and Dehdasht (3 main having received blood and/or blood products, unsafe sexual townships in the province) that were at high risk for acquiring practice, and history of other risk factors such as receiving tattoos, HCV. Participants were comprised of inmates (total inmates in 3 body piercing, and history of surgery or dental care. main prisons in the province: 616), IDUs (158) health care workers A total of 5 ml of blood was taken from each subject and sera

272 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 HCV Infection in a Southwest Area of Iran

Table 4. Association between HCV positivity and risk factors in high risk groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran.

95% CI for Exp (B) High risk behavior Df Sig Odds ratio Lower Upper History of drug use 1 0.105 1.603 0.906 2.838 Thalassemia 1 0.000 3.761 1.909 7.409 Transfusion/ hemophilia 1 0.907 1.101 0.221 5.487 Needle stick 1 0.389 1.538 0.577 4.101 History of imprisonment 1 0.033 8.231 1.191 56.884 were tested for anti-HCV antibodies by an enzyme-linked in Kohgiloyeh and Boyerahmad Province. The study was justified immunosorbant assay (ELISA, DIALab, Austria). The sensitivity by the lack of information about HCV infection in this area. of this test (a third generation ELISA) is 99.55% and specificity is Prevalence of HCV antibody positivity among all participants 99.79%. of this study was 8.6%. Findings of this study demonstrated a Collected data were analyzed by SPSS version 13 software. relatively high prevalence of HCV in this area. Since the recruited Standard x2 test was used to assess the univariate correlation of subjects of this study were from selected high risk groups, demographic and behavioral variables and HCV seropositivity. therefore the rate of HCV in the entire population of the district might be different. Because of religious beliefs and possible lack Results of co-operation in answering questions related to sexual behaviors, many individuals did not properly answer this question. Such data Of 2009 subjects, 802 (39.9%) were from Yasuj, 803 (40%) were was not considered in the statistical analysis. Self-reporting of from Gachsaran, and 404 (20.1%) were from Dehdasht. Males behaviors such as sexual activity and drug use are other limitations constituted 66.4% of subjects whereas 33.4% of participants were of this study. female. Most subjects (39.6%) were among the 21 – 30 year-old It is worth mentioning that the seropositivity of HCV does not age group and most were married (60.3%). Table 1 shows the mean HCV infection since spontaneous resolution of HCV might demographic characteristics of participants in this study. occur in HCV-infected individuals. In such cases ELISA results are HCV antibodies were detected in 172 (8.6%) cases. Rate of positive but the patient is not HCV-infected. infection was higher in males (11.4%) compared to females (3.2%). Despite the low HCV seroprevalence in the Iranian general popu- Rate of infection in inmates was 11.7% while this rate was 42.4% lation, recent studies have shown a high prevalence of HCV in- in IDUs, 4.2% in health care workers, and 6.1% in thalassemic fection among Iranian prisoners. Of 460 inmates in a prison in patients. The highest prevalence of HCV (9.3%; 64/691) was Guilan, 45.4% were HCV antibody positive.7 In our study the found in the 21 – 30 year-old age group. Table 2 represents the rate of seropositivity in prisoners was lower (11.6%). Participants prevalence of HCV infection in each high risk group in this study. who spent more time in prison were significantly more likely to Unemployed people were found to be the main victims of this be positive for antibodies to HCV in our study. The current study disease. Significant correlation was found between marital status found a positive correlation between being in prison and HCV and HCV seropositivity. The rate of seropositivity in unmarried seropositivity. Such connection has been reported in a study by subjects was 11.4% compared with 6.4% for married individuals Alizadeh et al. of prisoners in Hamedan, Iran where they reported (P < 0.05). a prevalence of 30% for HCV antibodies.9 Significant correlation was found between HCV seropositivity The overall seroprevalence of HCV among Iranian blood donors and sex (more common in males), history of imprisonment, drug has been estimated to be 0.12%.10 The prevalence of anti-HCV addiction, level of education (more common in illiterate and antibodies among 7897 healthy voluntary blood donors in Shiraz, less educated subjects) and place of residence (more common Iran was 0.59% in 1998.11 This approximated the frequency of in Gachsaran). No significant correlation P ( > 0.05) was found anti-HCV recently reported in a population-based study in Iran.3 between HCV seropositivity and age, history of needle stick, Khedmat et al. reported a frequency of 2.07% for anti-hepatitis C and employment. Table 3 shows the risk factors which might be among Iranian blood donors in 2009.12 In our study, 4.1% of pa- associated with HCV seropositivity in this study. Multivariate tients who had a history of transfusion were positive for anti-HCV analysis, using backward selection logistic regression, revealed antibodies. a correlation between history of imprisonment, thalassemia and The prevalence of HCV infection in hemophilic patients in Iran HCV positivity. Table 4 shows the details of this correlation. has been reported to be 15.6% in Fars, 44.3% in Kerman, 29.6% in Zahedan, 59.1% in Hamadan, 71.3% in Guilan, and 76.7% Discussion in Northwest Iran. The overall estimate of HCV in these patients in the entire country is estimated to be 50%.6,13–15 In our study the Approximately 3% of the world’s population are infected with numbers of hemophilic patients were too few to draw any conclu- HCV.1 The high risk groups for HCV infection are those who prac- sion about prevalence of HCV in this high risk group in the region. tice activities such as blood transfusions, medical or dental care, Thalassemic patients are at high risk for hepatitis C infection; acupuncture and tattooing, IDUs, imprisonment, and health care 19.3% in 732 patients with beta-thalassemia from 5 provinces of 16 workers. HCV-positive individuals might expose their friends, Iran have been reported to be infected with HCV. In our study families and general community to HCV infection. In this study 6.1% of thalassemic patients were HCV-positive. we have evaluated the seroprevalence of HCV in high risk groups HCV infection is a significant health problem in dialysis units

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 273 B. Sarkari, O. Eilami, A. Khosravani, et al. in Iran. Seroprevalence of hepatitis C in hemodialysis patients in based study from Iran. Int J Infect Dis. 2010; 14: 113 – 116. Guilan, northern Iran was reported to be 24.8%.17 Recent studies 4. Vahdani P, Hosseini-Moghaddam SM, Family A, Moheb-Dezfouli R. Prevalence of HBV, HCV, HIV and syphilis among homeless subjects have reported a decline in prevalence of HCV in hemodialysis pa- older than fifteen years in Tehran.Arch Iran Med. 2009; 12: 483 – 487. tients in Iran from 14.4% in 1999 to 4.5% in 2006.18 It has been 5. Hosseini Asl SK, Avijgan M, Mohamadnejad M. High prevalence of shown that blood transfusion and duration of dialysis treatment are HBV, HCV, and HIV infections in gypsy population residing in Shahr- important risk factors for HCV infection in patients on maintenance E-Kord. Arch Iran Med. 2004; 7: 20 – 22. 6. Alavian SM, Fallahian F. Epidemiology of hepatitis C in Iran and the hemodialysis. The more units transfused, the higher the risk for world. Shiraz E-Med J. 2009; 10(4): 162 – 172. HCV infection. 7. Alavian SM, Adibi P, Zali MR. Hepatitis C virus in Iran: Epidemiology There is a wide range of HCV infection, 2 – 100%, in IDUs in of an emerging infection. Arch Iran Med. 2005; 8: 84 – 90. different parts of the world.19 8. Rahimi-Movaghar A, Razaghi EM, Sahimi-Izadian E, Amin-Esmaeili M. HIV, hepatitis C virus, and hepatitis B virus co-infections among The findings of the current study have shown that 42.4% of IDUs injecting drug users in Tehran, Iran. Int J Infect Dis. 2010; 14: 28 – 33. are infected with HCV; thus they are a very important reservoir for 9. Alizadeh AHM, Alavian SM, Jafari K, Yazdi N. Prevalence of hepatitis the spread of HCV to others in the community. Alavi et al. have C virus infection and its related risk factors in drug abuser prisoners in Hamedan - Iran. World J Gastroenterol. 2005; 11: 4085 – 4089. reported a higher seroprevalence of HCV (52.11%) in IDUs in Ah- 10. Alavian SM, Gholami B, Masarrat S. Hepatitis C risk factors in Iranian 20 vaz, Iran. volunteer blood donors: A case-control study. J Gastroenterol Hepatol. In conclusion, the findings of the present study have provided 2002; 17: 1092 – 1097. epidemiologic features of hepatitis C and its risk factors in 11. Ghavanini AA, Sabri MR. Hepatitis B surface antigen and anti-hepatitis C antibodies among blood donors in the Islamic Republic of Iran. Kohgiloyeh and Boyerahmad Province in Southwest Iran. This East Mediterr Health J. 2000; 6: 1114 – 1116. information contributes to our understanding of the worldwide 12. Khedmat H, Fallahian F, Abolghasemi H, Alavian SM, Hajibeigi B, prevalence of hepatitis C and may help to contain the spread of Miri SM, et al. Seroepidemiologic study of hepatitis B virus, hepatitis HCV infection in this and other similar settings in the region. The C virus, human immunodeficiency virus and syphilis infections in Ira- nian blood donors. Pak J Biol Sci. 2007; 15: 4461 – 4466. findings of this study may assist in improving surveillance and pre- 13. Karimi M, Ghavanini AA. Seroprevalence of HBsAg, anti-HCV, and vention of HCV infection in the community through management anti-HIV among haemophiliac patients in Shiraz, Iran. Haematologia. and monitoring of infected individuals. 2001; 31: 251 – 255. 14. Sharifi-Mood B, Eshghi P, Sanei-Moghaddam E, Hashemi M. Hepa- titis B and C virus infections in patients with hemophilia in Zahedan, Acknowledgments southeast Iran. Saudi Med J. 2007; 28: 1516 – 1519. 15. Mansour-Ghanaei F, Fallah MS, Shafaghi A, Yousefi-Mashhoor M, This study was financially supported by the Governor of Ramezani N, Farzaneh F, et al. Prevalence of hepatitis B and C se- romarkers and abnormal liver function tests among hemophiliacs in Kohgiloyeh and Boyerahmad Province. We thank the medical and Guilan (northern province of Iran). Med Sci Monit. 2002; 8: 797 – 800. nursing staff of Shahid Beheshti and Imam Sadjjad hospitals for 16. Mirmomen S, Alavian SM, Hajarizadeh B, Kafaee J, Yektaparast B, their assistance with sample collection. We particularly express Zahedi MJ, et al. Epidemiology of hepatitis B, hepatitis C, and human our appreciation to those who provided blood samples for this immunodeficiency virus infections in patients with beta-thalassemia in Iran: A multicenter study. Arch Iran Med. 2006; 9: 319 – 323. study. 17. Amiri ZM, Shakib AJ, Toorchi M. Seroprevalence of hepatitis C and risk factors in haemodialysis patients in Guilan, Islamic Republic of References Iran. East Mediterr Health J. 2005; 11: 372 – 376. 18. Alavian SM, Mahdavi-Mazdeh M, Bagheri-Lankarani K. Hepatitis B and C in dialysis units in Iran, changing the epidemiology. Hemodial 1. Global surveillance and control of hepatitis C. Report of a WHO Con- Int. 2008; 12: 378 – 382. sultation organized in collaboration with the Viral Hepatitis Prevention 19. Aceijas C, Rhodes T. Global estimates of prevalence of HCV infection Board, Antwerp, Belgium. J Viral Hepat. 1999; 6: 35 – 47. among injecting drug users. Int J Drug Policy. 2007; 18: 352 – 358. 2. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002; 20. Alavi SM, Alavi L. Seroprevalence study of HCV among hospitalized 36: 21 – 29. intravenous drug users in Ahvaz, Iran (2001-2006). J Infect Public 3. Merat S, Rezvan H, Nouraie M, Jafari E, Abolghasemi H, Radmard Health. 2009; 2: 47 – 51. AR, et al. Seroprevalence of hepatitis C virus: The first population-

274 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Treatment of Choledocholithiasis

Original Article Assessment and Treatment of Choledocholithiasis when Endo- scopic Sphincterotomy is not Successful

Abolfazl Shojaiefard MD1, Majid Esmaeilzadeh MD2, Zhamak KhorgamiMD•1, Rasoul Sotoudehmanesh MD3, Ali Ghafouri MD1

See the pages: 269 – 270

Abstract Background: Choledocholithiasis exists in approximately 15% of patients with gallstones and is present in 3%-10% of those undergoing cholecystectomy. Methods: In this study, we retrospectively analyzed the outcome patients with choledocholithiasis that were managed by open common bile duct (CBD) exploration according to our center’s protocol. Endoscopic retrograde cholangiopancreatography (ERCP) was performed for CBD stone clearance. If ERCP and sphincterotomy were not successful, open surgical exploration of CBD was performed with T-tube insertion without routine intraoperative cholangiography (IOC). Results: We studied 1462 patients with choledocholithiasis. ERCP was successful in in 1276 (87.2%) patients. A total of 186 (12.8%) underwent surgery. Of these, 82 (45.2%) had CBD exploration and T-tube insertion without IOC. Choledochoduodenostomy was performed in 82 (44.1%) patients and choledochojejunostomy was performed in 20 (10.8%). Retained stones were found only in 4 cases which were treated by ERCP. Conclusion: ERCP is successful in most cases with choledocholithiasis. If ERCP fails, open exploration of CBD and T-tube insertion, or biliary-enteric anastomosis are acceptable ways for CBD drainage. The rate of retained stone is not more than expected, thus elective IOC is more acceptable than routine IOC. Routine IOC is time-consuming and particularly difficult in elderly patients and emergency conditions.

Keywords: Choledochoduodenostomy, Choledochojejunostomy, Choledocholithiasis, ERCP

Cite this article as: Shojaiefard A, Esmaeilzadeh M, Khorgami Z, Sotoudehmanesh R, Ghafouri A. Assessment and Treatment of Choledocholithiasis when Endo- scopic Sphincterotomy is not Successful. Arch Iran Med. 2012; 15(5): 275 – 278.

Introduction modalities.6,7 Other methods include electrohydraulic lithotripsy (EHL), extracorporeal shockwave lithotripsy (ESWL), laser litho- holedocholithiasis is a medical condition that mandates sur- tripsy and dissolving solutions that are advocated for special condi- gical intervention. It may occur in 3% – 10% of patients tions.8,9 C with cholecystectomy,1 and as high as 14.7% in some se- Although, ERCP and laparoscopic CBD exploration are preferred ries.2 Generally, the prevalence of asymptomatic bile duct stones is methods in most centers, open CBD exploration should never be reported between 5.2% and 12%.3 abandoned. Some studies have proposed choledochotomy with There are several diagnostic approaches for common bile duct primary laparoscopic closure of the CBD which eliminates the (CBD) stones. These include: laboratory analysis, ultrasonography need for a T-tube, thus reducing surgical time and postoperative (US), computed tomography scans (CT scan), magnetic resonance morbidity.10 However, open CBD exploration with T-tube inser- cholangiopancreatography (MRCP), endoscopic ultrasonography tion remains the standard procedure for most patients. (EUS), and endoscopic retrograde cholangiopancreatography In this study, we review the results of surgical management in (ERCP). Intraoperative cholangiography (IOC) during cholecys- 186 out of 1462 patients with choledocholithiasis. We present our tectomy can be performed routinely or selectively to diagnose protocol for the management and treatment of choledocholithiasis, choledocholithiasis.4,5 Nowadays, 2 groups of interventions have particularly in cases of unsuccessful ERCP and sphincterotomy. a significant role in the management of patients with gallstone and CBD stones: pre- or post-cholecystectomy ERCP with endoscopic Materials and Methods sphincterotomy (ES), which is a two-stage procedure, and surgical bile duct clearance and cholecystectomy by single open or From June 2007 to March 2010, 1462 patients with choledocho- laparoscopic surgery (one-stage procedure). Several randomized lithiasis referred to Shariati Hospital, Tehran University of Medical controlled trials have shown comparable effectiveness of these Sciences. After primary evaluation with laboratory tests and US, Authors’ Affiliations: 1Department of Surgery and Research Center for Improv- patients’ diagnoses were confirmed by EUS or MRCP. ment of Surgical Outcomes and Procedures, Shariati Hospital, Tehran University We performed ERCP and ES in confirmed cases to extract CBD 2 of Medical Sciences, Tehran, Iran, Department of General, Visceral and Transplan- stones. When ERCP was not successful the patient underwent sur- tation Surgery, University of Heidelberg, Germany, 3Digestive Diseases Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran . gery. We administered antibiotic therapy (ceftriaxone 1 gr/IV/BD •Corresponding author and reprints: Zhamak Khorgami MD, Department of and metronidazole 500 mg/IV/TDS) to patients with cholangitis Surgery, Tehran University of Medical Sciences, Shariati Hospital, Kargar Ave, and/or cholecystitis. This therapy continued for 5 – 7 days in pa- Tehran, Iran. Tel.: +98-21-84902450, Fax: +98-21-88633039, E-mail: [email protected]. tients with acute cholangitis and for 48 hours after elective sur- Accepted for publication: 21 October 2011 geries in those without cholangitis. Surgical procedures included

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 275 A. Shojaiefard, M. Esmaeilzadeh, Z. Khorgami, et al.

Table 1. Frequency of main presentation, comorbid disease, and type of surgery in 186 patients with choledocolithiasis. Frequency Percent (%) Main presentation Cholecystitis 98 52.7 Cholangitis 62 33.3 Biliary colic 15 8.1 Pancreatitis 11 5.9 Comorbid diseases Diabetes mellitus 27 14.5 Hypertension 22 11.8 Ischemic heart disease 5 2.7 Chronic obstructive pulmonary disease 3 1.6 Other 8 4.3 Type of surgery CBD exploration and T-tube insertion 84 45.2 Choledochoduodenostomy 82 44.1 Choledochojejunostomy 20 10.7

CBD exploration and T-tube insertion or biliary enteric anastomo- bilirubin was 2.7 ± 1.7 mg/dl. Alkaline phosphatase was greater sis (choledochoduodenostomy and choledochojejunostomy). Fig- than 300 U/dL in 96 (51.6%) patients. US showed a mean CBD di- ure 1 shows the algorithmic approach to patients with choledocho- ameter of 14.4 ± 6.4 mm; the mean stone size was 13.3 ± 4.8 mm. lithiasis at Shariati Hospital. There was a history of previous cholecystectomy in 45 (24.2%) In our center, laparoscopic cholecystectomy is the surgery of patients. choice. However, due to insufficient experience in laparoscopic ERCP was successful in 1276 of 1462 (87.3%) patients and 186 exploration of CBD and previous open cholecystectomy in some (12.7%) underwent open surgical CBD exploration. Main reasons patients who had subsequent adhesions, we performed open sur- for ERCP failure were multiple stones, large stones (≥1.5 cm) and gery in these cases through a right subcostal or upper abdominal impacted stone in the distal portion of the CBD, among others. midline incision. We inserted a T-tube in the CBD when its diam- Existence of periampullary diverticulum (3 cases), bulbar defor- eter was less than 12 mm and in patients with cholangitis. In other mity of the duodenum (1 case), and ampullary polyp (1 case) also patients that underwent elective surgery with CBD diameter more prevented ERCP. than 12 mm, we performed biliary-enteric anastomosis (choledo- In 84 (45.2%) out of 186 patients CBD exploration and T-tube choduodenostomy or choledochojejunostomy). insertion were performed. Of these, 40 (47.6%) had acute cholan- Routine IOC after T-tube insertion can determine retained stones. gitis, 33 (39.3%) had cholecystitis, and 11 (13.1%) had pancreati- However, because IOC is time-consuming we did not perform this tis. There were 4 cases with retained stones after T-tube insertion procedure if we could pass appropriate biliary dilators through the according to postoperative T-tube cholangiography. Endoscopic sphincter of oddi after stone extraction and certainty of CBD clear- sphincterotomy and stone extraction were successfully performed ance. This timesaving approach was particularly important in older to extract the retained stones. or critically ill patients. Then, after irrigation of the CBD with nor- We performed biliary-enteric anastomoses in 102 (54.8%) pa- mal saline, we inserted a 14 or 16 Fr T-tube in the CBD and closed tients whose surgical conditions were not urgent and had CBD the choledocotomy with absorbable (Vicryl 3-0) separate sutures. diameters of 12 mm or more. Included in this group were patients Seven to eight days after surgery, T-tube cholangiography was per- with cholangitis who were responsive to antibiotic therapy. For 82 formed. In cases without retained stones the T-tube was extracted (44.1%) patients, choledochoduodenostomy was performed and 14 to 21 days after surgery. 20 (10.7%) underwent choledochojejunostomy. The latter was performed when adhesions or deformity of the duodenum and dif- Statistical analysis ficulty in its mobilization were present. Statistical analysis was performed using SPSS for Windows ver- Mean surgery time was 128 ± 23 minutes. The length of hospi- sion 16.0 (SPSS Inc., Chicago, IL). For quantitative data, mean talization was 6.8 ± 3.8 days, which was less in patients who had and ranges were calculated. Quantitative data were reported as T-tube insertions when compared with biliary-enteric anastomosis relative frequencies and percentages. In this study, the significant (6.4 ± 3.4 days vs. 8.5 ± 4 days, p = 0.02). The age of patients with variables analysis was entered into both the chi-square and t-tests. T-tube insertion was less than those with biliary-enteric anastomo- P values < 0.05 were considered statistically significant. sis (54.4 ± 14.4 vs. 63.7 ± 16.5 years, p = 0.01). A total of 33 (17.7%) patients were transferred to the intensive Results care unit (ICU) after surgery, mainly due to older age and comorbid diseases. The mean time in the ICU was 2.7 days (range: 1 – 5 There were 186 out of 1462 patients with choledocholithiasis days). who underwent surgery. Of these, 82 (44%) were women and 104 Postoperative complications were seen in 14 (7.5%) patients and (56%) were men. Patients’ mean age was 58.6 ± 15 years (range: included wound infection (8), pneumonia (3) and pancreatitis after 21 – 78 years). The main presentations and comorbid diseases are surgery (3). Mortality occurred in 3 (1.6%) female patients, who shown in Table 1. Comorbidities of hypertension, diabetes mel- were all over 50 years of age, as a result of sepsis (2) and myocar- litus, ischemic heart disease, and chronic obstructive pulmonary dial infarction (1). disease were present in 65 (34.9%) patients. Patients were followed at two weeks, one, three, and six months, Sixty-six (35.5%) patients had leukocytosis (wbc > 11,000/mm3). and one year after surgery. Follow-up evaluations included physi- Jaundice was present in 38 (20.4%) patients and the mean total cal examination, laboratory tests, and US. There were no cases of

276 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Treatment of Choledocholithiasis

Figure 1- Algorithmic approach at Shariati Hospital for choledocholithiasis recurrent choledocholithiasis or any long-term complications. The rate of retained CBD stones in our study was not greater than other studies. For this reason, we have proposed that routine IOC is Discussion not necessary after surgical CBD exploration and clearance. In our center, the appropriate surgical method was chosen based The management of choledocholithiasis has always been chal- on the patient’s condition. In patients with sepsis due to cholangitis lenging. Nowadays, ERCP has essentially replaced open surgery and accompanying diseases, it was necessary to shorten the time for safe and effective CBD stone extraction. Open CBD explora- of surgery. In addition, biliary-enteric anastomosis increased the tion is an important surgical procedure when ERCP fails and ex- risk of complications. In such cases, the T-tube was inserted fol- pertise for laparoscopic CBD exploration is not available. lowing CBD exploration. In cases with CBD diameters less than The optimal method for performing open CBD exploration is 12 mm, the T-tube was used because of the high risk for anasto- unclear.11 The routine use of IOC during laparoscopic cholecys- motic stricture15 and subsequent complications. Most authors have tectomy remains controversial.12 Stuart et al. have performed IOC preferred insertion of T-tube for CBD drainage, but some centers in 348 patients, of which it was abnormal in 17 (5%) cases. How- have utilized transcystic tubes (C-tube) or antegrade stenting with ever, documented retained stones that existed in 5 patients were choledochorrhaphy for CBD drainage.16 In patients with residual removed by CBD exploration or ERCP in that study.13 Mir et al. distal stone, ductal imaging in the postoperative period and provi- did not perform IOC, and reported reductions in costs and hospital sion of an access route for removal of residual CBD stones has stay.14 We did not perform IOC in order to reduce the surgical time. been performed.17 In our study, there were cases of 4 retained stones in patients with The most commonly used choledochoenterostomy is side-to- T-tube insertion that were successfully extracted by ERCP. Gener- side choledochoduodenostomy, usually in the setting of a dilated ally, ERCP is more feasible in this subgroup since postoperative CBD.18 In cases where duodenal anastomosis was impossible, cho- T-tube cholangiography shows the anatomy of the biliary tree and ledochojejunostomy was performed. large or impacted stones that have been extracted during surgery. Currently, many centers use laparoscopy for CBD surgeries. Ex-

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 277 A. Shojaiefard, M. Esmaeilzadeh, Z. Khorgami, et al. pert surgical teams have reported a CBD clearance rate of about ment of bile duct stones (Review). Cochrane Database Syst Rev. 2006; 97%.19 The morbidity rate has been reported to be 9.5% and re- 19(2): CD003327. 20 8. Caddy GR, Tham TC. Symptoms, diagnosis and endoscopic manage- tained stone rate of 2.7% for exploratory laparoscopic CBD. ment of common bile duct stones. Best Practice & Research Clinical Nevertheless, in comparison to open surgery, laparoscopic surgery Gastroenterology. 2006; 20: 1085 – 1101. is more time consuming,21 yet has shorter postoperative hospital- 9. Evans AJ, Branch MS. The recalcitrant bile duct stone. Techniques in ization. Open surgery is still straightforward for management of Gastrointestinal Endoscopy. 2007; 9: 104 – 113. 10. Ahmed I, Pradhan C, Beckingham IJ, Brooks AJ, Rowlands BJ, Lobo choledocholithiasis and has a higher stone clearance rate. DN. Is a T-tube necessary after common bile duct exploration? World J Surg. 2008; DOI 10.1007/s00268-008-9475-2 Conclusion 11. Gurusamy KS, Samrai K. Primary closure versus T-tube drainage after open common bile duct exploration. Cochrane Database Syst Rev. 2007; 1: CD005640. Choledocholithiasis remains a challenging problem for clinicians. 12. Ciulla A, Aqnello G, Tomasello G, Castronovo G, Maiorana AM, Currently, ERCP is used mainly for extraction of CBD stones, but Genova G. The intraoperative cholangiography during videolaparo- surgery is the method of choice when ERCP fails. Performing scopic cholecystectomy. What is its role? Results of a non randomized study. Ann Ital Chir. 2007; 78(2): 85 – 89. an IOC assists in the detection of CBD stones but routine use of 13. Stuart AS, Simpson T, Alvord L, Williams M. Routine intraoperative IOC remains controversial. Although ERCP and then laparoscopic laparoscopic cholangiography. Am J Surgery. 1998; 176: 632 – 637. CBD exploration are selective methods in most centers, open CBD 14. Mir IS, Mohsin M, Kirmani O, Majid T, Wani K, Hassan MU, et al. Is exploration is the most effective method. Selection of treatment intraoperative cholangiography necessary during laparoscopic cholecystectomy? A multicentre rural experience from a developing world depends on physicians’ experience and available resources. country. World J Gastroenterol. 2007; 13(33): 4493 – 4497. 15. Ramirez P, Parrilla P, Bueno FS, Abad JMP, Muelas MS, Candel MF, et al. Choledochoduodenostomy and sphincterotomy in the treatment of References choledocholithiasis. Br J Surg. 1994; 81: 121 – 123. 16. Isla AM, Griniatsos J, Karvounis E, Arbuckle JD. Advantages of lapa- 1. Schirmer BD, Witers KL, Edlich RF. Choledocholithiasis and chole- roscopic stented choledochorrhaphy over T-tube placement. Br J Surg. cystitis. J Long Term Eff Med Implants. 2005; 15: 329 – 338. 2004; 91: 862 – 866. 2. Riciarel R, Islam S, Canete JJ, Avcand PL, Stoker ME. Effectiveness 17. Petelin JB. Laparoscopic common bile duct exploration. Surg Endosc. and long term results of laparoscopic common bile duct exploration. 2003; 17: 1705 – 1715. Surg Endoscopy. 2003; 17: 19 – 22. 18. Hungness ES, Soper NJ. Management of common bile duct stones. J 3. Rosseland AR, Glomsaker TB. Asymptomatic common bile duct Gastrointestinal Surgery. 2006; 10(4): 612 – 619. stones. Eur J Gastrentrol Hepatol. 2000; 12: 1171 – 1173. 19. Petelin JB. Laparoscopic common bile duct exploration. Surg Endosc. 4. Freitas M, Bell R, Duffy A. Choledocholithiasis: Evolving standards 2003; 17: 1705 – 1715. for diagnosis and managements. World J of Gastroentrology. 2006; 12: 20. Lien HH, Huang CC, Huang CS, Shi MY, Chen DF, Wang NY, et al. 3162 – 3167. Laparoscopic common bile duct exploration with T-tube choledochot- 5. Schwarz J, Simsa J, Pazdirek F. Our experience with preoperative cho- omy for the management of choledocholithiasis. J Laparoendosc Adv ledochoscopy. Rozhl Chir. 2007; 86(4): 180 – 183. Surg Tech A. 2005; 15(3): 298 – 302. 6. Clayton ESJ, Connor S, Alexakis N, Leandros E. Meta analysis of en- 21. Mandry AC, Bun M, Ued ML, Iovaldi ML, Capitanich P. Laparoscopic doscopy and surgery versus surgery alone for common bile duct stones treatment of common bile duct lithiasis associated with gallbladder li- with the gallbladder in situ. Br J Surg. 2006; 93: 1185 – 1191. thiasis. Cir Esp. 2008; 83(1): 28 – 32. 7. Martin DJ, Vernon DR, Toouli J. Surgical versus endoscopic treat-

278 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Reliability and Validity of the Modifiable Activity Questionnaire

Original Article Reliability and Validity of the Modifiable Activity Questionnaire (MAQ) in an Iranian Urban Adult Population

Amir Abbas Momenan MD MPH1, Maryam Delshad BS2, Narges Sarbazi MD1, Nasrollah Rezaei_Ghaleh MD2,3, Arash Ghanbarian MD•1, FereidounAzizi MD2

Abstract Background: The purpose of this study is to evaluate the validity and reliability of a Persian translation of the Modifiable Activity Questionnaire (MAQ) in a sample of adults from Tehran, Iran. Methods: There were 48 adults (53.1% males) enrolled to test the physical activity questionnaire. A sub-sample included 33 participants (45.5% males) who assessed the reliability of the physical activity questionnaire.The validity was tested in 25 individuals (48.0% males). The reliability of two MAQs was calculated by intraclass correlation coefficients. The validation study was evaluated with the Spearman correlation coefficients to compare data between the means of 2 MAQs and the means of 4 physical activity records. Results: Intraclass correlation coefficients between 2 MAQs for the previous year's leisure time was 0.94; for occupational, it was 0.98;and for total (leisure and occupational combined) physical activity, it was 0.97. The Spearman correlation coefficients between the means of the 2 MAQs and means of the 4 physical activity records was 0.39 (P = 0.05) for leisure time, 0.36 (P = 0.07) for occupational, and 0.47 (P = 0.01) for total (leisure and occupational combined) physical activities. Conclusions: High reliability and relatively moderate validity were found for the Persian translated MAQ in adults from Tehran. However, further studies with larger sample sizes are suggested to more precisely assess the validity of the MAQ.

Keywords: Persian, physical activity, questionnaire, reliability, validity

Cite this article as: Momenan AA, Delshad M, Sarbazi N, Rezaei_Ghaleh N, Arash Ghanbarian A, Azizi F. Reliability and Validity of the Modifiable Activity Ques- tionnaire (MAQ) in an Iranian Urban Adult Population. Arch Iran Med. 2012; 15(5): 279 – 282.

Introduction widely used method to assess usual physical activity patterns in population studies.6 ecent interventions have been designed primarily to increase Physical activity includes multiple social domains (household, the level of physical activity in adults because the role of occupational, transportation related, leisure time), and recent re- Rphysical activity behavior has been confirmed as an impor- searches have augmented the importance of assessing activities tant factor for health.1 In large epidemiological studies, selecting encountered in daily life.7 The health risk associated with physical the proper assessment tool is a challenging task for researchers2 activity differs according to the different dimensions such as type and there are several different techniques used to assess physical of activity, duration and intensity. So, it is important that physi- activity, such as questionnaires, diaries, 7-day recall, movement cal activity questionnaires assessing professional, domestic and sensors and doubly labeled water.3 The gold standard method is the leisure time activity, differentiate the intensity of activity and ad- doubly labeled water that measure total energy expenditure, but it dressing the usual individual energy expenditure.4 The Modifiable is not suitable for large population studies because that is compli- Activity Questionnaire (MAQ) assesses current (past year and past cated and expensive.4 For practical reason and in the absence of week) physical activity during occupation and leisure time, as well inexpensive, readily available, relatively noninvasive, valid and as extreme levels of inactivity due to disability.6 This questionnaire reliable technology for measuring physical activity in large num- was designed for easy modification to maximize the ability to as- bers of free-living humans, most epidemiological studies rely on sess physical activity in a variety of populations.6 Because physi- questionnaires to assess physical activity.4,5 Questionnaires are cal activity patterns and accuracy of self reports may differ across both comprehensive and easy to use in longitudinal studies, they cultural/ethnic backgrounds or gender, it is necessary to use reli- are generally well accepted by individuals and easy to administer able and validated the instrument in each study population.8 Few to a large number of study participants at a low cost so it is the most questionnaires have been tested on the Iranian urban adult population for evaluating physical activity. This paper describes the study Authors’ Affiliations: 1Prevention of Metabolic Disorders Research Center, Re- of the validity and reliability of the Persian translated MAQ in a search Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 2Endocrine Research Center, Research Institute for En- sample population of Tehranian adults. docrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 3 Max Plank Institute for Biophysical Chemistry, Research Group Protein Structure Methods Determination using NMR,Gottingen, Germany. •Corresponding author and reprints: Arash Ghanbarian MD, Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Study population Shahid Beheshti University of Medical Sciences, Parvaneh St., Yaman St., Cham- The Tehran Lipid and Glucose Study (TLGS) were designed in ran Exp., Tehran, Iran. E-mail: [email protected] Accepted for publication: 13 July 2011 order to investigate the prevalence of non-communicable disorders

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 279 A.A Momenan, M. Delshad, N. Sarbazi, et al. and their risk factors in a sample of Iranian population. The par- tivity was based on using the number of hours per week of light, ticipants of the present study were selected from the framework of moderate and hard intensity activity, summed to express hours per the TLGS, a prospective study among urban population in district week of occupational activity over the past year. Final occupation- No. 13 of Tehran, Iran.9 Based on the least sample size needed for al (MET-h/wk) activity was calculated by multiplying the number validity10 and an attrition rate of 30%, we invited 40 males and 40 of hours per week of each three categories of occupational activity females, aged 19 years and over with Stratified Random Sampling. to MET values.12 Total physical activities was expressed in hours According to the following formula for reliability sample size, of activity per week or MET-h/wk by adding leisure time physical considering α = 0.05 and β = 0.1, the above mentioned sample size activity to occupational activity. was satisfactory for reliability test, too. Reliability Participants completed the MAQ twice, with an interval of four weeks to evaluate the reliability. The standard time frame for test- retest studies is one to two weeks. But, a four-week interval was chosen because of the practical issues. The subjects were a part of Forty eight adults (53.1% were males) accepted the invitation a large scale community-based study (the TLGS) and there were to fill the physical activity questionnaire in 2002 (response rate, difficulties in recruiting them for shorter intervals. 60%). For validity, we excluded those who did not complete at least three physical activity records. So, of a total of 48 subjects, Validity the validity of the physical activity questionnaire was assessed in All participants were asked to complete a weekly record form of 25 individuals (48.0 % were males). The reliability was assessed physical activity and record all the activities in one typical week in in those same subjects who accepted the invitation. From those, 33 every season, preferably in the middle of each season. They were participants (45.5% were males) were completed two MAQs and trained how to record the activities. For convenience, the whole included for testing the reliability. 24-hours were divided into 3 intervals in our questionnaire; 8 – 14, The research ethical committee of Research Institute for Endo- 14 – 22 and 22 to 8 am of next day. They were asked to record any crine Sciences of the Shahid Beheshti University of Medical Sci- activities during each interval, including leisure time and occupa- ences approved this study protocol and an informed written con- tional activities.The physical activity record questionnaires com- sent was obtained from each participant. pleted in the middle of each season and were compared with mean of two MAQs to evaluate the convergent validity of the MAQ. Measurements The modifiable activity questionnaire Statistical analysis The original version of the MAQ11 was translated into Persian Using the P-P plot test, the distribution of mean of MET-h/wk and then back-translated into the English. Based on Iranian culture, wasn’t normal, so we used non-parametric tests. Data from both minor adaptations to fit in the current context in terms of usual MAQs and from the four physical activity records were reported leisure time physical activity performed by Iranian people were as mean (± SD) values for age, weight, height, BMI (Body Mass made. All the modifications, as well as translations, were approved Index), MET-h/wk. Mann-Whitney test was used to compare by original MAQ author through email communication. Data were the means of two MAQs. Since there was no significant differ- collected by the participants, assisted by trained interviewers when ence between two MAQs, we used the mean of two MAQs to be needed. Participants were asked to report the activities that they compared with four physical activity records. Intraclass Correla- had participated at least 10 times during the past 12 months in their tion Coefficients were used to calculate the reliability of the two leisure times and then identified the frequency and duration for MAQs. Intraclass Correlation Coefficients estimates ≥ 0.7 were each leisure time physical activities. Total number of minutes per considered asacceptable reliability.13 To evaluate the convergent year, calculated for every physical activity were summed and then validity, Spearman Correlation Coefficients were used to compare divided by 60 and 52 to estimate the hours per week of total lei- means of two MAQs and means of four physical activity records. sure time physical activity. The calculation of MET-h/wk is summarized as below: Results

MET-h/wk= (MET × months per year × time per month × minute The mean (± SD) values of age, weight, height, BMI and the per- per time) / (60×52) centage of sex and education levels for participants are presented in Table 1. The mean age of the participants was 39.5 ± 14.7 yr MET-h/wk of leisure time activity was calculated by multiply- and 45.5% were men. Average BMI was 25.9 ± 4.7 kg/m2 and the ing the number of hours per week of each leisure time activity to prevalence of normal weight, overweight and obesity were 35.5%, metabolic equivalent (MET). One MET is set at 3.5 ml of oxy- 45.2% and 19.4%, respectively. All subjects were literate. Table 2 gen consumed per kilogram body mass per minute (1kcal/kg/h) shows the estimations of MET-h/wk measured by physical activ- and represents the resting metabolic rate. The numbers of METs ity record questionnaires and two MAQs. Based on two MAQs, corresponding to each activity were calculated using the average the mean of MET-h/wk for leisure time, occupational and total metabolic cost for each activity.12 (leisure and occupational combined) physical activities were 23.4, According to the questionnaire, individuals had to identify the 52.3 and 75.7, respectively. Besides, the mean of total MET-h/wk number of month and hours participated in physical activity at was 86.3 MET-h/wk according to the data derived from physical work (standing, house work, work activities more intense than activity records of four seasons. For past year leisure time, occupa- standing) over the past year. The assessment of occupational ac- tional and total (leisure and occupational combined) physical ac-

280 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Reliability and Validity of the Modifiable Activity Questionnaire

Table 1. Main characteristics of study population Measurement mean SD Minimum Maximum Age (year) 39.5 14.7 19.0 66.0 Sex (men)* 45.5% - - - Weight (kg) 72.1 14.8 43.0 98.0 Height (cm) 166.6 9.9 150 185 BMI (kg/m2) 25.9 4.7 18.3 35.1 Education (academic) † 9.1% - - - *= Sex presented as percentage; † = The percentage of individuals who were graduated from university.

Table 2. Physical activity (MET-h/wk) measures obtained with the mean of two Modifiable Activity Questionnaires and the mean of four physical activity records Two MAQs Four physical activity records Measurement ρ† P-value† (Mean ±S.D)* (Mean ±S.D) Leisure time 23.41 ± 26.05 12.86 ± 13.81 0.39 0.050 Occupational 52.32 ± 17.56 53.97 ± 52.58 0.36 0.070 Total 75.73 ± 71.58 86.37 ± 63.55 0.47 0.017 * = Standard error; † = ρ and P-value calculated by spearman correlation coefficients tivity, Intraclass Correlation Coefficients were 0.94, 0.98 and 0.97 and total (leisure and occupational combined) physical activities respectively. Spearman Correlation Coefficients between means presented relatively moderate correlation. of two MAQs and means of four physical activity recordsare pre- Gabriel et al. based on MAQ, reported that leisure physical ac- sented in Table 2. The Spearman Correlation Coefficient was 0.39 tivity during the past month and the past week was reliable and (p = 0.05), 0.36 (p = 0.07) and 0.47 (p = 0.01)for leisure time, oc- associated with physical activity and physical fitness.2 Our results cupational and total (leisure and occupational combined) physical suggested a high Intraclass Correlation Coefficients between two activities, respectively. MAQs for leisure time (0.94), occupational (0.98) and total (leisure and occupational combined) (0.97) physical activity. Discussion As a conclusion and based on our results, the Farsi translated MAQ has a high reliability. However, the validity of the Persian This is the first study to assess test-retest reliability and validity of version is in doubt because of our study limitations. Using four the Persian translated MAQ in samples of males and females from physical activity records may result in recall bias or have language an Iranian urban adults. We used four physical activity records to and educational barriers and that cannot be gold standard to evalu- compare MET-h/wk from the MAQs and physical activity records. ate the exact validity of the MAQ. Objective activity monitors

The reliability assessed by Intraclass Correlation Coefficient be- such as accelerometers, Vo2max, and the doubly labeled water tween the results of two MAQs with a one-month interval. Our technique have numerous advantages and provides a more pre- results demonstrated excellent reliability and relatively moderate cise way to validate the subjective method that estimate of energy validity of the MAQ among an Iranian adult sample population. expenditure. Since those methods are complicated and expensive The MAQ, developed by Kriska, assesses current (past year and and are not simple to do, we used physical activity record to es- past week) physical activity level during both leisure and occupa- timate participants’ physical activity levels when those objective tional time.14–16 and it is a retrospective quantitative questionnaire methods not provided. Furthermore, primarily and besides physi- that represents the most comprehensive form of physical activity cal activity records, we had considered Vo2max as a gold standard recall survey. This questionnaire designed for easy modification and objective methods to evaluate the exact validity of the MAQ to maximize the ability to assess physical activity in a variety of in our study. However, performing Vo2max measurement was not populations and it`s culture free.16 Reliability and validity of the feasible in our study due to the lack of resources. On the other hand MAQ were previously reported in some other populations.16,17 some previous epidemiological studies that used questionnaires Measurement of total energy expenditure by the doubly labeled have not been evaluated physical activity levels against objective water method demonstrated validity of the MAQ.17 In Kriska et measures.18 al. study, spearman correlation coefficients found 0.92 (ages The small sample size of the present study and the moderately low 21 – 36) and 0.88 (ages 37 – 59) for past year leisure time and participation rate are other limitations of this study. Moreover, we for occupational and total (leisure and occupational combined) didn’t have any information about non responded to be reported. physical activity were 0.88 and 0.89 respectively.14 Results from On the other hand, as it is shown, our data were from just young, Schulz study showed that Spearman Correlation Coefficients for over weight and mainly not having academic education subjects past-year leisure time (0.56) and total (0.74) physical activity (Table 1). So, data from older subjects or people with normal were significantly related to total energy expenditure assessed by weight or obese or even academic educated ones may show dif- doubly-labeled water.17 Evaluation of physical activity in middle- ferent results. aged women showed that both the leisure physical activity during In conclusion and considering that the original MAQ has an the past month and the past week demonstrate good stability and ability to assess the P.A. levels in a variety of different populations. convergent validity.2 In our study, validity results for leisure time The present study shows that the Persian translated version is

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 281 A.A Momenan, M. Delshad, N. Sarbazi, et al. reliable but can be used in the TLGS Tehranian population with Reproducibility and validity of the Shanghai Women’s Health Study caution because of relatively moderate convergent validity. It can physical activity questionnaire. Am J Epidemiol. 2003; 158(11): 1114 – 1122. be answered quickly and requires little cooperation by the patient. 8. Jurj AL, Wen W, Xiang YB, Matthews CE, Liu D, Zheng W, et al. Re- However, it is suggested to perform further studies with large producibility and validity of the Shanghai Men’s Health Study physical sample size and better gold standard to assess the validity of this activity questionnaire. Am J Epidemiol. 2007; 165(10): 1124 – 1133. tool more precisely, if it is going to be used with no doubt and in 9. Azizi F, Ghanbarian A, Momenan AA, Hadaegh F, Mirmiran P, He- dayati M, et al; Tehran Lipid and Glucose Study Group. Prevention other Iranian population. of non-communicable disease in a population in nutrition transition: Tehran Lipid and Glucose Study phase II. Trials. 2009; 10: 5 – 19. References 10. FleissJL. The design and analysis clinical experiments. The simple rep- lication reliability study. 1st ed. Canada: wilely 1999; 8 – 13. 11. Kriska AM, Edelstein SL, Hamman RF, Otto A, Bray GA, Mayer-Da- 1. Stewart AL, Mills KM, King AC, Haskell WL, Gillis D, Ritter PL. vis EJ, et al. Physical activity in individuals at risk for diabetes: Diabe- CHAMPS physical activity questionnaire for older adults: outcomes tes Prevention Program. Med Sci Sports Exerc. 2006; 38(5): 826 – 832. for interventions. Med Sci Sports Exerc. 2001; 33(7): 1126 – 1141. 12. Montoye HJ. Energy Costs of Exercise and Sport. In: Maughan j, edi- 2. Pettee Gabriel K, McClain JJ, Lee CD, Swan PD, Alvar BA, Mitros tor. Nutrition in sport.7th ed. london: Blackwell Science 2000; 53. MR, et al. Evaluation of physical activity measures used in middle- 13. Hinton P.R. Statistics Explained, 2nd ed. Rout ledge Press. aged women. Med Sci Sports Exerc. Public Health Nutr. 2009; 1403 14. Kriska AM., Knowler WC, LaPorte RE, Drash AL, Wing RR, Blair – 1412. SN, et al. Development of questionnaire to examine relationship of 3. Martínez-González MA, López-Fontana C, Varo JJ, Sánchez-Villegas physical activity and diabetes in Pima Indians. Diabetes Care. 1990; A, Martinez JA. Validation of the Spanish version of the physical ac- 13: 401 – 411. tivity questionnaire used in the Nurses’ Health Study and the Health 15. Kriska AM, Bennett PH. An epidemiologic perspective of the relation- Professionals’ Follow-up Study. Public Health Nutr. 2005; 8(7): 920 ship between physical activity and NIDDM: from activity assessment – 927. to intervention. Diabetes Metab. 1992; 8: 355 – 372. 4. Camões M, Severo M, Santos AC, Barros H, Lopes C. Testing an adap- 16. Kriska AM, Pereira MA, FitzGerald SJ, Gregg EW, Joswiak ML, Ryan tation of the EPIC physical activity questionnaire in Portuguese adults: WJ, et al. Modifiable activity questionnaire. In: A collection of physi- a validation study that assesses the seasonal bias of self-report. Ann cal activity questionnaires for health-related research. Med. Sci. Sports Hum Biol. 2010; 37(2): 185 – 197. Exerc. 1997; 29: S73 – S78. 5. Neilson HK, Robson PJ, Friedenreich CM, Csizmadi I. Estimating 17. Schulz LO, Harper IT, Smith CJ, Kriska AM, Ravussin E. Energy inactivity energy expenditure: how valid are physical activity question- take and physical activity in Pima Indians: comparison with energy naires? Am J Clin Nutr. 2008; 87(2): 279 – 291. expenditure measured by doubly-labeled water. Obes. Res. 1994; 2: 6. Vuillemin A, Oppert JM, Guillemin F, Essermeant L, Fontvieille AM, 541 – 548. Galan P, et al. Self-administered questionnaire compared with inter- 18. Pettee Gabriel K, McClain JJ, Schmid KK, Storti KL, Ainsworth BE. view to assess past-year physical activity. Med Sci Sports Exerc. 2000; Reliability and convergent validity of the past-week Modifiable Activ- 32(6): 1119 – 1124. ity Questionnaire. Public Health Nutr. 2010; 15: 1 – 8. 7. Matthews CE, Shu XO, Yang G, Jin F, Ainsworth BE, Liu D, et al.

282 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Harm Reduction in Smoking Cessation

Original Article Efficacy of Harm Reduction Programs among Patients of a Smoking Cessation Clinic in Tehran, Iran

Hooman Sharifi MD MPH1, Roghieh Kharaghani MSc1, Habib Emami PhD•1, Zahra Hessami MD MPH1, Mohammad Reza Masjedi MD2

Abstract Background: Recently, harm reduction programs have been used to reduce mortality and morbidity among smokers. The main objective of this study was to evaluate the effect of harm reduction programs on the smoking patterns of subjects who presented to a smoking cessation clinic in Tehran, Iran. Methods: This observational study was conducted between September 2008 – September 2009 on 132 patients who were unable to quit smoking. Patients were enrolled by the first come first service method. During the study period, subjects were assigned to either group or individual visits every 15 days in conjunction with the use of nicotine gum. The main objective of this study was to evaluate at the third and sixth months of follow-up: the number of smoked cigarettes, level of expired carbon monoxide (CO), and numbers of nicotine gum used. Data were analyzed by the Wilcoxon rank, Fisher's exact, and Pearson's chi-square tests and SPSS version 17 software. Results: A total of 87.1% of the subjects were males. We noted decreases in the number of cigarettes smoked daily and the level of expired CO, whereas the amount of nicotine gum used significantly increased during the time interval between the first session and the third and sixth month follow-up visits (p <0.001 for all variables). During the follow up sessions, 64.4% of subjects reduced the number of cigarettes they smoked daily by at least 50% and 12.9% of subjects quit smoking. Conclusion: Behavioral and pharmacological therapy in harm reduction programs result in a decrease in the number of cigarettes smoked daily and a reduction in the amount of expired CO. Therefore, these methods can be beneficial in achieving complete smoking cessation.

Keywords: Cigarette, harm reduction, nicotine, Tehran, treatment

Cite this article as: Sharifi H, Kharaghani R, Emami H, Hessami Z, Masjedi MR. Efficacy of Harm Reduction Programs among Patients of a Smoking Cessation Clinic in Tehran, Iran. Arch Iran Med. 2012; 15(5): 283 – 289.

Introduction bronchitis, and emphysema.5 The World Bank estimates the annual expenses of smoking-related diseases in the United States to be obacco smoking is among the most common preventable more than 200 million dollars, which is more than the profit from causes of death worldwide. According to a report by the sales by multinational tobacco companies.6 T World Health Organization (WHO), the smoking-related Smoking is preventable. During the past decades there have death toll will reach 8 million by the year 2030,1 half of which will been remarkable improvements in nicotine-dependence treatment. occur in developing countries.2 There are more than one billion These behavioral and pharmacological therapies have increased smokers globally.3 In 2006, Iran became a member of the Frame- the rate of 6-month abstinence to about 2 – 3 times.7 Following work Convention on Tobacco Control (FCTC) and legalized to- the effective steps taken by the US Tobacco Prevention and Con- bacco control. A primary action to reach the goal of tobacco control trol Center, the US smoking rate decreased from 42.4% in 1965 is to evaluate and acquire baseline information on the issues ad- to 24.1% in 1998.8 However, many smokers who quit smoking dressed in FCTC. Prior to FCTC, in 2005 the Islamic Republic has relapse and others may never attempt to quit. In a study by the banned tobacco consumption in public places and subsequently Smoking Cessation Clinic affiliated with the Tobacco Prevention passed a law (article 13) to penalize and fine those who disobey. and Control Research Center in Iran, 87.5% of participants who Based on a report by the Ministry of Health and Medical Education smoked quit tobacco smoking at the end of the first month of the in Iran, 24.1% of men and 4.3% of women (15-64 years old) are study. In the mentioned study, 23.4% of participants relapsed dur- smokers.4 ing the first month, 40.7% during the third month, 47.2% during Smoking is the cause of at least 85% of lung cancers, chronic the sixth month, and 52.4% during the first year following abstinence.9 Thus, the number of smokers resistant to treatment seemed 10 Authors’ Affiliations: 1Tobacco Prevention and Control Research Center (TP- to increase over time. CRC), Masih Daneshvari Hospital, Shaheed Beheshti Medical Science Univer- Finding new techniques for quitting smoking may be helpful in sity, Tehran, Iran,2National Research Institute of Tuberculosis and Lung Diseases filling the gap between what the smoker hopes to accomplish and (NRITLD), Masih Daneshvari Hospital, Shaheed Beheshti Medical Science Uni- versity, Tehran, Iran what he is capable of, since most smokers have repeatedly attempt- •Corresponding author and reprints: Habib Emami PhD, Tobacco Prevention ed to quit but with no success.11 and Control Research Center (TPCRC), Masih Daneshvari Hospital, Shaheed Be- Harm reduction methods focus on reducing the harmful effects heshti Medical Science University, Shaheed Bahonar Avenue, Darabad, Tehran, Iran. Tel: +989127147041, Fax: +982126106003 , Office: +9827122029, E-mail: of tobacco products, rather than emphasizing nicotine withdrawal [email protected]. syndrome.12 These methods are designed to establish a temporary Accepted for publication: 25 January 2012 reduction in the number of cigarettes smoked by those who are un-

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 283 H. Sharifi, R. Kharaghani, H. Emami, et al.

Table 1. Baseline socio-demographic characteristics of participants.

Variables Numbers Percent Sex (male) 115 87.1 Age: Males (years) 37.3±10.7* _ Females (years) 40.7±12.2* _ Education Illiterate and primary 10 7.5 Guidance and high school 31 23.5 Diploma and higher 91 68.8 Social class Clerical or non-manual skilled 65 49.2 Manual skilled 47 35.6 Unskilled or semiskilled 20 15.2 Tenure Owner occupied 69 52.3 Rent/other 63 47.7 Marital status Married 85 64.4 Single 35 26.5 Widowed, divorced or other 12 9.1

* = Mean±standard deviation

25 25 NumberMean Numberof cigarettes of cigarettes smoked smokedper day per day NumberMean Numberof nicotine of gumsnicotine used gums per used day per day 22.19 22.19 20.6 20.6 20 20 15.57 15.5713.25 13.25 12.12 12.12 11.3 11.3 11.34 11.34 15 15

10 10

5 5 5.5 5.5 5.59 5.59 5.46 5.46 5.63 5.63 3.34 3.34

0 0 0.03 0.03 0.34 0.34 Session Session1 Session 1 Session2 Session 2 Session3 Session 3 Session4 Session 4 Session5 3-month 5 3-month6-month 6-month f ollow-upf ollow-upf ollow-upf ollow-up Figure 1. Mean number of cigarettes smoked and number of nicotine gums used per day from baseline to 6-month follow up. Differences were all statically significant p( < 0.001). able to quit completely.13,14 Nicotine replacement drugs contain small amounts of nicotine Materials and Methods which is gradually released and somehow prevents cigarette crav- ing.15 Use of these nicotine-containing products for a long time is Study design not harmful and it is definitely superior to smoking cigarettes.16,17 This pre-post design interventional study was conducted at an Considering the prevalence of smoking, large number of ex- inner-city smoking cessation clinic with approximately 1000 par- smokers who relapse, and limited number of smoking cessation ticipants between September 2008 and September 2009 in Tehran, interventions in Iran, the present study has sought to determine if Iran. prolonged smoking cessation programs in which nicotine replacement products used by current smokers helped to decrease daily Sample selection cigarette consumption and exhaled carbon monoxide (CO). This The Tobacco Prevention and Control Research Center’s Smok- study was conducted to assess the efficacy of harm reduction pro- ing Cessation Clinic was considered as the main setting for sample grams for smoking cessation clinic patients. The main objectives selection. The inclusion criteria were: participants who had previ- of this study were to evaluate: i) the number of cigarettes smoked ously attended smoking cessation programs in this center, those per day, ii) exhaled CO levels, and iii) number of nicotine gums who were unsuccessful in quitting smoking or relapsed after quit- used per day. ting, and those willing to participate in this study who offered their

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(n)

Figure 2. Expired carbon monoxide (CO) levels from baseline to 6-month follow up. Differences were all statically significant on Fisher’s exact test p( < 0.001). consent. The exclusion criteria were the inability to actively par- shown a strong, statistically significant relationship between level ticipate in the study or not having enrolled in a smoking cessation of reported smoking during the past 24 hours and breath CO lev- program. A total of 132 patients were enrolled. els.22 Although presumed unsuitable for epidemiological studies that Data collection gather information during a single visit, breath CO testing could A questionnaire was designed according to International Union be a valuable tool for monitoring abstinence from smoking during Against Tuberculosis and Lung Diseases (IUATLD) and WHO- cessation trials that have regular follow-up intervals.26 structured questionnaires, pilot tested, and revised. The first two The Smokerlyzer measures breath CO levels in parts per million sections of the questionnaire were self-administered, whereas the (ppm) based on the conversion of CO to CO2 over a catalytically third section was completed by counselors during the smoking ces- active electrode. On breath holding, the CO in the blood forms sation course. The questionnaire included demographic data, histo- equilibrium with CO in the alveolar air; therefore, there is a high ry, and pattern of smoking. Before beginning the course, in order to degree of correlation between breath CO levels and COHb con- assess nicotine use, the Fagerström Test for Nicotine Dependence centration. This enables the Smokerlyser to accurately estimate (FTND) was performed. the blood COHb concentration from the breath CO level. We have The social status of the participants was determined based on the calibrated the Smokerlyzer weekly by using a mixture of 50 ppm Registrar General Model of Social Classes, and participants were CO in air. classified into 6 groups.18 The numbers of cigarettes smoked daily and consumed nicotine Procedures gums were recorded at every visit. Patients were initially asked to participate in this study by phone There is no or little doubt about the reliability of the responses on contact using their previous records. Those who met the inclusion questionnaires administered in the first visit of smoking cessation criteria were scheduled for their initial assessment visit following clinics, however many smokers mispronounce their situation dur- the first group therapy session. All 132 participants who consented ing follow-up sessions.19 In studying nicotine replacement thera- to enroll in this study were divided into 10 groups of 5 – 15 par- pies such as nicotine gum, cotinine cannot be used as a marker of ticipants each. Participants were visited approximately every two cigarette abstinence, because cotinine is a metabolite of nicotine. weeks, on weekdays, and a smoking counselor attended each ses- Accordingly, cotinine’s first use for verification of self reports of sion. Participants came to the Smoking Cessation Clinic at 2, 4, 6, abstinence during treatment is limited to non-nicotine containing 8 and 10-week intervals following initiation of the study to partici- medications.20,21 pate in group therapy, and at 3 and 6 months for follow up assess- Since the determination of breath CO levels is noninvasive, in- ments. In all sessions respiratory CO levels were assessed. expensive, and yields immediate results, it is the method of choice The study protocol was approved by the Research Committee of in research and clinical practice.22 In this study, CO level was the Tobacco Prevention and Control Research Center. measured using a hand-held portable CO monitor (Bedfont Micro Smokerlyser, Kent, England) that had previously been shown to Intervention be effective in validating the participants’ self-reports regarding No new intervention was implemented following the completion smoking status.23,24 of all measurements. Subjects were monitored to achieve a certain CO has a 3 – 6 hour half-life, which depends on the level of ex- percentage of reduction in smoking rate (at least 50%). Therefore, ercise and environmental CO. Previous studies have shown that 2 mg nicotine gums were administered to all subjects, the same as smoking within the past 24 hours generally results in elevated in the cessation program. breath CO levels which are above the normal physiological range. The treatment procedure was started in a routinely conventional However, this could depend on both the quantity of cigarettes cessation program and categorized in three steps: i) one session smoked and the last time a cigarette was smoked.25 One study has as a baseline assessment; ii) two sessions for gradual reduction

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Table 2. Baseline smoking status, habits, and dependence. Variables Mean±standard deviation Age at smoking onset (years) 18.5±5.6 Number of cigarettes smoked per day 22.1±10.4 Expired carbon monoxide (CO) level 101 (76.5)** Number of nicotine gums used per day 0.03±0.43 Pack of cigarettes smoked per year 22.3±16.9 Q-MAT* score 14.9±4.1 HAD† score 16.9±6.7 FTND‡ score 5.9±2.8 * Motivation to quit smoking; ** Number (percent); † Hospital anxiety and depression test; ‡ Fagerström Test for Nicotine Dependence;

Figure 3. Percent abstinence after treatment from second session until 6-month follow up.

that used 2 mg nicotine gums; and iii) two maintenance sessions Wilcoxon rank test was used since two outcome variables (number (steady amount of nicotine gum and cigarettes) following two of cigarettes and nicotine gums used per day) did not have normal maintenance sessions that aimed at further reduction or cessation distributions as shown by the Kolmogorov-Smirnov test. Pearson’s of smoking. During the first session (baseline assessment), subjects chi-square test was used to determine the efficacy of intervention precisely stated the mean number of cigarettes they smoked daily in decreasing CO levels. All data were analyzed using SPSS ver- and their reduction amount for each day for 2 weeks, considering sion 17.0 software. Statistical tests used were two-tailed with 5% the counselor’s advice. Based on the recordings of the first session significance level. regarding smoking status, subjects were advised to decrease smoking over a 2-week period by 50% (reduction goal). In case of any Results difficulty following the schedule, the reduction pace was lessened. Upon achieving the 50% reduction goal, subjects were advised to Characteristics of the subjects further decrease their consumption or quit smoking completely. Among participants, 87.1% (n = 115) were men with a mean age of 37.33 ± 10.72 years and 12.9% (n = 17) were women Outcome measures with a mean age of 40.70 ± 12.24 years. A total of 64.4% (n = Outcome measures in this study included the decrease in the num- 85) of the subjects were married, 26.5% (n = 35) were single, ber of cigarettes smoked per day and the amount of nicotine gums and the remainder were divorced, widowed or separated. Regard- used per day. Successful reduction was defined as a self-reported ing their level of education, approximately 69.2% (n = 90) had reduction by 50% in the number of cigarettes smoked per day. a high school diploma or lower educational level. Homeowners comprised about 52.3% (n = 69) of subjects. All were from low Data analysis class strata; most (49.6%, n = 65) were employed in clerical work First, the estimated prevalence was calculated for all variables or non-manual skilled labor, whereas 6.8% (n = 9) were unem- through numbers, percentages, means and standard deviations. ployed (Table 1). Second, in order to determine the efficacy of the intervention, the

286 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Harm Reduction in Smoking Cessation

Figure 4. Estimated survival curves for 50% reduction in daily cigarette consumption through 3 months.

Smoking pattern and nicotine dependence Smoking reduction may encourage smoking cessation by allow- The mean age of smoking initiation was 18.5 ± 5.6 years and the ing smokers to gradually take control of this habit. Similar stud- mean number of cigarettes smoked daily was 22.19 ± 1.03. The ies that have aimed to decrease smoking in those trying to quit mean amount of expired CO for 76.5% (n = 101) of subjects was noted complete smoking cessation in a significant number of more than 20 ppm. According to FTND, the mean score of nico- smokers.27–31 In our study, the gradual reduction in smoking was tine dependence was 5.9 ± 2.8. The mean score for readiness to followed by a 12.9% successful quit rate. quit smoking was 14.9 ± 4.1 based on motivation to quit smoking One concern in harm reduction programs is that smokers who questionnaire (Questionnaire de motivation à l’arrêt du tabac) (Q- reduce the number of daily cigarettes may balance their intake of MAT) and according to the Hospital Anxiety and Depression test tobacco by smoking fewer cigarettes but more forcefully. In this (HAD), the mean score for suffering from depression or anxiety study, reduction in expired CO levels and number of daily ciga- was 16.9 ± 6.7 (Table 2). rettes is statistically significant. Therefore, even if this hypothesis is true, we have reached a significant reduction in expiratory CO Treatment efficacy levels due to the consumption of nicotine gums while participants During the first 6 months, the number of cigarettes smoked daily still smoked. significantly decreased; the number of nicotine gums used signifi- Some researchers suggest that high dose nicotine replacement cantly increased. At the beginning of the study these rates were therapy should be used to reduce the health risks due to compensa- 22.9 for number of smoked cigarettes and 0.03 for the number of tory smoking.31 nicotine gums used. This declined to 11.34 for the number of ciga- Nicotine Replacement Therapy (NRT) increases lasting absti- rettes smoked and 5.63 for number of nicotine gums used at the nence rates by 50% to 70%, irrespective of the method of prescrip- 6-month follow up. All were statistically significant p( < 0.001; tion in smokers motivated to quit.32 The 6-month abstinence rate Figure 1). According to the chi-square test, differences in expired in our study (12.9%) was the same as that observed in a number CO levels were statistically significant p( < 0.001 for all; Figure 2). of previous studies on NRT products for smoking reduction (8% In this study, 85 subjects (64.4%) decreased their number of daily – 12%),27–30 but lower than observed in a recent trial by Kralikova cigarettes by a minimum of 50%. During the follow-up visits, the et al. which showed that 18.7% of participants quit smoking in an number of subjects who quit gradually increased. Finally at 3 and intervention group that used nicotine gums.33 This was possibly 6-month follow-up visits, 17 subjects (12.9%) quit smoking (Fig- due to the fact that Kralikova and colleagues recruited smokers ure 3). After 4 weeks of observation there was a minimum of 50% who wanted to manage their smoking, which meant either decreas- reduction in daily cigarette consumption among the participants ing cigarette consumption or immediate cessation; whereas, in the (Figure 4). present study our participants were smokers who had failed to quit. The NRT-assisted reduction phase aims to promote cessation and Discussion engage smokers who are ready to quit in a time-limited course of structured reduction to reach a quitting endpoint. The reduce-to- This study explained the feasibility of reduction and eventual ces- quit approach is not the only technique that uses NRT. A compara- sation of cigarette smoking among Iranian people who previously ble approach, described as “cut down to quit”, encourages smokers failed to quit. The reduction in level of expired CO was statistically who are not currently interested in quitting to use NRT for smoking significant, even at the 6-month follow up, which validated the ef- reduction over a period of up to 12 months. The meta-analysis con- ficacy of smoking reduction programs in this study. ducted by Wang et al. in 2008 have reported that this approach was

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 287 H. Sharifi, R. Kharaghani, H. Emami, et al. successful but less cost effective than immediate cessation. The Office of the Assistant Secretary for Health, Office on Smoking and two approaches address different populations with different plans, Health. The health consequences of smoking: The changing cigarette. 34 A report of the Surgeon General. 1981. Available from: URL: http:// making it difficult to compare the results. www.quit-smoking-stop.com/articles-tobacco-health.html. (Accessed Our data suggest that although prolonged observation is not 2011 August 20). included in conventional smoking cessation programs, we could 8. Centers for Disease Control and Prevention (CDC). Cigarette smoking design our interventions for a longer period of time to address ces- among adults-United States, 1998. Morb Mortal Wkly Rep. 2000;49: 881 – 884. sation in smokers. Moreover, a structured treatment on the first 9. Masjedi M, Azaripour MH, Hosseini M, Heydari G. Effective factors two months of the course with regular follow-ups could clearly on smoking cessation among the smokers in the first “Smoking Cessa- enhance the quit rate. tion Clinic” in Iran. Tanaffos. 2002; 1: 61 – 67. Available from: URL: This study’s strengths include the presence of detailed data on http:// www.sid.ir/en/VEWSSID/J_pdf/100220020403.pdf. (Accessed 2011 August 20). smoking pattern and biochemical measures of smoke exposure. 10. Irvin JE, Hendricks PS, Brandon TH. The increasing recalcitrance of Another strong point is the report of smoking prevalence in a smokers in clinical trials II: Pharmacotherapy trials. Nicotine Tob Res. 6-month period instead of point prevalence at the end of a conven- 2003; 5: 27 – 35. Available from: URL: http://ntr.oxfordjournals.org/ cgi/reprint/5/1/27.pdf. (Accessed 2011 August 20). tional treatment, which is a less relevantoutcome. 11. Lindson N, Aveyard P, Hughes JR. Reduction versus abrupt cessation In summary, this study shows that reduction in smoking can be in smokers who want to quit. Cochrane Database Syst Rev.2010, Issue achieved through prolonged counseling sessions and NRT. Smok- 3. Art. No.: CD008033. DOI: 10.1002/14651858.CD008033.pub2.. ing reduction in people unable to stop smoking immediately seems 12. Frances RJ, Miller SI, Marck AH. Clinical Textbook of Addictive Dis- orders. 3rd ed. Location of publishing company? The Guilford Press. to be a step forward towards improved health and may finally pro- Available from: URL: http://www.informaworld.com/smpp/content~co ceed to complete smoking cessation. ntent=a911177929~db=all~jumptype=rss. (Accessed 2011 August 20). The results of this study support the efficacy of harm reduction 13. Warner KE, Slade J, Sweanor DT. The emerging market for long- programs. This is particularly useful for smoking cessation coun- term nicotine maintenance. J. Am. Med. Assoc. 1997; 278: 1087 – 1092. Available from: URL: http://jama.ama-assn.org/cgi/content/ab- selors to know that continuation of conventional programs can stract/278/13/1087. (Accessed 2011 August 20). augment the success rate of quitting in smokers. We hope that the 14. Kunze M. Maximizing help for dissonant smokers. Addiction. 2002; results of this study may be useful for tobacco control programs 95: 13 – 17. DOI: 10.1046/j.1360-0443.95.1s1.1.x and policy making. Further studies are also recommended in this 15. Peto R, Lopez AD, Boreham J, Thun M, Heath C Jr. Mortality from tobacco in developed countries: Indirect estimation from national regard. vital statistics. Lancet. 1992; 339: 1268 – 1278. DOI: 10.1016/0140- Last but not least, similar studies in other regions and countries 6736(92)91600-D can help support and generalize our findin 16. Tilashalski K, Rodu B, Cole P. Seven year follow-up of smoking cessation with smokeless tobacco. J Psychoactive Drugs.2005; 37: 105 – 108. Available from: URL: http://www.ncbi.nlm.nih.gov/pubmed/15916256. Acknowledgments (Accessed 2011 August 20). 17. Rodu B. Swedish tobacco use: Smoking, smokeless and history. ACSH This article is based on a project supported and funded by the To- Health Facts and Fears. 2004. Available from: URL: http://www.acsh. org/factsfears/newsID.362/news_detail.asp. (Accessed 2011 August bacco Prevention and Control Research Center, Shaheed Beheshti 20). Medical Science University. The author would like to thank all 18. Currie CE, Elton RA, Todd J, Platt S. Indicators of socioeconomic sta- participants in this study and the staff who facilitated the process. tus for adolescents: The WHO Health Behavior in School-aged Chil- Without their support and participation, this study would not have dren Survey. Health Education Research. 1997; 12: 385 – 397. Avail- able from: URL: http://her.oxfordjournals.org/cgi/reprint/12/3/385.pdf. been performed. (Accessed 2011 August 20). 19. Barrueco M, Jiménez Ruiz C, Palomo L, Torrecilla M, Romero P, Ries- co JA. Veracity of smokers’ reports of abstinence at smoking cessation clinics [Article in Spanish]. Arch Bronconeumol. 2005; 41: 135 – 140. References 20. Ahluwalia JS, Harris KJ, Catley D, Okuyemi KS, Mayo MS. Sus- tained-release bupropion for smoking cessation in African Americans: 1. WHO Report on the Global Tobacco Epidemic. Implementing smoke- A randomized controlled trial. J Am Med Assoc. 2002; 288: 468 – 474. free environments. 2009. Available from: URL: http://www.who.int/ 21. Hall SM, Humfleet GL, Reus VI, Munoz RF, Hartz DT, Maude-Griffin tobacco/mpower/en/index.html. (Accessed 2011 August 20). R. Psychological intervention and antidepressant treatment in smoking 2. Ortiz A, Martinez M, Torres A, Casal J, Rodriguez W, Nazario S. cessation. Arch Gen Psychiatry. 2002; 59: 930 – 936. Predictors of smoking cessation success. Puerto Rico Health Science 22. Javors MA, Hatch JP, Lamb RJ. Cut-off levels for breath carbon mon- Journal. 2003; 22: 173 – 177. Available from: URL: http://www.bio- oxide as a marker for cigarette smoking. Addiction. 2005; 100: 159 medexperts.com/Abstract.bme/12866142/Predictors_of_smoking_ – 167. cessation_success. (Accessed 2011 August 20) 23. Jarvis MJ, Belcher M, Vesey C, Hutchison D C S. Low cost carbon 3. General Surgeon Report. Important factors in smoking cessation; monoxide monitors in smoking assessment. Thorax. 1986; 41: 886 – women and smoking, a Report of the Surgeon General. 2007. Available 887. from: URL: http://www.cdc.gov/mmwr. (Accessed 2011 August 20). 24. Tilashalski K, Rodu B, Cole P. A pilot study of smokeless tobacco 4. Ministry of Health and Medical Education. Center for Disease Control. in smoking cessation. Am J Med 1998; 104: 456 – 458. Avail- A national profile of non-communicable disease risk factors in the Is- able from: URL: http://www.sciencedirect.com/science/article/pii/ lamic Republic of Iran. 2005. Available from: URL: http://www.who. S0002934398000850. (Accessed 2011 August 20). int/chp/steps/IR_IranSTEPSReport.pdf. (Accessed 2011 August 20). 25. Benowitz NL, Jacob P, Ahijevych K, Jarvis MF, Hall S, LeHouezec J, 5. Slama K. Tobacco Control and Prevention. A Guide for Low-income et al. Biochemical verification of tobacco use and cessation. Nicotine Countries. Paris: IUATLD; 1998. Available from: URL: http://www. Tob Res. 2002; 4: 149 – 159. iuatld.org/pdf/en/guides_publications/tobac coguide.pdf. (Accessed 26. Kauffman RM, Ferketich AK, Murray DM, Bellair PE, Wewers ME. 2011 August 20). Measuring tobacco use in a prison population. Nicotine Tob Res. 2010; 6. Curbing the epidemic: Governments and the economics of tobacco 12: 582 – 588. control. The World Bank. Tobacco Control. 1999; 8: 196 – 201. Avail- 27. Bolliger CT, Zellweger JP, Danielsson T, Van BX, Robidou A, Westin A, able from: URL: http://www.worldbank.org/tobacco/. (Accessed 2011 et al. 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(Accessed 2011 August 20). 31. Hatsukami D, Mooney M, Murphy S, LeSage M, Babb D. Effects 28. Wennike P, Danielsson T, Landfeldt B, Westin A, Tonnesen P. Smok- of high dose transdermal nicotine replacement in cigarette smokers. ing reduction promotes smoking cessation: Results from a double blind, Pharmacol Biochem Behav.. 2007; 86: 132 – 139. DOI:10.1016/j. randomized, placebo-controlled trial of nicotine gum with 2-year follow- pbb.2006.12.017. up. Addiction. 2003; 98: 1395 – 1402. Available from URL: http://www. 32. Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replace- ncbi.nlm.nih.gov/pubmed/14519176. (Accessed 2011 August 20). ment therapy for smoking cessation. Cochrane Database Syst Rev. 29. Batra, A., Klingler, K., Landfeldt, B., Friederich, H.M., Westin, A. 2008 Jan 23;(1):CD000146. DOI: 10.1002/14651858.CD000146.pub3 and Danielsson, T. (2005) Smoking reduction treatment with 4-mg 33. Kralikova E, Kozak JT, Rasmussen T, Gustavsson G, Le Houezec nicotine gum: A double-blind, randomized, placebo-controlled study. J. Smoking cessation or reduction with nicotine replace. DOI: Clinical Pharmacology & Therapeutics, 78, 689 – 696. doi:10.1016/j. 10.1186/1471-2458-9-433. clpt.2005.08.019 (Accessed 2011 August 20). 34. Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D. 30. Rennard SI, Glover ED, Leischow S, Daughton DM, Glover PN, Cut down to quit’ with nicotine replacement therapies in smoking ces- Muramoto M, et al. Efficacy of the nicotine inhaler in smoking re- sation: A systematic review of effectiveness and economic analysis. duction: A double-blind, randomized trial. Nicotine Tob Res. 2006; Journal of Technology Assessment in Health Care. 2008; 12: 1 – 135. 8: 555 – 564. Available from: URL: http://www.ncbi.nlm.nih.gov/ DOI: 10.3310/hta12020. pubmed/16920653. (Accessed 2011 August 20).

Mohtasham Garden in Rasht, Gilan Province - Iran, founded during Nasser al-Din Shah Qajar Period (1848 – 1896) (Photo by M.H. Azizi MD)

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 289 A.Poorkaveh, A. Modabbernia, M. Ashrafi et al.

Original Article Validity, Reliability and Factor Structure of Hepatitis B Quality of Life Questionnaire Version 1.0: Findings in a Large Sample of 320 patients

Atefeh Poorkaveh MSc1,2, Amirhossein Modabbernia MD1,3, Mandana Ashrafi MD1, Shervin Taslimi MD, MPH1, Maryam Karami BSN1, Mojtaba Dalir BSN1, Arezoo Estakhri MD1, Reza Malekzadeh MD 1, Hassan Pasha Sharifi PhD4, Hossein Poustchi MD PhD•1

Abstract Background: Quality of life is of significant importance in chronic hepatitis B (CHBV). We aimed to assess the psychometric properties of the Hepatitis B Quality of Life Questionnaire v1.0 (HBQOL) in a large sample of 320 Iranian patients with CHBV. Methods: After adapting the Iranian version through forward-backward translation and expert panel discussion, we administered HBQOL together with Short-Form 36 (SF-36), Medical Outcome Study Social Support Questionnaire (MOS-SS), Hospital Anxiety and Depression Scale (HADS), and the Iowa Fatigue Scale (IFS) to 320 non-cirrhotic Iranian patients. We used principal component analysis with Varimax rotation to determine the factor structure. To evaluate the psychometric properties of HBQOL, test-retest and internal consistency reliabilities, divergent and convergent validity with other instruments, and discriminatory power were calculated. Results: Thirty-one questions loaded on to six factors (Anticipation anxiety, Stigma, Psychological well-being, Vitality, Transmissibility and Vulnerability) which explained 63.6% of total variance. Test-retest reliability was 0.66. Cronbach’s α was 0.94 for the overall scale and between 0.7 and 0.9 for subscales, with the exception of the Vulnerability subscale. HBQOL and its subscales showed acceptable convergent and divergent validity with other instruments. Furthermore, Vulnerability subscale of HBQOL discriminated between patients with chronic active and chronic inactive hepatitis. Conclusion: The Iranian version of HBQOL is reliable, valid, and sensitive to the clinical conditions of the patients. This instrument has acceptable factor structure to measure several aspects of quality of life in patients with chronic HBV.

Keywords: Anxiety, depression, factor analysis, fatigue, hepatitis B quality of life questionnaire version 1.0, reliability, validity

Cite this article as: Poorkaveh A, Modabbernia AH, Ashrafi M, Taslimi S, Karami M, Dalir M, et al. Validity, Reliability and Factor Structure of Hepatitis B Quality of Life Questionnaire Version 1.0: Findings in a Large Sample of 320 patients. Arch Iran Med. 2012; 15(5): 290 – 297.

Introduction Because biological outcomes or generic instruments may miss key disease-related components of HRQOL and overlook pa- n recent years, health-related quality of life (HRQOL) has tients’ perceptions of their HRQOL, a disease-specific instrument become a main measure of health and an important outcome seems necessary.7 Until 2007, the measures used for evaluation of I in clinical trials. Although clinicians are more concerned with HRQOL in patients with CHBV were either generic [i.e., Short the biological outcomes of their patients, patients mainly worry Form-36 (SF-36)] or liver-specific (but not CHBV-specific) qual- about their quality of life.1 Chronic diseases can negatively affect ity of life questionnaires such as the Chronic Liver Disease Quality HRQOL and chronic hepatitis B (CHBV) is no exception. Several of Life Questionnaire (CLDQ) and the Liver Disease Quality of studies have shown impairment of HRQOL in patients with Life Questionnaire (LDQLQ).8–10 CHBV.2–6 Instruments to assess HRQOL consist of two different In 2007, Spiegel et al.11 developed a disease-targeted quality of categories: generic and disease-specific. Generic instruments can life questionnaire for non-cirrhotic patients with CHBV entitled be used for all disease types and allow for comparison among dis- the Hepatitis B Quality Of Life Instrument, version 1.0 (HBQOL eases, whereas disease-specific instruments focus on a specific dis- v1.0). Their factor analysis showed the following six distinct fac- ease or a specific group of diseases, evaluating the condition in a tors: Psychological well-being, Anticipation anxiety, Vitality, more specific manner.1 Two of the most important features of dis- Stigma, Vulnerability, and Transmissibility. An extra a priori-de- ease-specific questionnaires which make them useful outcome fined factor, related to Viral response, was also added which was a measure, particularly in clinical trials, are their capability to dif- combination of Vulnerability and Transmissibility. They described ferentiate between different severities of the disease as well as their high test-retest reliability, internal consistency, and discriminant sensitivity to change in clinical condition over time.7 validity for the questionnaire. However, after development of the Authors’ Affiliations: 1Digestive Disease Research Center, Shariati Hospital, HBQOL, no study evaluated the psychometric characteristics of Tehran University of Medical Sciences, Tehran, Iran, 2Department of Counseling, the questionnaire. Additionally, this instrument has not been eval- Islamic Azad University, Tehran, Iran, 3Department of Psychiatry, Roozbeh Psy- uated in different cultural contexts. CHBV is quite prevalent in chiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran, 4Depart- ment of Psychology and Psychometrics, Islamic Azad University, Roodehen, Iran Asian countries and the results from the English version cannot be •Corresponding author and reprints: Hossein Poustchi MD PhD, Digestive generalized to other languages and cultures. Disease Research Center, Shariati Hospital, North Kargar Ave, Tehran, Iran , To assess the psychometric properties of HBQOL in a larger 14117-13135. Tel: +98-21-82415141, Fax: +98-21-8241300, E-mail: [email protected]. sample of non-cirrhotic patients with CHBV and to evaluate the Accepted for publication: 6 July 2011 questionnaire in people with different cultural and language back-

290 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Validity, Reliability and Factor Structure of HBQOL V1.0

Table 1. Instruments used in the validation of HBQOL. Adapting the Developers/year Cronbach’s α Number Iranian version Instrument [reference Subscales Cronbach’s α of the Iranian of items [Reference number] version number] Ware and Mental and physical component Short-Form 36 36 > 0.85 Montazeri et al.14 0.65– 0.9 Sherbourne/ 199213 summary (MCS and PCS) Medical Emotional/Informational Outcome Study Sherbourne and 19 support, Tangible support, > 0.9 Our group 0.95 Social Support Stewart /199113 Affection, Positive interaction Questionnaire Iowa Fatigue Cognitive, Fatigue, Energy, Hartze el al./ 200315 11 0.9 Our group 0.81 Scale Productivity Hospital Anxiety Anxiety: 0.8 Zigmond and Anxiety: 0.78 and Depression 14 Anxiety, Depression Depression: Montazeri et al.17 Snaith/ 198316 Depression: 0.86 Scale 0.76 grounds, we administered HBQOL to Iranian patients with CHBV. translation recommended by World Health Organization to adapt Next, we performed a factor analysis and determined the question- the Persian version of the HBQOL.12 naire’s reliability. To ensure the convergent and divergent validity We used the following four generic questionnaires: i) SF-36,13,14 of HBQOL, we used several generic instruments. ii) Iowa Fatigue Scale (IFS),15 Medical Outcome Study Social Support Questionnaire (MOS-SS),13 and the Hospital Anxiety and Materials and Methods Depression Rating Scale (HADS).16,17 Table 1 provides a summary of these instruments. Subjects There are several “rules of thumb” for determining sample size From March to September 2010, we evaluated 320 patients with in factor analysis. Many authors believe that a sample size of 10 CHBV who referred to a university clinic in Shariati Hospital, Teh- individuals per item, 50 individual per factor, or at least 300 is ad- ran, Iran. Inclusion criteria were: confirmed CHBV diagnosis, age equate.18 For the purpose of this study, we determined a sample > 18 years, and ability to communicate. Co-infection with hepa- size of 300, with an additional 20 subjects for possible missing titis C or HIV, severe psychiatric disorders and any other severe data. Since the completed questionnaires were examined for com- comorbid diseases were exclusion criteria. All patients read and pleteness by the interviewer before the patient left the clinic, we signed an informed consent form. The Ethics Committee of the considered a 7% loss of samples rather than the more routine 15%. Digestive Disease Research Institute of Shariati Hospital approved The first 300 patients also completed other questionnaires based the proposal. on a random block method. There were 13 blocks, each of which contained 23 individuals who were given the questionnaire. Based Data collection on another “rule of thumb” for bivariate correlation, a sample size Two trained interviewers collected important baseline character- of more than 100 (according to some, 104) is considered appropri- istics and clinical data in separate questionnaires. In addition to ate. However some authors consider numbers as low as 50 to be HBQOL, we administered several generic questionnaires to evalu- acceptable.18,19 Thus, we have applied a ratio of 1.875 (15/8 in each ate quality of life, social support, fatigue, depression, and anxiety block) and the overall MOS-SS was administered to 104 patients. with the intent to determine the convergent and divergent validity The other patients received HADS and IFS questionnaires. Since of HBQOL. Because of the large number of questions, we admin- SF-36 was the main measure of validity in our study, it was administered each instrument to a proportion of patients, so that each istered to as many patients as possible, unless time limitations of patient completed two or three questionnaires in addition to the the clinic prevented us from doing so. HBQOL. All questionnaires were self-administered and interviewers were responsible for interviewing illiterate patients as well as Data analysis supervising other patients as they completed the questionnaires. SPSS version 15.00 (Chicago, USA) was used for data analysis. We used exploratory factor analysis (principal component analy- Assessment instruments sis) with Varimax rotation with Kaiser Normalization.20 Factors HBQOL11 consists of 31 questions. Each contains a 5-point Lik- with eigenvalues of more than one were retained for analysis. ert-type scale and is loaded onto six factors: Psychological well- Items, which loaded more than 0.4 onto at least one factor and being, Anticipation anxiety, Vitality, Stigma, Vulnerability, Trans- ranked first or second in the scale loadings, were retained in that mission (plus a priori defined factor, Viral response). Cronbach’s factor. In addition, we determined the inclusion or exclusion of an α was 0.96 for the overall score and with a range of 0.75 – 0.9 for item in a factor based on face validity (i.e., discussion with our subscales. The scale showed high test-retest reliability and its re- expert panel). To evaluate the quality of sampling, we used Kaiser- lated subscales showed high convergent validity with SF-36 MCS Meyer-Olkin (KMO) and Bartlett’s test of sphericity. and PCS (mental and physical component summaries). Spiegel et To report the score of our patients, we used the 100-point scale al.11 found high discriminatory power of the viral response item with higher scores showing better quality of life. Skewness was between viral responders and viral non-responders. used to evaluate data distribution. To compare subgroups, the para- Similar to the study by Spiegel et al.11 ,we changed the total metric tests was used for normally distributed data whereas the score of HBQOL (range: 31 – 155) to a 100-point scale with lower non-parametric tests were used for skewed data. Floor and ceiling scores showing lower quality of life. We used forward-backward effects were noted to be present if 15% of participants achieved the

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 291 A.Poorkaveh, A. Modabbernia, M. Ashrafi et al. lowest or highest possible scores.21 naire. Table 2 shows baseline characteristics of participants. Be- To calculate test-retest reliability, we administered the HBQOL cause of supervision at the time of administration of the question- to a number of patients two weeks after the first administration and naires, none of the questionnaires had missing data. Mean time calculated the intraclass correlation coefficient.22 To determine the for completion of HBQOL was 6 (3 to 10) minutes. The overall internal consistency we calculated Cronbach’s α for each factor score and scores of factors one to four on the percentile scale had and for the overall HBQOL score. Cronbach’s α of 0.7 or more was a negative skewed distribution (better quality of life) while factors considered acceptable. five to seven showed normal distribution. The mean ± SD score To determine questionnaire validity, we assessed content valid- for HBQOL was 66.12 ± 20.90. Patients with recently diagnosed ity, construct validity, and discriminatory power of the question- CHBV showed lower scores of HBQOL and its subscales (except naire.23–25 Developers of the questionnaire had approved the con- Vulnerability) than the patients with previously diagnosed CHBV tent validity in their own study. Besides, we discussed the translated (P < 0.05 for Vitality, and P < 0.01 for overall scale and other questionnaire with a number of experts in the fields of hepatology, subscales). Of patients, 0.9% achieved the highest possible score, psychology, and psychometrics to ensure its content validity. whereas 0.9% also achieved the lowest possible scores which in- Construct validity determines how much a questionnaire mea- dicated the absence of floor and ceiling effects. The effects of sev- sures the construct of interest. To determine construct validity, we eral variables on scores of the HBQOL scale and its subscales are evaluated both convergent and divergent validities.23 There are shown in Table 3. many ways to assess these validities; all equally efficient. What is consistent among all studies for assessment of construct validity is Table 2. Baseline characteristics of patients. correlational analysis. Variable Value Convergent validity is the correlation of the questionnaire with Male gender (%) 210 (65.6%) Age (mean ± SD) 39.63 ± 13.37 other well-validated instruments that have the same construct Educational level (i.e., measuring the same thing). A correlation coefficient of 0.21 Illiterate (%) 43 (13.5%) to 0.4 is considered fair, 0.41 to 0.6 is good, 0.61 to 0.8 is very Less than diploma (%) 120 (37.5%) 26 Diploma (%) 96 (30%) good, and more than 0.8 is excellent. A good correlation coef- BS (%) 51 (15.9%) ficient was considered evidence of good convergent validity in our MS and over (%) 10 (3.1%) study. We hypothesized that MCS , depression, and anxiety should Residence Capital (%) 127 (39.7%) have at least good correlation with the mental-related subscales Other cities (%) 193 (60.3%) of HBQOL (most importantly Psychological well-being, and An- Marital status ticipation anxiety), while PCS and IFS should have at least good Single (%) 50 (15.6%) correlation with the physical-related subscales of HBQOL (Vital- Married (%) 263 (82.2%) Divorced (%) 7 (2.2%) ity). In addition, these factors should be less correlated with other Widowed (%) 0 (0%) less-related subscales when compared with their correlation with Habitual history more-related subscales. None (%) 226 (70.6%) Cigarette (%) 67 (20.9%) Divergent validity shows how much an instrument correlates Alcohol (%) 50 (15.6%) with a construct that it should not measure.23,25 We determined Illicit drug (%) 24 (7.5%) divergent validity by calculating the correlation of HBQOL and Comorbid conditions (%) 85 (26.5%) MOS-SS, each of which were designed to measure completely Possible transmission route Vertical (%) 68 (21.25%) different constructs. Therefore, we hypothesized that HBQOL, al- Sex (%) 2 (0.6%) though related to social support should have a fair correlation (0.2 Blood-born (%) 32 (10%) – 0.4) with MOS-SS. Unknown (%) 218 (68.15%) Chronic active hepatitis (%) 72 (22.5%) The discriminatory power of an instrument shows the ability of Time since diagnosis (mean ± SD) 68.1 ± 68.6 (month) an instrument to discriminate between two clinically distinct con- Recently (< 6 months) diagnosed patients (%) 59 (18.4%) ditions. Any outcome measure intended for health care purposes SF-36 scores PCS (mean ± SD) 47.9 ± 9.1 should be sensitive to changes in health status. In the study by MCS (mean ± SD) 47.2 ± 11.5 Spiegel et al., this was determined as the capability of the Viral HADS scores response subscale to distinguish between viral responders and Anxiety (mean±SD) 7.5±4.6 nonresponders. Since the design of the present study was not lon- Depression (mean±SD) 4.6±4.1 IFS score (mean±SD) 26.8±8.3 gitudinal, we determined discriminatory power by a comparison MOS-SS score (mean±SD) 73.6±17.7 of HBQOL and its subscale scores between patients with chronic active hepatitis (CAH) and patients with chronic inactive hepatitis Factor analysis (CIH). A six-factor solution emerged accounting for 63.6% of the total variance. The KMO test was 0.938 and Bartlett’s test of sphericity Results was significant at a level of P < 0.001, which showed high quality of the sampling. Anticipation anxiety, with eight items, explained Sample characteristics and HBQOL scores 15.5% of the variance followed by Stigma, Psychological well-be- A total of 320 patients (110 females and 210 males) with a mean ing, Vitality, Transmissibility, and Vulnerability. We also included ± SD age of 39.6 ± 13.4 years participated in the study. No sig- the Viral response factor, which consists of items of Transmissi- nificant difference was observed in age, gender, marital status or bility and Vulnerability (Table 4). After primary analysis, because educational level between patients who were administered a par- Productivity (F12) loaded onto the Psychological well-being (it ticular questionnaire and those who were not given that question- loaded onto Vitality in the study by spiegel et al.) we hypothesized

292 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Validity, Reliability and Factor Structure of HBQOL V1.0

Table 3. Effect of several variables on HBQOL and its subscales.

HBQOL components Variable A n t i c i p a t i o n Psychological Stigma Vitality Transmissibility Vulnerability Viral response HBQOL anxiety well-being Gender Female 57.5 ± 27.4 76.7 ± 24.3 68.8 ± 24.6 63.3 ± 27.9 56.8 ± 35.7 48.4 ± 30.9 52.6 ± 24.6 64.9 ± 20.9 Male 62.7 ± 26.0 73.7 ± 24.5 71.7 ± 24.8 68.5 ± 26.7 52.6 ± 37.1 48.8 ± 30.2 50.7 ± 26.3 66.7 ± 20.9 Age r = 0.062 r = 0.078 r = 0.100 r = 0.025 r = -0.030 r = 0.006 r = -0.013 r = 0.062 Duration r = -0.069 r = 0.024 r = 0.072 r = -0.060 r = 0.057 r =-0.027 r = 0.043 r = 0.008 Diagnosis Recent 52.5 ± 28.0** 67.7± 24.0** 56.8 ± 25.0** 58.7 ± 29.7* 41.5 ± 37.0** 43.2 ± 31.3 42.3 ± 26.5** 56.6 ± 20.1** Past 62.8 ± 25.9 76.4 ± 24.2 73.8 ± 23.6 68.5 ± 26.3 56.9 ± 36.0 49.9 ± 30.2 53.4 ± 25.1 68.2 ± 20.5 Living in Tehran 62.1 ± 28.0 75.4 ± 23.9 71.9 ± 25.2 66.4 ± 27.8 59.3 ± 36.0* 48.6 ± 30.2 53.9 ± 24.9 67.1 ± 21.4 Other cities 60.2 ± 25.6 74.3 ± 24.8 69.9 ± 24.5 66.9 ± 26.9 50.6 ± 36.8 48.7 ± 30.7 49.7 ± 26.2 65.4 ± 20.5 1Marital status Single 63.3 ± 26.0 72.0 ± 24.8 67.5 ± 26.5 68.1 ± 30.7* 60.0 ± 35.1 47.7 ± 24.5 53.8 ± 23.0 65.7 ± 65.7 Married 60.4 ± 26.6 75.1 ± 24.4 71.2 ± 24.3 67.2 ± 26.2 52.4 ± 36.9 49.1 ± 29.7 50.7 ± 26.3 66.1 ± 66.1 Divorced 61.1 ± 32.3 82.6 ± 25.9 73.2 ± 29.5 39.2 ± 25.1 75.0 ± 32.2 39.2 ± 27.4 57.1 ± 20.8 65.7 ± 65.7 Educational level Less than 61.7 ± 27.6 72.4 ± 26.1 68.8 ± 26.8 64.5 ± 28.3* 54.2 ± 36.8 47.8 ± 29.3 51.0 ± 24.4 64.9 ± 21.9 diploma Diploma and 61.8 ± 25.9 77.0 ± 23.3 73.5 ± 22.9 72.4 ± 25.2 56.7 ± 36.7 51.2 ± 31.9 54.0 ± 26.9 68.6 ± 20.2 over Comorbid disease No 62.5 ± 26.1 74.4 ± 25.4 72.6 ± 24.6 70.8 ± 26.8** 57.3 ± 36.6 50.1 ± 30.9 53.7 ± 25.4 67.7 ± 20.9 Yes 59.5 ± 28.7 75.1 ± 23.6 66.8 ± 26.2 61.3 ± 27.0 50.1 ± 36.7 47.6 ± 30.0 48.9 ± 26.1 63.8 ± 21.5 Viral activity status Active 60.7 ± 28.7 75.6 ± 24.6 71.4 ± 22.5 65.4 ± 27.2 56.9 ± 37.6 37.8 ± 27.4** 47.3 ± 25.6* 65.7 ± 19.8 Inactive 61.0 ± 26.0 74.5 ± 24.5 70.5 ± 25.4 67.1 ± 27.2 53.2 ± 36.4 51.8 ± 30.6 52.5 ± 25.7 66.2 ± 21.2 Values are presented as mean ± SD. * = P < 0.05; ** = P < 0.01; r = Spearman ranked correlation coefficient;1 Vitality scores differ between married and divorced, single and divorced patients. that patients may have different concepts of Productivity based on being and MOS-SS (Table 5). educational level. We found that in patients with lower educational Vulnerability and Viral response discriminated between patients levels, Productivity loaded more onto Vitality than other factors. with CAH and patients with CIH (defined by viral load and liver enzymes) and thus showed discriminatory power (P < 0.001 for Reliability, validity, and discriminatory power Vulnerability and P < 0.05 for Viral response). Testing of internal consistency showed satisfactory Cronbach’s α for five of the six main subscales (Anticipation anxiety = 0.9, Discussion Stigma = 0.86, Psychological well-being = 0.88, Vitality = 0.83, Transmissibility = 0.7, Vulnerability and Viral response = 0.55). The present study was the first, to our knowledge, which evalu- HBQOL total scores had Cronbach’s α of 0.94. The Vulnerability ated HBQOL after its development. Two of the main advantages of subscale had a Cronbach’s α of < 0.6 which showed poor, but not our study were its large sample size and the use of several instru- ‘unacceptable’ coefficient.27 Substantial (defined as > 0.6) test-re- ments to validate HBQOL. Our results showed that the Vulnerabil- test reliability was observed in 29 patients who were retested two ity subscale was able to differentiate between patients with CAH weeks after the initial questionnaire administration (ICC = 0.660). and CIH. According to Spiegel et al.11 the Viral response factor Scores of MCS and PCS significantly correlated with HBQOL discriminated between viral responders and non-responders. While scores. However, the strength of correlation was higher for MCS we found that the same factor was able to distinguish between pa- (r = 0.616 for MCS and 0.399 for PCS; P < 0.001). In addition, tients with CAH and CIH, this was totally attributable to the Vul- among the subscales, the Psychological well-being factor had nerability subscale, which was a subset of the Viral response factor. the highest correlation with MCS (r = 0.646, P < 0.001). Among Because the design of the present study was cross-sectional, we the HBQOL subscales, Vitality had the highest correlation with were unable to detect any “change” in our patients. The differ- both PCS and IFS (Table 5). As seen in Table 5, Anxiety had the ence between patients with normal and abnormal liver functions strongest relation with Psychological well-being (r = -0.625, P < has been shown in other studies that used different instruments. 0.001) while depression had the highest correlation with Vitality Lam et al.5 and Ong et al.4 showed that the Worry subscale of the (r = -0.621, P < 0.001). There was a significant correlation be- CLDQ and MCS subscale of SF-36 were capable of differentiating tween HBQOL and MOS-SS scores (r = 0.322, P < 0.001). Of the between patients with normal and abnormal liver function, respec- HBQOL subscales, the strongest relation was between Vitality and tively. MOS-SS (r = 0.422, P < 0.001) followed by Psychological well- The recent diagnosis of CHBV significantly affected our patients’

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 293 A.Poorkaveh, A. Modabbernia, M. Ashrafi et al.

Table 4. Factor structure of HBQOL v1.0. Components 1 3 Items 2 4 5 6 (Anticipation (Psychological (Stigma) (Vitality) (Transmissibility) (Vulnerability) anxiety) well-being) C1: Concern failure 0.782 0.141 0.119 0.185 0.023 0.071 C2: Concern cancer 0.719 0.280 0.091 0.187 0.187 -0.077 C15: Concern worsen 0.660 0.203 0.216 0.126 0.296 0.165 C5: Concern flare 0.653 0.236 0.100 0.076 0.404 0.157 C12: Concern survival 0.622 0.249 0.204 0.146 0.371 0.131 F9: Bad 0.608 0.214 0.468 0.086 0.056 0.015 C6: Concern sick easily 0.606 0.133 0.092 0.185 0.306 0.192 C9: Concern survival 0.504 0.326 0.322 0.207 0.190 0.170 F2: Stigmatized 0.188 0.762 0.072 0.095 -0.075 0.046 F1: Ashamed 0.164 0.625 0.334 0.009 0.048 0.074 C14: Concern embarrassed 0.185 0.603 0.347 0.076 0.317 0.085 C3: Concern boss 0.247 0.569 0.003 0.123 0.183 0.016 F8: Isolated 0.188 0.565 0.451 0.138 0.149 0.012 C11: Concern socially isolated 0.186 0.557 0.349 0.209 0.414 0.051 C10: Concern self-conscious 0.209 0.554 0.446 0.101 0.362 0.088 F4: Frustrated 0.216 0.532 0.492 0.224 -0.030 -0.055 F3: Sad 0.408 0.486 0.422 0.128 -0.060 -0.017 F10: Less enjoyable 0.203 0.286 0.684 0.195 0.108 0.051 F11: Sex difficult 0.033 0.109 0.680 0.188 0.153 0.307 F13: Scared 0.559 0.118 0.632 0.115 0.024 0.002 F7: Angry 0.207 0.226 0.575 0.227 0.075 -0.050 F6: Anxious 0.458 0.259 0.523 0.255 -0.027 -0.044 F12: Unproductive 0.022 0.370 0.523 0.346 0.242 -0.067 P3: Muscle aches 0.202 -0.003 0.152 0.796 0.031 0.075 P1: Tiredness 0.215 0.249 0.212 0.787 0.018 0.043 P2: Memory problems 0.125 0.069 0.182 0.733 0.128 0.048 F5: Worn out 0.210 0.430 0.302 0.599 -0.090 0.089 C4: Concern transmit child 0.208 0.079 0.071 -0.006 0.759 -0.027 C7: Concern transmit sex 0.318 0.084 0.087 0.062 0.730 0.084 C13: Concern eat 0.026 0.076 0.142 0.001 0.071 0.800 C8: Concern medicines 0.239 0.015 -0.070 0.139 -0.001 0.771 Rotated eigenvalues 4.8 4.1 4.0 2.8 2.2 1.5 Variance explained (%) 15.5% 13.4% 13.1% 9.2% 7.3% 4.9%

Table 5. Spearman’s ranked correlation coefficient (95% CI) between HBQOL and other instruments HBQOL components Instruments Anticipation Psychological HBQOL total Stigma Vitality Transmissibility Vulnerability anxiety well-being score r = 0.340** r = 0.230** r = 0.402** r = 0.544** r = 0.057 r = 0.082 r = 0.399** PCS (0.209 to 0.458) (0.101 to 0.367) (0.277 to 0.514) (0.437 to 0.636) (-0.084 to 0.196) (-0.059 to 0.220) (0.273 to 0.510) r = 0.508** r = 0.506** r = 0.646** r = 0.627** r = 0.179* r = 0.043 r = 0.616** MCS (0.396 to 0.605) (0.393 to 0.603) (0.556 to 0.721) (0.534 to 0.705) (0.040 to 0.312) (-0.098 to 0.182) (0.521 to 0.696) r = -0.544** r = -0.608** r = -0.681** r = -0.215** r = -0.625** r = -0.450** r = -0.099 IFS (-0.636 to (-0.689 to (-0.750 to (-0.345 to (-0.704 to (-0.555 to -0.330) (-0.237 to 0.042) -0.437) -0.511) -0.598) -0.077) -0.531) r = -0.616** r = -0.625** r = -0.620** r = -0.202** r = -0.171* r = -0.666** r = -0.511** Anxiety (-0.696 to (-0.700 to (-0.700 to (-0.333 to (-0.304 to (-0.738 to (-0.608 to -0.400) -0.520) -0.526) -0.526) -0.063) -0.031) -0.580) r = -0.492** r = -0.507** r = -0.621** r = -0.190** r = -0.587** r = -0.435** r = -0.090 Depression (-0.592 to (-0.681 to (-0.701 to (-0.322 to (-0.672 to (-0.542 to -0.314) (-0.227 to 0.051) -0.378) -0.499) -0.527) -0.051) -0.487) r = 0.216* r = 0.281** r = 0.366** r = 0.422** r = 0.056 r = -0.045 r = 0.322** MOS-SS (0.024 to 0.392) (0.094 to 0.449) (0.187 to 0.522) (0.249 to 0.568) (-0.138 to 0.246) (-0.235 to 0.149) (0.138 to 0.485) * = P<0.05; ** = P <0.01.

HRQOL. Patients who were diagnosed for longer durations might original questionnaire). Regarding face validity, both items point have adopted coping mechanisms which might have lowered the out a “future” incident and may be more appropriately considered influence of CHBV on their HRQOL. under Anticipation anxiety. Although the present study confirms the psychometric proper- While Stigma was the fourth important factor in the study by ties reported by the primary study, some points need clarification. Spiegel et al.11, it was the second most important factor in our For example, items F9 and C6 loaded onto Anticipation anxiety in work. This may reflect cultural differences between the popula- our study (rather than Psychological well-being and Vitality in the tions of these studies, as the rate of perceived stigma in patients

294 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Validity, Reliability and Factor Structure of HBQOL V1.0

Table 6. Comparison of HBQOL with other liver disease-related HRQOL questionnaires.

Time Number of Questionnaire Developer(year) needed to Subscales Reliability Validity questions complete

Fatigue, Emotional function, Related subscales: Chronic α = 0.72 – 0.95 Younossi et al.10 29(previous Worry, Abdominal symptoms, 0.69 – 0.85 Liver Disease 10 min Test-retest: (1999) two weeks) Activity, Systemic symptoms, Unrelated subscales: Questionnaire 0.58 – 0.79 Sleep (new subscale) 0.33 – 0.48

69 All eight SF-36 subscales, Related subscale: > 0.6 Hepatitis Quality of Bayliss et al.32 (previous NA Sleep, health distress, CHC α = 0.81 – 0.94 Unrelated subscale: Life Questionnaire (1998) four weeks) distress, CHC limitations 0.33

Itching, Joint pain/discomfort, 12 Pain in the upper abdomen, α = 0 .79 – 0.86 Liver Disease Unal et al.33 Unrelated subscales: (previous <6 min Drowsiness, Sleeping during the Test-retest: 0.72 Symptoms Index (2001) < 0.6 one week) day, Lack of appetite, Fear of – 0.84 complications

Itch, Joint pain, Pain in the right upper abdomen , Sleepiness 18 α ≥ 0.79 Related subscales: Liver Disease Van der Plas et during the day, Worry about (previous NA Test-retest: 0.55 0.52 – 0.8 Symptoms Index 2.0 al.34 (2004) family situation, Decreased one week) – 0.99 appetite, Depression, Fear of complications, Jaundice

All eight SF-36 subscales, Symptoms of liver disease, Effects of liver disease , Liver Disease 111 Concentration, Memory, Quality Worse HRQOL is Gralnek et al.9 α = 0.62 – 0.95 Quality of Life (previous 38.3 min of social interaction, Health associated with worse (2000) Questionnaire four weeks) distress, Sleep , Loneliness , severity Hopelessness, Stigma of Liver disease , Sexual functioning, Sexual problems

Psychological wellbeing, Related subscales: Hepatitis B α = 0.73 – 0.96 Spiegel et al.11 Anticipation anxiety, Vitality, 0.55 Quality of Life 31 6 min test-retest = (2007) Stigma, Transmissibility, Unrelated subscale Questionnaire 1.0 0.96 Vulnerability, Viral response < 0.4 α = Cronbach’s α; Numbers under Validity column show correlation coefficients. Test-retest values show intra-class correlation coefficients. with chronic conditions in developing countries is twice as high as Transmissibility. However, in the primary study, the loading of this developed countries.28 Furthermore, while item F8 was considered item differed only 0.05 between the Psychological well-being and an item of psychological well-being in the primary study, it was Transmissibility factors. The highest correlation of this item with related to Stigma in the present work. In a study on HIV patients, other items in the Psychological well-being was: “I feel my life Fife and Wright found four distinct dimensions for stigma: social is less enjoyable because of hepatitis B” (r = 0.528). Regarding rejection, financial insecurity, internalized shame, and social iso- these findings, it seemed that our patients’ main concern was less lation.29 Of note, because in HBQOL at least three of these four enjoyable life because of difficult sex rather than the transmission dimensions (other than financial insecurity) are addressed, this tool of the virus to another person. Since correlation is not necessarily may be considered a disease-specific tool for stigma. indicative of causation, such interpretation is a hypothetical one Eight items loaded on to Psychological well-being in our study, and needs further investigation. six of which were common between our study and the study by Vitality highly correlated with IFS and PCS scores showing that Spiegel et al.11 Two items, sexual activity (F11) and productiv- this scale is mainly a measure of somatic aspect of the quality of ity (F12), loaded on Psychological well-being, while in the pri- life. High relation between Vitality and Depression scores may in- mary study F11 loaded on to Transmissibility and F12 loaded on dicate a high relation between depression and somatization, par- to Vitality. However, F12 was loaded on Vitality in less educated ticularly in Iranian patients.30 As mentioned previously, somatic patients. Vitality mainly consists of items that describe physical symptoms may be of major importance in patients with low educa- function (as shown by its high correlation with PCS and IFS). Be- tional levels. This may be the reason why our low-level educated cause educational level is regarded as a key item in socioeconomic patients had more impaired Vitality scores than the patients with status, it may be interpreted that patients with lower educational high-levels of education. levels rely more on their physical function to do their jobs; so they Low Cronbach’s α of the Vulnerability subscale can be interpret- consider their productivity as an important consequence of their ed in several ways. First, the low number of items in the subscales physical function, rather than psychological well-being. Surpris- can affect this coefficient. Alternatively, it can reflect a low cor- ingly, the item “I feel like sexual activity is difficult for me because relation between two items in the factor. Cronbach’s α of less than of hepatitis B” loaded mostly on to Psychological well-being, than 0.5 is considered unacceptable.31 Because the Cronbach’s α did not

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 295 A.Poorkaveh, A. Modabbernia, M. Ashrafi et al. reach the unacceptable threshold and because this item showed the paper. high discriminatory power, we retained it in the final analysis of the questionnaire. The Viral response item was created by develop- References ers of the questionnaire using the combination of Transmissibility and Vulnerability.11 Although this item also showed discriminatory 1. Younossi ZM. Chronic liver disease and health-related quality of life. power in our study, this was a result of the Vulnerability factor Gastroenterology. 2001; 120(1): 305 – 307. 2. Svirtlih N, Pavic S, Terzic D, Delic D, Simonovic J, Gvozdenovic E, rather than the whole subscale. et al. Reduced quality of life in patients with chronic viral liver disease There are multiple liver (but not CHBV)-specific HRQOL instru- as assessed by SF12 questionnaire. J Gastrointestin Liver Dis. 2008; ments available in the literature.9–11,32-34 The most important pos- 17(4): 405 – 409. sible superiority of the HBQOL compared with other instruments 3. Modabbernia A, Ashrafi M, Keyvani H, Taslimi S, Poorkaveh A, Merat 11 S, et al. Brain-derived neurotrophic factor predicts physical health in is that it is CHBV-specific. Thereby as shown by Spiegel et al. untreated patients with hepatitis C. Biol Psychiatry. 2011; 70(5): e31 and the present study, HBQOL is more likely to detect changes in – e32. health status in this subset of patients. This may justify its use in 4. Ong SC, Mak B, Aung MO, Li SC, Lim SG. Health-related quality clinical trials, although this statement definitely requires more evi- of life in chronic hepatitis B patients. Hepatology. 2008; 47(4): 1108 – 1117. dence. Because of its nature (i.e., being disease-specific), HBQOL 5. Lam ET, Lam CL, Lai CL, Yuen MF, Fong DY, So TM. Health-related is unable to address HRQOL in patients with other diseases; thus quality of life of Southern Chinese with chronic hepatitis B infection. it cannot be used for comparison among the patients with dis- Health Qual Life Outcomes. 2009; 7: 52. 6. Sepanlou SG, Kamangar F, Poustchi H, Malekzadeh R. Reducing the eases other than CHBV. Table 6 provides a comparison between burden of chronic diseases: A neglected agenda in Iranian health care HBQOL and other liver disease-related instruments. system, requiring a plan for action. Arch Iran Med. 2010; 13(4): 340 The present study had several strengths. The adequate sample – 350. size for this design minimized the probability of type II error, as 7. Patrick DL, Deyo RA. Generic and disease-specific measures in assessing health status and quality of life. Med Care. 1989; 27(3 mentioned in Materials and Methods. The adequate sample size Suppl):S217-32. was also confirmed by Bartlett’s test of sphericity and the KMO 8. Lam ET, Lam CL, Lai CL, Yuen MF, Fong DY. Psychometrics of test. Supervision to ensure completion of questionnaires addition- the chronic liver disease questionnaire for Southern Chinese patients ally strengthened our study. Another advantage of our study was with chronic hepatitis B virus infection. World J Gastroenterol. 2009; 15(26): 3288 – 3297. the comparison of HBQOL and its subscales with several instru- 9. Gralnek IM, Hays RD, Kilbourne A, Rosen HR, Keeffe EB, Artinian ments that measured similar constructs, to ensure its convergent L, et al. Development and evaluation of the Liver Disease Quality of validity as well as the use of different constructs to ensure diver- Life instrument in persons with advanced, chronic liver disease--the gent validity. Exhaustive construct validation in the present study LDQOL 1.0. Am J Gastroenterol. 2000; 95(12): 3552 – 3565. 10. Younossi ZM, Guyatt G, Kiwi M, Boparai N, King D. Development together with the extensive content validation process performed of a disease specific questionnaire to measure health related quality of in the study by Spiegel et al.11 provided substantial evidence for the life in patients with chronic liver disease. Gut. 1999; 45(2): 295 – 300. validity of HBQOL. Moreover, both studies showed the HBQOL 11. Spiegel BM, Bolus R, Han S, Tong M, Esrailian E, Talley J, et al. De- to be reliable in most of its dimensions by test-retest and Cron- velopment and validation of a disease-targeted quality of life instrument in chronic hepatitis B: The hepatitis B quality of life instrument, bach’s α. version 1.0. Hepatology. 2007; 46(1): 113 – 121. Our study had also some limitations. The cross-sectional design 12. World Health Organization. Process of translation and adaptation of in- did not allow us to measure the change in the scores of HBQOL struments Available from URL: http://www.who.int/substance_abuse/ research_tools/translation/en/. Accessed January 2009 (i.e., responsiveness testing). Regarding generalizability, although 13. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health sur- the study was undertaken in one clinic, the sample size of this vey (SF-36). I. Conceptual framework and item selection. Med Care. study could be considered a representative of Iranian patients, both 1992; 30(6): 473 – 483. because diverse ethnic groups live in Tehran and because our clinic 14. Montazeri A, Goshtasebi A, Vahdaninia M, Gandek B. The Short Form 14 Health Survey (SF-36): Translation and validation study of the Iranian is a referral center that accepts patients from throughout Iran. version. Qual Life Res. 2005; 14(3): 875 – 882. 15. Hartz A, Bentler S, Watson D. Measuring fatigue severity in primary Conclusion care patients. J Psychosom Res. 2003; 54(6): 515 – 521. 16. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983; 67(6): 361 – 370. The Iranian version of HBQOL v1.0 is a psychometrically sound 17. Montazeri A, Vahdaninia M, Ebrahimi M, Jarvandi S. The Hospital measure with acceptable validity, reliability, and factor structure Anxiety and Depression Scale (HADS): Translation and validation and can distinguish between different clinical conditions. Further study of the Iranian version. Health Qual Life Outcomes. 2003; 1: 14. 18. VanVoorhis CRW, Morgan BL. Understanding power and rules of studies for longitudinal assessment of this instrument, particularly thumb for determining sample sizes. Tutorial Quant Meth Psychol. in clinical trials, are warranted. In addition, studies in other cultures 2007; 3(2): 43 – 50. and languages can generalize the administration of HBQOL as a 19. Green SB. How many subjects does it take to do a regression analysis? useful tool to assess the HRQOL in patients with CHBV. Multivar Behav Res. 1991; 26: 499 – 510. 20. Floyd FJ, Widaman KF. Factor analysis in the development and refine- ment of clinical assessment instruments. Psychol Assessment. 1995; Conflict of interests:None 7(3): 286-299. Financial support: Digestive Disease Research Center, Tehran 21. Terwee CB, Bot SD, de Boer MR, van der Windt DA, Knol DL, Dekker University of Medical Sciences, Tehran, Iran J, et al. Quality criteria were proposed for measurement properties of health status questionnaires. J Clin Epidemiol. 2007; 60(1): 34 – 42. 22. Weir JP. Quantifying test-retest reliability using the intraclass correla- Acknowledgement tion coefficient and the SEM. J Strength Cond Res. 2005; 19(1): 231 – 240. 23. Campbell DT, Fiske DW. Convergent and discriminant validation by We thank Dr. Ali Montazeri for his assistance in providing HADS the multitrait-multimethod matrix. Psychol Bull. 1959; 56(2): 81 – 105. and SF-36 questionnaires and his kind advice for improvement of 24. Bagozzi RP, Yi Y, Phillips LW. Assessing construct validity in organi-

296 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Validity, Reliability and Factor Structure of HBQOL V1.0

zational research. Admin Sci Quart. 1991; 36: 421 – 458. 1992; 157(3): 295 – 300. 25. Peter JP. Construct validity: A review of basic issues and marketing 31. Gliem, J.A., and Gliem, R.R. Calculating, Interpreting, and Reporting practices. J Marketing Res. 1981; 18: 133 – 145. Cronbach’s Alpha Reliability Coefficient for Likert-Type Scales. In 26. Nunnally JC BI. Psychometric Theory. 3rd ed. New York: McGraw- Midwest Research to Practice Conference in Adult, Continuing, and Hill; 1994. Community Education. Ohio: Ohio State University. 2003; 82-88. 27. Baiardini I, Pasquali M, Braido F, Fumagalli F, Guerra L, Compalati E, 32. Bayliss MS, Gandek B, Bungay KM, Sugano D, Hsu MA, Ware JE, Jr. et al. A new tool to evaluate the impact of chronic urticaria on quality of A questionnaire to assess the generic and disease-specific health out- life: Chronic urticaria quality of life questionnaire (CU-QoL). Allergy. comes of patients with chronic hepatitis C. Qual Life Res. 1998; 7(1): 2005; 60(8): 1073 – 1078. 39 – 55. 28. Alonso J, Buron A, Bruffaerts R, He Y, Posada-Villa J, Lepine JP, et 33. Unal G, de Boer JB, Borsboom GJ, Brouwer JT, Essink-Bot M, de al. Association of perceived stigma and mood and anxiety disorders: Man RA. A psychometric comparison of health-related quality of life Results from the World Mental Health Surveys. Acta Psychiatr Scand. measures in chronic liver disease. J Clin Epidemiol. 2001; 54(6): 587 2008; 118(4): 305 – 314. – 596. 29. Fife BL, Wright ER. The dimensionality of stigma: A comparison of its 34. van der Plas SM, Hansen BE, de Boer JB, Stijnen T, Passchier J, de impact on the self of persons with HIV/AIDS and cancer. J Health Soc Man RA, etal. The Liver Disease Symptom Index 2.0; validation of Behav. 2000; 41(1): 50 – 67. a disease-specific questionnaire.Qual Life Res .2004; 13:1469-1481. 30. Pliskin KL. Dysphoria and somatization in Iranian culture. West J Med.

A view of Persepolis – Achaemenid Empire (c.550 – 331 BCE), around 60 Km northeast of Shiraz-Iran (Photo by M.H. Azizi MD)

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 297 N. Nikbakhsh, F. Saidi, H. Fahimi

Original Article A New Technical Approach to Cancers of the Cervical Esophagus

Novin Nikbakhsh MD•1, Farrokh Saidi MD, FACS, FRCS2, Hossein Fahimi MD3

Abstract Background: The aim of this study was to assess the possibility of a primary end-to-end pharyngoesophageal anastomosis after standard tumor resection of the cervical esophagus by acute flexion of the neck. Methods: A total of 34 consecutive patients with primary cervical esophageal cancer, none having received prior radio- or chemotherapy, were treated by two methods based on intraoperative findings. In 18 patients, reconstruction after esophageal resection was carried out by the standard gastric pull-through technique (control group). In 16 patients, acute flexion of the neck after tumor resection allowed for reconstruction by primary end-to-end pharyngoesophagostomy (experimental group). Results: There was no operative mortality in either group. The mean operative time for the experimental group was about 50 minutes less compared to the control group. Self-limited postoperative anastomotic leakage in the neck was twice as common in the experimental group. Postoperative dysphagia was about three times as common in the experimental group [5 patients (31%)] compared to the control group [2 patients (11%)]. Conclusion: In selected cases, segmental resection of primary cervical esophageal cancers reconstructed by end-to-end pharyngoesophagostomy is technically feasible by bending the neck acutely forward during anastomosis and maintaining it in the flexed position during a postoperative period of about 7 days. The advantages are reduced scope and duration of the operation. The downside is doubling of the frequency of postoperative cervical leakage.

Keywords: Cervical esophagus, esophageal cancer, squamous cell carcinoma

Cite this article as: Nikbakhsh N, Saidi F, Fahimi H. A New Technical Approach to Cancers of the Cervical Esophagus. Arch Iran Med. 2012; 15(5): 298 – 302.

Introduction tween 36% – 73% after curative chemoradiotherapy in a 2-year rate.7 In these circumstances the management of local recurrence, bout 6% of esophageal cancers arise from the cervical seg- furthermore, becomes hazardous and technically demanding be- ment lying between the cricopharyngeus and the thoracic cause of prior radiotherapy.8–11 Death occurs by suffocation or mas- A inlet;1 the vast majority are squamous cell carcinomas. At sive local bleeding and rarely because of distant metastases. presentation, one-third of patients have extension of the tumor be- The purpose of this study was to evaluate the practicality of an yond the confines of the esophagus and in one-fifth, the trachea or end-to-end esophageal anastomosis in the neck after tumor resec- vocal cords are involved.1,2 The reported operative mortality ranges tion, thereby lowering the extent of surgical trauma associated with from 5% to 31%,3,4 and 7% to 37% of patients have postoperative formal laparotomy, mobilization, and transfer of the stomach to anastomotic leakage.3, 4 Neither mortality nor recurrence rates can the neck. There has been, unintentionally, refutation of the axi- be improved upon by removal of the entire length of the esopha- om against primary end-to-end anastomosis anywhere along the gus.5 Old reconstructive techniques consisted of fashioning a full esophageal length. thickness skin tube in the neck (Wookey procedure) or interposition of free jejunal grafts. Both procedures were time consuming Patients and Methods and cumbersome, and have been abandoned.3,6 Surgical management of cervical esophageal cancer differs from Between March 2001 and September 2008, a total of 34 consecu- that of other portions of the esophagus in two major aspects. Re- tive patients with primary, biopsy proven squamous cell carcinoma moval of the larynx with permanent loss of phonation is unavoid- of the cervical esophagus were admitted to the teaching hospitals able, and reconstruction by gastric pull-up greatly expands the of Beheshti University of Medical Sciences, Tehran and Babol scope of the surgery. University of Medical Sciences, Babol, Iran. None of the patients For these two reasons, chemo-radiotherapy has replaced surgery (15 males and 19 females; age range: 56 to 74 years) that enrolled in many centers as the preferred treatment modality. Overall sur- in the study had any co-morbidities or received prior chemoradio- vival has not improved, however, nor has the rate of local recur- therapy. Permission for the study was granted by the Institutional rence diminished. Review Board of the respective universities, and informed con- A recent study has shown locoregional relapse-free survival be- sent was obtained from all patients after full explanation of the two technical approaches being considered. The need for permanent Authors’ Affiliations: 1Babol University of Medical Sciences, Babol, Iran, 2Be- tracheostomy was explained, the psychological impact of perma- heshti University of Medical Sciences, Tehran, Iran, 3Mehr Hospital, Tehran, Iran. nent aphonia lessened by demonstrating one of the currently avail- •Corresponding author and reprints: Novin Nikbakhsh MD, Department. of Thoracic Surgery, Beheshti Hospital, Babol University of Medical Sciences, able hand-held mechanical speech devices. Babol, Iran.Tel. +98-9111227003, Fax: +98-1113232665 The decision regarding the manner of reconstruction was de- Accepted for publication: 24 August 2011 ferred until the resection was completed, in the following manner:

298 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 A New Technique in Cervical Esophagus Cancer

Table 1. Patients’ characteristics Sex Age Patient’s numbers Male Female (mean±SD) Gastric bypass n=18 n=8 (44%) n=10 (56%) 64.5±8 Neck flexion n=16 n=7 (44%) n=9 (56%) 65.3±9

Table 2. Tumor characteristics in the two groups. Gastric bypass group (n=18) Neck flexion group (n=16) T statusa T1 ------T2 1 (6%) 2 T3 10 (55%) 8 T4 7 (39%) 6 N statusa N0 5 4 N1 13 12 M statusa M0 18 16 M1 ------Stagea I ------II 6 (35%) 4 (25%) III 11 (59%) 12 (75%) IV 1 (6%) ---- Residual disease R0 16 (89%) 15 (94%) R1 2 (11%) 1 (6%) R0 = no residual tumor; R1 = microscopically residual tumor; aAccording to the TNM system (AJCC, 2002)

Table 3. Hospital morbidity and mortality. Complications Gastric bypass Neck flexion P value Minor anastomotic leaka 2 (11%) 4 (25%) 0.387 Major anastomotic leakb 1 (6%) 2 (13%) 0.591 Cardiac arrhythmias 5 (28%) 1 (6%) 0.180 Respiratory failure 0 0 ------Blood transfusion required 2 (11%) 0 0.487 Late stricture with dysphagia 2 (11%) 5 (31%) 0.214 aAnastomotic leaks apparent after the seventh postoperative day; bAnastomotic leaks apparent before the seventh postoperative day.

Table 4. Patterns of recurrence. Recurrence pattern Gastric bypass (n=18) Neck flexion group (n=16) P value Locoregional 2 (11%) 3 (19%) 0.648 Distant 4 (22%) 3 (19%) 1.000 Both 1 (6%) 2 (13%) 0.591

With the patient in the semi-sitting supine position, a mid-cervi- ynx (above) and the esophagus (below) to ensure microscopically cal collar incision allowed the lower skin flap to be opened enough tumor-free edges. No attempt was made to mobilize any portion of to accommodate the permanent tracheostomy opening. The strap the remaining distal esophagus, either laterally from its bed or in- muscles were transected, and the exploratory finger inserted in the feriorly into the thorax. The only tension-releasing maneuver used plane between the esophagus and anterior vertebral fascia. Oblit- consisted of gentle finger dissection around the open stump of the eration of this space, which may not have been fully apparent on pharynx, allowing for about 2 to 3 centimeters of downward dis- preoperative CT scans, meant unresectability of the lesion, as did placement of the pharyngeal opening to be used for anastomosis. gross involvement of the carotid vessels. The trachea was tran- Visible and palpable lymph nodes were removed, but no formal sected distal to the specimen in a beveled manner for tension-free neck dissection was performed. accommodation to the skin aperture in the center of the lower skin With the specimen removed and the neck in the normal anatomic flap. A prepared sterile endotracheal tube was inserted into the new position, the resulting anatomic defect in the neck was measured tracheal opening (end- tracheostomy), which replaced the initial with calipers. A gap of 8 centimeters or less suggested that a ten- orally inserted endotracheal tube. sion free, end-to-end anastomosis might succeed, but was verified Staying in the midline, the thyroid lobes and attached parathy- by a somewhat more reliable maneuver, as follows: roids were displaced laterally to avoid injury. The larynx and Pulling gently on two previously placed traction sutures on the proximal trachea attached to the cervical portion of the esopha- sides of the pharyngeal opening (above) and the esophageal open- gus where the tumor was located and mobilized in preparation for ing (inferior), an unscrubbed assistant would grasp the back of transection, superiorly at the level of the hyoid bone and inferiorly the patient’s head and gently flex it forward to a maximal, but not at a distance above the thoracic inlet. Having superiorly entered forced degree (Figures 1, 2). The degree of final tension that would the pharynx and sacrificing the epiglottis, the specimen could be be transferred on the anastomosis could subjectively assessed by lifted off its base to allow for transection of the esophagus infe- noting how readily the traction sutures would come together while riorly above the thoracic inlet with a grossly tumor-free margin. flexing the neck. If the caliper measured defect was greater than 8 Multiple biopsies were taken from the two open ends of the phar- centimeters or the neck flexion maneuver indicated an intolerable

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 299 N. Nikbakhsh, F. Saidi, H. Fahimi

Figure 1. Operative X-ray with neck in the neutral position showing a he- Figure 2. Same patient. The neck has now been flexed about 45° forward, mostat on the lower rim of the proximal remnant of the esophageal seg- bringing the two hemostats much closer together. ment, with another hemostat on the sternal angle.

Figure 3. Overall survival curve.

tension at the anastomosis, a transhiatal gastric pull-up would be skin closed in two layers without drainage. A feeding jejunostomy undertaken. Otherwise, primary end-to-end anastomosis was per- was placed through a limited laparotomy incision, to be used on formed in the following manner: the first postoperative day. A stout chin suture further assured that With the head brought back to its normal anatomic position, a the neck would be kept in the flexed position during the entire posterior followed by an anterior row of interrupted 2-0 Vicryl ® postoperative period of 7 days. The endotracheal tube, its balloon sutures (0.5 centimeters apart) were placed and kept in sequential deflated, was kept in place for about 2 days to ensure access for order, but not tied. The neck was fully flexed as described, essen- the tracheobronchial toilet as needed. When signs of leakage such tially obscuring the site of anastomosis. Tying down the sutures, as cervical wound erythema or drainage were seen, we performed beginning with the posterior row, was carried out in a blind man- a dilute barium study to verify leakage. Its management was by ner relying on the sense of touch in deciding the minimal degree cervical wound opening, dressing and nutrition via a jejunostomy of tension needed to bring the two open ends of the gullet together. tube. The mean duration of leakage in the neck flexion group was If any doubt existed, the anastomosis was not completed, but re- 5 days for minor anastomotic leak (anastomotic leaks became ap- construction shifted to the gastric pull-up procedure. The anasto- parent after the seventh postoperative day) and 10 days for ma- mosis was not tested for leaks by either air or saline insufflations. jor anastomotic leak (anastomotic leaks became apparent before At the end of the anastomosis, having maintained the head in the the seventh postoperative day). During the leakage period, mouth flexed position, the strap muscles were re-approximated and the washing with normal saline and oral intake of metronidazole syrup

300 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 A New Technique in Cervical Esophagus Cancer was prescribed. After 5 days, in all leakage cases, oral nutrition of cardiovascular disease, and 4 patients were alive without dis- was started with liquids and metronidazole syrup. Swallowing ease. The cause of death in the remaining patient was unknown. was achieved in all of these patients. Discussion Statistical analyses Survival analyses were performed using the Kaplan–Meier meth- This study showed the feasibility of primary pharyngoesopha- od. Comparisons of survival between groups were assessed by the gostomy by neck flexion with overall lower morbidity than the log-rank test. Differences in clinicopathologic variables among standard method. As shown in Table 3, a doubling of postoperative various groups were calculated using the chi2 test, Fisher exact anastomosis leakage and late stricture in our study was offset by test, and student t-test when appropriate. Multivariate analysis with significant saving of operative time and avoidance of complica- a stepwise Cox regression model was conducted to evaluate the tions with the gastric pull-up procedure. independent prognostic factors. A P value of less than 0.05 was Most studies12–16 prefer gastric transposition as the best surgical considered significant. All analyses were performed with SPSS technique for restoring alimentary continuity after laryngopharyn- software version 11.0 (SPSS, Inc., Chicago, IL). gectomy. Ayshford et al. have reported that 58% of British surgeons elected gastric pull-up as their favorite method17 of restoring Results alimentary continuity after cervical esophageal reconstruction. The mortality rate ranged from 5% to 31% and anastomotic leakage A total number of 34 patients (55.9% female; mean age ± SD: rate ranged from 7% to 37%. Sullivan and associates have reported 64.9 ± 4.9; range: 56 – 74 years) were enrolled in the study during results of 32 consecutive pharyngogastric reconstructions with a a 90 month period. The mean total surgical time ± SD was 196.6 12% mortality rate and anastomotic leakage rate of 31%.18 ± 28.0 minutes. Patients and tumor characteristics are shown in An unavoidable loss of the larynx has, understandably, swayed Tables 1 and 2. many surgeons towards chemoradiotherapy in managing primary There was no significant relationship between sex and the two cancers of the cervical esophagus. The benefits of chemoradiother- surgery type groups (P = 0.9), nor was seen between the mean pa- apy for lower-end esophageal cancers are being assessed,19–21 but tients` age and two surgery type groups (P = 0.7). Analysis of pa- the results are not necessarily applicable to upper-end esophageal tients’ process data also indicated that the mean surgical time(min) cancers. Any attempt, therefore, at ameliorating the plight of pa- ± SD in the standard gastric pull-through technique group was tients afflicted with cervical esophageal cancer would seem justi- 220.3 ± 14.0 and in the primary end-to-end pharyngoesophagos- fied. Reverting to a completely surgical approach initially has the tomy group, it was 170.0 ± 8.9, which was significant P( < 0.001). benefit of facilitating reoperations for local recurrence, something Overall, there was no significant relationship between sex and which would be technically difficult and hazardous after radiother- mean time (P = 0.9). apy to the neck. Results of chemoradiation for cervical esophageal A noticeable issue in this study was the weak reverse-correlation cancer by Burmeister et al.22 among 34 patients has shown a failure between duration of surgery and age of patients (Pearson correla- rate of 12% for local control. Three patients (9%) died from persis- tion: -0.072), however this relationship was not significant P( = tent local disease and 2 (6%) patients died as a result of treatment 0.8). [5 (15%)]. With well functioning, relatively inexpensive, hand- Outcome details for both the ‘gastric bypass’ and the ‘neck flex- held laryngeal voice devices now available, it is possible that there ion’ techniques of reconstruction are summarized in Table 3. will be a reversal to surgical management of cervical esophageal One patient in the gastric bypass group had a splenectomy be- cancers in the future. cause of inadvertent trauma to the spleen, and two patients re- The neck-flexion maneuver, which allows for primary end-to- quired blood transfusions. The mean duration of hospital stay was end pharyngoesophagostomy, rightfully raises the question as to similar for both groups, 15 days (10 – 30 days) in the neck flexion whether there might be some compromise with extent of cancer group and 12 days (10 – 20 days) in the standard method group. resection needed for a possible cure. The only way to avert this There was no mortality in either group. There was no need for possibility would be to postpone the final decision regarding re- conversion once the neck flexion technique had been decided construction until resection has been accomplished, according to upon at completion of resection. This lent weight to the reliability oncological principles. The next problem is the maximal length of of simple inspection and palpation in assessing anastomotic ten- the final esophageal defect after resection that would allow for a sion. successful primary end-to-end. One-half of the tracheal length is There was local tumor recurrence in 7 (39%) patients in the con- considered the maximum that can be removed and tracheal conti- trol group and 8 (51%) patients in the experimental group, with nuity restored by primary anastomosis.23 No comparable measure a mean delay of 16 months postoperatively (range: 3-80 months). exists for the esophagus, and the final decision rests on correct Two patients in the control group developed tumor recurrence in judgment. The length of the cervical portion of the esophagus var- the pulled-up stomach. Patterns of recurrence are depicted in Table ies according to body build of patients, which varies as does the 4. Overall actuarial survival in both groups is shown in Figure 3. degree of neck flexion tolerated by different individuals. Assigning We could complete follow-up in all 34 patients. Of the 16 patients a numerical value to the length of the esophageal defect that can be in the control group, 7 patients (40%) died of disease (locoregional bridged by neck flexion would, therefore, be much less valuable and distant metastasis), 4 patients died from cardiovascular dis- than a visual and palpatory assessment of permissible tension, as eases, 1 patient died due to a car accident and 4 patients were alive described. The final results confirmed the reliability of this type of and disease free. In the experimental group, 8 patients (50%) died subjective assessment of the safety of performing an end-to-end because of disease (locoregional and distant metastasis), 2 patients anastomosis in the neck. The only tension releasing maneuvers died because of cerebrovascular accident, 3 patients died because permitted are limited to digitally freeing the pharynx in the neck.

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 301 N. Nikbakhsh, F. Saidi, H. Fahimi

Any attempt at mobilizing the esophagus out of the thorax inferi- 486 – 491. orly should be resisted, the normal contractive pull of the freed-up 6. Schusterman MA, Shestak K, deVries EJ, Swartz W, Jones N, Johnson J, et al. Reconstruction of the cervical esophagus: Free jejunal transfer esophagus making this maneuver counter-productive. End-to-end versus gastric pull-up. Plast Reconstr Surg. 1990; 85(1): 16 – 21. pharyngoesophagostomy runs counter to accepted surgical prin- 7. Huang SH, Lockwood G, Brierley J, Cummings B, Kim J, Wong R, et ciples. Its execution in the neck, however, is made possible by the al. Effect of concurrent high-dose Cisplatin chemotherapy and confor- exceptional laxity brought about by neck flexion. This maneuver mal radiotherapy on cervical esophageal cancer survival. Int J Radiat 24 Oncol Biol Phys. 2008; 71(3): 735 – 740. has also been used by Pirmoazen in the management of long seg- 8. Newalshy GA, Read GA, Duncan W, Kerr GR.Results of radical ra- ment cervical esophageal strictures relieved by the Heineke–Mi- diotherapy of squamous cell carcinoma of the oesophagus. Clin Radiol. kulicz procedure, readily bringing together the two ends of the lon- 1982; 33: 347 – 752. gitudinal incision. Maintaining the neck in the flexed position for 9. Langer M, Choi NC, Orlow E, Grillo H, Wilkins EW. Radiation therapy alone or in combination with surgery in the treatment of carcinoma a minimum of 7 days proved not to be a problem. A few patients of the esophagus. Cancer. 1986; 58: 1208 – 1213. voluntarily kept their head bent forward for an additional day or 2. 10. Peracchia A, Bardini R, Ruol A, Segalin A, Castoro C, Asolati M, et al. Postoperative cervical anastomotic leakage was not as frequent Surgical management of carcinoma of the hypopharynx and cervical esophagus. Hepatogastroenterology, 1990; 37: 371 – 375. or serious as expected, nor delayed strictures as severe as feared. 11. Hennessy TP, O’Connell R. Carcinoma of the hypopharynx, esophagus The bent–neck posture was tolerated quite well by patients after and cardia. Surg Gynecol Obstet. 1986; 162: 243 – 247. tracheal resection for 7 or more days, and the same was observed 12. Fredrickson JM, Wagenfeld DJ, Pearson G. Gastric pull-up vs. delto- for the neck flexion group in this study. The total number of cases pectoral flap for reconstruction of the cervical esophagus.Arch Otolar- yngol. 1981; 107: 613 – 616. in this study was not large enough to show whether, in the long 13. Moores DW, Ilve R, Cooper JD, Todd TR, Pearson FG. One-stage re- run, the overall risk–benefit balance of the neck flexion maneuver construction for pharyngolaryngectomy: Esophagectomy and pharyn- manner of reconstruction after cervical esophageal resection sur- gogastrostomy without thoracotomy. J Thorac Cardiovasc Surg. 1983; passes that of the standard gastric pull-through procedure. 85: 330 – 336. 14. Harrison DF, Thumpson AE. Pharyngolaryngoesophagectomy with pharyngogastric anastomosis for cancer of the hypopharynx: Review Conclusion of 101 operations. Head Neck Surg. 1986; 8: 418 – 428. 15. Goldberg M, Freeman J, Gullane PJ, Patterson GA, Todd TR, Mc- Shane D. Transhiatal esophagectomy with gastric transposition for Resection of cervical esophageal cancer, based on oncological pharyngolaryngeal malignant disease. J Thorac Cardiovasc Surg. principles, with reconstruction carried out by primary end-to-end 1989; 97: 327 – 333. pharyngoesophagostomy is technically feasible, with no unaccept- 16. Azurin DJ, Go LS, Kirkland ML. Palliative gastric transposition fol- ably high postoperative cervical leakage rates or local stricture for- lowing pharyngolaryngoesophagectomy. Am Surg. 1997; 63: 410 – 413. mation. 17. Ayshford CA, Walsh RM, Watkinson JC. Reconstructive techniques currently used following resection of hypopharyngeal carcinoma. J Acknowledgments Laryngol Otol. 1999; 113: 145 – 148. 18. Sullivan MW, Talamonti MS, Sithanandam K, Joob AW, Pelzer HJ, Joehl RJ. Results of gastric interposition for reconstruction of pharyn- The authors thank the hospital authorities, and operation room goesophagus. Surgery. 1999; 126: 666 – 671. and ICU staff. We express deep thanks to our patients. 19. DeMeeester SR. Adenocarcinoma of the esophagus and cardia: A review of the disease and its treatment. Ann Surg Oncol. 2005; 13(1): 12 – 30. 20. Leonard L, Gunderson LL, Matthew D, Callister MD, Dawn E, Jaro- Refrences szewski DE, et al. Localized gastric or gastroesophageal cancer- chemoradiation is a pertinent component of adjuvant treatment for 1. Weisberger E. Cancer of the cervical esophagus. Operative techniques patients at high risk of relapse. Gastrointest Cancer Res.. 2009; 3(2): in otolaryngology. Head and Neck Surgery. 2005; 16(1): 67 – 72. S26 – S32. 2. Chu PY, Chang SY. Reconstruction after resection of hypopharyngeal 21. Apisarnthanarax S, Tepper E. Crossroads in the combined-modality carcinoma: Comparison of the postoperative complications and onco- management of gastroesophageal junction carcinomas. Gastrointest logic results of different methods. Head Neck. 2005; 27(10): 901 – 908. Cancer Res. 2008; 2: 235 – 242. 3. DeVries EJ, Stein DW, Johnson JT, Wagner RL, Schusterman M, My- 22. Burmeister B, Dickie G, Smithers M. Thirty-four patients with carci- ers EN, et al. Hypopharyngeal reconstruction: A comparison of two noma of the cervical esophagus treated with chemoradiation therapy. alternatives. Laryngoscope. 1989; 99: 614 – 617. Arch Otolaryngol Head Neck Surg. 2000; 126: 205 – 208. 4. Lam KH, Wong J, Lim ST, Ong GB. Pharyngogastric anastomosis fol- 23. Grillo HC, Donahue DM, Mathisen DJ, Wain JC, Wright CD. Postintu- lowing pharyngolaryngoesophagectomy. Analysis of 157 cases. World bation tracheal stenosis: Treatment and results. J Thorac Cardiovasc J Surg. 1981; 5:509 – 516. Surg. 1995; 109: 486 – 493. 5. Fujita H, Kakegawa T, Yamama H, Sueyoshi S, Hikita S, Mine T, et 24. Pirmoazen N, Seirafi M, Javaherzadeh M, Saidi F. Flexing the neck re- al. Total esophagectomy versus proximal esophagectomy for esopha- lieves tension on cervical esophageal anastomosis. Arch Iranian Med. geal cancer at the cervicothoracic junction. World J Surg. 1999; 23: 2006; 9(4): 339 – 343.

302 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Severe Thrombocytopenia due to Brucellosis

Original Article Severe Thrombocytopenia and Hemorrhagic Diathesis due to Brucellosis

Hasan Karsen MD•1, Fazilet Duygu MD2, Kubilay Yapıcı MD3, Ali İrfan Baran MD3, Huseyin Taskıran MD4, İrfan Binici MD3

Abstract Background: We aimed to examine cases of brucellosis that presented with severe thrombocytopenia and hemorrhagic diathesis. Methods: A total of 10 brucellosis cases with severe thrombocytopenia were included in this case-series study. Patients’ files were reviewed for their clinical and laboratory findings, as well as clinical outcomes and complications. Platelet counts of < 20000/mm³ were diagnosed as severe thrombocytopenia. Results: The lowest thrombocyte count was 3000/mm³ while the highest was 19000/mm³ (mean: 12000/mm³). Patients had the following symptoms: epistaxis (7 cases), petechia with epistaxis (4 cases), bleeding gums (3 cases), ecchymosis with epistaxis (2 cases), melena and renal failure (2 cases), and hematuria (1 case). Patients were given rifampicin and doxycycline along with supportive hematological therapy. All were treated successfully with no evidence of recurrence at follow-up visits. Conclusion: Since brucellosis is endemic in developing countries, it must be considered in the differential diagnosis of cases that present with severe thrombocytopenia and hemorrhagic diathesis.

Keywords: Brucellosis, hemorrhagic diathesis, severe thrombocytopenia

Cite this article as: Karsen H, Duygu F, Yapıcı K, Baran AI, Taskıran H, Binici I. Severe Thrombocytopenia and Hemorrhagic Diathesis due to Brucellosis. Arch Iran Med. 2012; 15(5): 303 – 305.

Introduction in (CRP); liver and renal function profiles; urinalysis; IgM anti- CCHF (Crimean-Congo hemorrhagic fever); as well as coagula- rucellosis is a multisystem disease with a wide variety of tion parameters such as prothrombin time (PT), activated partial symptoms that include hematological abnormalities such as thromboplastin time (aPTT), and fibrinogen levels were measured. B anemia, thrombocytopenia, pancytopenia and leucopoenia. Complete blood cell count was repeated when the results were ab- Disseminated intravascular coagulation (DIC) and hemorrhagic normal or when indicated.. We also tested patients for enteric fever, diathesis are rarely seen.1,2 In some studies, hematological findings malaria, acute viral hepatitis, and toxoplasmosis. ranging from mild anemia to pancytopenia are reported to be more Brucellosis was diagnosed by the presence of antibodies against than 50%.3,4 Various rates of thrombocytopenia due to brucellosis brucella with a titer of ≥ 1:160 by the standard tube agglutina- have been reported; however, to the best of our knowledge, all tion test (Brucella abortus antisera, Cromatest, Linear Chemi- published studies except for case-reports regarding severe throm- cals, Barcelona, Spain) and/or by isolation of brucella from blood bocytopenia due to brucellosis were pediatric case-series, until (BACTEC, Becton Dickinson, USA) in addition to clinical symp- now. In this paper, 10 adults cases with severe thrombocytopenia toms consistent with brucellosis. Anemia, thrombocytopenia, and and hemorrhagic diathesis due to brucellosis have been presented. leucopenia were defined as hemoglobin (Hb) levels of < 12 g/dL, a platelet count of < 150000/mm³, and leukocyte count of < 4000/ mm³, respectively. Platelet counts < 20000/mm³ were considered 5 Materials and Methods as severe thrombocytopenia.

This was a case-series study. Patients’ files were reviewed for Results their clinical and laboratory findings, symptoms, prognosis, age and gender as well as complications and clinical outcomes. The There were 4 male and 6 female patients with severe thrombocy- study protocol was approved by the local research committee for topenia. Patients’ mean age was 35.24 ± 6.12 years (range: 18 to ethics. The Brucella Wright test; blood culture; complete blood 64 years). Standard agglutination test was positive in all patients, count; erythrocyte sedimentation rate (ESR); C-reactive prote- however B. melitensis was present in the blood cultures of only 3 patients. Authors’ Affiliations: 1Harran University Faculty of Medicine, Department of Pancytopenia was present in 5 cases, bicytopenia (thrombocyto- Infectious Diseases and Clinical Microbiology, Sanliurfa, Turkey, 2Tokat State Hospital, Clinical Infectious Diseases, Tokat, Turkey, 3Yuzuncu Yil University, penia and anemia or thrombocytopenia and leucopenia) was seen Faculty of Medicine, Department of Infectious Diseases and Clinical Microbio- in 4 cases, and there was only one case of isolated thrombocy- logy, Van, Turkey, 4Private Zirve Medical Center, Internal Medicine Clinic, Nizip, topenia. The lowest thrombocyte count was 3000/mm³ while the Turkey. •Corresponding author and reprints: Hasan Karsen MD, Harran University, highest was 19000/mm³ (mean: 12000/mm³). The mean Hb level Faculty of Medicine, Department of Infectious Diseases and Clinical Microbio- was 9.17 g/dL and white blood cell level was 5720/mm³. Totally, logy, Sanliurfa, Turkey. Tel: +904143183000, E-mail: [email protected]. the mean decrease in thrombocytes was 92% while it was 23.6% in Accepted for publication: 7 September 2011 Hb levels. There was no decrease in white blood cell count.

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 303 H. Karsen, F. Duygu, K. Yapıcı, et al.

Table 1. The cases of thrombocyte, hemoglobin, and leukocyte values and clinical symtoms Case Number Platelet(/mm3) Hb(g/dL) WBC(/mm3) Complications seen in cases 1 3000 12.4 9000 Epistaxis, petechia, neuropyschiatric symptoms 2 7000 8.5 2700 Melena, gum bleeding 3 9000 10.6 73000 Epistaxis, ecchymose 4 10000 9.5 4900 Epistaxis, ecchymose, gum bleeding 5 10000 5.5 3900 Melena, hematuria, renal failure, pyschiatric symptoms 6 13000 7 3700 This case had no bleeding symptoms 7 15000 7.8 7600 Neuropyschiatric symptoms 8 16000 4.7 10900 Epistaxis, petechia, renal failure, pyschiatric symptoms 9 18000 12.7 3700 Epistaxis, petechia, 10 19000 13 3500 Epistaxis Mean±SD 12000±51 9.17±2.96 6800±2150.21 ------Hb: Hemoglobin, WBC: White blood cell

As seen in Table 1, clinical symptoms were as follows: epistaxis 10000 /mm³, Hb of 5.5 mg/dL, creatinine level of 9.1 mg/dL (nor- (7 cases), petechia with epistaxis (4 cases), bleeding gums (3 cas- mal 0.8 – 1.2), total bilirubin of 4.1 mg/dL (normal 0.2 – 1.2), and es), ecchymosis with epistaxis (2 cases), melena and renal failure indirect bilirubin of 3.4 mg/dL (normal 0 – 0.75). He received (2 cases), and hematuria (one case). The following elevated labora- thrombocyte infusion and antimicrobial treatment tory abnormalities were present: ESR (6 cases), CRP (10 cases), Our eighth case had the following clinical symptoms: convulsion PT (7 cases), PTT (2 cases), and PT together with aPTT and INR and hallucinations, loss of consciousness, fever of 39.8°C, throm- (one case). The one case which had elevated PT, aPTT and INR bocyte count of 16000/mm³, Hb of 4.7 mg/dL, creatinine level of levels also had a low fibrinogen result. All patients were treated 2.52 mg/dL, total bilirubin level of 4.8 mg/dL, and indirect biliru- with rifampicin and doxycycline and platelet suspensions. Hb lev- bin level of 4 mg/dL. He received antimicrobial treatment, platelet els were < 8 gr/dL in 4 patients and each of them received whole suspensions and whole blood transfusions. blood transfusions. All cases were negative for CCHF, enteric fe- Our third patient presented with DIC, whose laboratory findings ver, malaria, acute viral hepatitis, and toxoplasmosis. were: PT 26 sec (normal 10 – 15), active partial thromboplastin time (aPTT) 59 sec (normal 26 – 41) and INR 1.8 (normal: 0.8- 1.22), fibrinogen 67 mg/dL (normal: 150 – 400), and D-dimer 4.05 Discussion ug/mL (normal: 0 – 0.4). He received antibiotics, platelet suspensions and fresh-frozen plasma. Mild hematological abnormalities such as anemia and leucopenia Bleeding disorders such as epistaxis and hematuria have rarely are common in the course of human brucellosis. Severe thrombo- been reported.19 We have not seen any case report of brucellosis- cytopenia, acute hemolysis, DIC, hemorrhagic diathesis, immune induced melena, gum bleeding, and ecchymosis in the literature. thrombocytopenia, capillary leak syndrome (CLS), thrombotic As mentioned in Table 1, in addition to severe thrombocytopenia, thrombocytopenic purpura (TTP), and Evan’s syndrome are rarely our cases had complaints of epistaxis, ecchymosis, melena, hema- seen.6–10 In our study, the mainly affected blood elements were turia, gum bleeding, neuropsychiatric symptoms, and renal failure. thrombocytes. The pathogenesis of thrombocytopenia in brucel- The symptoms of our brucellosis cases were similar to those losis remains obscure but several possible mechanisms, including of hematologic malignancies and hemorrhagic viral diseases.20,21 hypersplenism, hemophagocytosis, granulomas, increased clear- Therefore, hematologists, ENT specialists, psychiatrists, derma- ance of damaged thrombocytes with endotoxins, thrombocyte ad- tologists, dentists, urologists, and gastroenterologists should bear herence to vascular surfaces, and bone marrow suppression due to in mind the possibility of brucellosis in patients who present with septicemia may account for it.11 In various studies, thrombocyto- bleeding. penia prevalence has been reported to be 3.4%-26%.3,4,12–15 Severe We agree with some authors who have suggested that throm- thrombocytopenia and bleeding disorder due to brucellosis have bocytopenia is a result of immunological reactions.16 In some of generally been studied in children. The papers regarding adults are our cases thrombocytopenia had developed as a result of an im- only case reports.16–18 Although severe thrombocytopenia, bleed- munological mechanism, which was the main reason for severe ing disorder, DIC, and thrombotic thrombocytopenic purpura thrombocytopenia. Hemorrhage results from either a decrease in (TTP) are rarely seen in brucellosis,4,6,15 in our study all cases had platelet counts or platelet dysfunction. Thrombocytopenia is rare; severe thrombocytopenia and bleeding disorders, 2 cases had TTP, only in very rare cases of brucellosis is it severe enough to cause and one case had DIC. bleeding.22 The high rates of bleeding in our cases (100%) warrant According to a study by Kiki et al., a 19-year-old woman pre- attention. After 4 days of treatment with antibiotics (rifampicin and sented with complaints of headache, fever, sweating, malaise, and doxycycline) and platelet suspensions, the hemorrhage stopped in jaundice. Her clinical signs and laboratory findings were consistent all our cases with bleeding. Fortunately, the severe thrombocyto- with TTP. She received plasma exchange and antibiotic therapy.17 penia which occurs in brucellosis is responsive to antibiotics and In a case presented by Erdem et al., a 51-year-old man had com- hematological supportive therapy. plaints of moderate confusion, depressed mood and dysarthria, fe- Within 2 weeks, thrombocytopenia improved in the majority of ver (38.5°C), jaundice, and petechial-purpuric skin lesions. Labo- cases. At the end of the third week, platelet counts were > 150000/ ratory tests showed white blood cell count of 9600/mm³, Hb 7.1 g/ mm³ in all patients. At the end of the fourth week of treatment dL, and platelets 18000/mm³. He received a plasma infusion and with anti-brucellosis drugs, hematological abnormalities as well as antimicrobial treatment.19 renal insufficiency, neuropsychiatric symptoms, and other symp- The clinical picture of our fifth case was as follows: confusion toms had completely disappeared. Akdeniz et al. have reported that and speech disturbance, fever of 38.8°C, thrombocyte count of platelet counts returned to normal within 2 – 3 weeks of initiating

304 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Severe Thrombocytopenia due to Brucellosis antibiotics.2 Dilek et al. have reported restoration of thrombocyto- 7. Sari I, Kocyigit I, Altuntas F, Kaynar L, Eser B. An unusual case of penia to normal ranges within one week after initiation of antimi- acute brucellosis presenting with Coombs-positive autoimmune hemo- 6 lytic anemia. Intern Med. 2008; 47: 1043 – 1045. crobial therapy. We have completed the antimicrobial treatment to 8. Turunc T, Demiroglu YZ, Kizilkilic E, Aliskan H, Boga C, Arslan H. 6 weeks in all patients. A case of disseminated intravascular coagulation caused by Brucella All our patients were treated successfully then discharged. Pa- melitensis. J Thromb Thrombolysis. 2008; 1: 71 – 73. tients were followed monthly for 12 months with clinical and 9. Pappas G, Kitsanou M, Christou L, Tsianos E. Immune thrombocytopenia attributed to brucellosis and other mechanisms of Brucella- laboratory findings. No recurrence of brucellosis was noted at induced thrombocytopenia. Am J Hematol. 2004; 75: 139 – 141. follow-ups. 10. Erkurt MA, Sari I, Gül HC, Coskun O, Eyigün CP, Beyan C. The first Some authors have reported successful results with the adminis- documented case of brucellosis manifested with pancytopenia and cap- tration of plasma, plasma exchange, intravenous gamma globulin, illary leak syndrome. Intern Med. 2008; 47: 863 – 865. 21,22 11. Al-Eissa Y, Al-Nasser M. Hematological manifestation of childhood and steroids in conjunction with brucellosis treatment. How- brucellosis. Infection. 1993; 21: 29 – 32. ever, in our cases, those treatment modalities were not necessary. 12. Demiroglu YZ, Turunc T, Calıs Kan H, Colakoglu S¸ Arslan H. Bru- In conclusion, since brucellosis is endemic in developing coun- cellosis: Retrospective evaluation of the clinical, laboratory and epidemiological features in 151 cases. Mikrobiyol Bul. 2007; 41: 517 – 527. tries, it must be considered in the differential diagnosis of viral 13. Hasanjani Roushan MR, Mohrez M, Smailnejad Gangi SM, Solemani hemorrhagic diseases and cases presenting with severe thrombo- Amiri MJ, Hajiahmadi M. Epidemiological features and clinical mani- cytopenia and bleeding disorders. Even with the development of festations in 469 adult patients with brucellosis in Babol, Northern Iran. severe thrombocytopenia and bleeding in patients with brucellosis, Epidemiol Infect. 2004; 132: 1109 – 1114. 14. Lulu AR, Araj GF, Khateeb MI, Mustafa MY, Yusuf AR, Fenech FF. successful results can be obtained with antibiotics and hematologic Human brucellosis in Kuwait: A prospective study of 400 cases. Q J supportive therapy. Med. 1988; 66: 39 – 54. 15. Colmenero JD, Reguera JM, Martos F, Sanchez De Mora D, Delgado M, Causse M, et al. Complications associated with Brucella melitensis References infection: A study of 530 cases. Medicine. (Baltimore) 1996; 75: 195 – 211. 1. Franco MP, Mulder M, Gilman RH, Smits HL. Human brucellosis. 16. Yilmaz M, Tiryaki O, Namiduru M, Okan V, Oguz A, Buyukhatipoglu Lancet Infect Dis. 2007; 7: 775 – 786. H, et al. Brucellosis-induced immune thrombocytopenia mimicking 2. Akdeniz H, Irmak H, Seçkinli T, Buzgan T, Demiröz AP. Hematologi- ITP: A report of seven cases. Int J Lab Hematol. 2007; 29: 442 – 445. cal manifestations in brucellosis cases in Turkey. Acta Med Okayama. 17. Kiki I, Gundogdu M, Albayrak B, Bilgiç Y. Thrombotic thrombocyto- 1998; 52: 63 – 65. penic purpura associated with Brucella infection. Am J Med Sc. 2008; 3. Aygen B, Doganay M, Sumerkan B, Yildiz O, Kayabas U. Clinical 335: 230 – 232. manifestations, complications and treatment of brucellosis: A retro- 18. Erdem F, Kiki I, Gundoğdu M, Kaya H. Thrombotic thrombocytope- spective evaluation of 480 patients. Med Mal Infect. 2002; 32: 485 – nic purpura in a patient with Brucella infection is highly responsive to 493. combined plasma infusion and antimicrobial therapy. Med Princ Pract. 4. Buzgan T, Karahocagil MK, Irmak H, Baran AI, Karsen H, Evirgen O. 2007; 16: 324 – 326. Clinical manifestations and complications in 1028 cases of brucellosis: 19. Sevinc A, Buyukberber N, Camci C, Buyukberber S, Karsligil T. A retrospective evaluation and review of the literature. Int J Infect Dis. Thrombocytopenia in brucellosis: Case report and literature review. J 2010; 6: 469 – 478. Natl Med Assoc. 2005; 97: 290 – 293. 5. Yodonawa S, Goto Y, Ogawa I, Yoshida S, Itoh H, Nozaki R, et al. 20. Vorou R, Pierroutsakos IN, Maltezou HC. Crimean-Congo hemorrha- Laparoscopic splenectomy for idiopathic thrombocytopenic purpura in gic fever. Curr Opin Infect Dis. 2007; 20: 495 – 500. a woman with situs inversus: Report of a case. Surg Today. 2010; 12: 21. Giordano S, Failla MC, Di Gangi M, Miceli S, Abbagnato L, Dones P. 1176 – 1178. Thrombocytopenia associated with brucellosis: A case report. [Article 6. Dilek I, Durmuş A, Karahocagil MK, Akdeniz H, Karsen, H, Baran AI in Italian]. Infez Med. 2008; 16: 158 – 161. Evirgen Ö. Hematological complications in 787 cases of acute brucel- 22. Tsirka A, Markesinis I, Getsi V, Chaloulou S. Severe thrombocytopenic losis in Eastern Turkey. Turk J Med Sci. 2008; 38: 421 – 424. purpura due to brucellosis. Scand J Infect Dis. 2002; 34: 535 – 536.

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 305 S. Nikseresht, S. Etebary, M. Karimian, et al.

Original Article Acute Administration of Zn, Mg, and Thiamine Improves Postpar- tum Depression Conditions in Mice

Sara Nikseresht MSc1, Sahabeh Etebary MSc2, Morteza Karimian PhD1, Fatemeh Nabavizadeh PhD1, Mohammad Reza Zarrindast PhD3, Hamid Reza Sadeghipour PhD•1

Abstract Background: Postpartum depression (PPD) affects approximately half of new mothers. Chronic exposure to progesterone during pregnancy and its withdrawal following delivery increases depression and anxiety. In addition, there are complex interactions between hormones, neurotransmitters, and trace elements. Zinc (Zn) and magnesium (Mg) influence the nervous system by impacting synaptic neurotransmis-

sion in the brain. Thiamine (Vit B1) deficiency results in a high percentage of depressive behaviors. Elevated levels of reactive oxygen species in pregnancy are implicated in the pathogenesis of major depression.

Methods: We examined the effects of different combinations of Zn, Mg, and Vit B1 in an animal model of PPD. ZnCl, MgCl, and thiamine- HCl were administered to PPD-induced mice. Depression, anxiety-related behavior, and total antioxidant capacity (TAC) were assessed. Depression and anxiety-like behavior were evaluated by the forced swimming test (FST) and elevated plus-maze, respectively.

Results: The acute combined administration of Zn, Mg, and Vit B1 significantly decreased immobility time in FST, increased the percentage of both time spent in- and entries to open arms in the elevated plus-maze, and augmented TAC.

Conclusion: Our data suggest that acute administration of combined treatment with Zn, Mg, and Vit B1 on postpartum day 3 improves depressive symptoms and anxiety-like behaviors. Our evaluation of TAC is in accordance with behavioral results.

Keywords: Anxiety, depression, magnesium, thiamine, Zinc

Cite this article as: Nikseresht S, Etebary S, Karimian M, Nabavizadeh F, Zarrindast MR, Sadeghipour HR. Acute Administration of Zn, Mg, and Thiamine Improves Postpartum Depression Conditions in Mice. Arch Iran Med. 2012; 15(5): 306 – 311.

Introduction neurological disorders that include premenstrual dysphoric disorder, premenstrual syndrome, menstrual migraine, PPD, and anxi- depressed mood is common during the postpartum period, ety. Based on recent studies, trace elements such as zinc (Zn) and affecting almost 50% of new mothers during the first days magnesium (Mg) also exert their antidepressant effects by acting A following delivery. This transient mood disturbance in vul- on neurotransmitter pathways.11–14 nerable women may lead to more serious and persistent depression Zn is a trace element, particularly abundant in the central nervous during subsequent weeks, finally fulfilling the diagnostic criteria system (CNS). Zn is important as a signaling factor in synaptic for major depression, known as postpartum depression (PPD).1,2 neurotransmission in the brain.15,16 Several studies have shown its Evidence suggests that maternal depression is harmful for new potential antidepressant activity in humans and suggest that Zn mothers, their infants, and family relationships. PPD can also im- may be involved in the mechanism of action of antidepressant pair the infant’s cognitive and social development. This situation therapy. In confirmation, anxiety-like behavior is increased in Zn- can even lead to suicidal tendencies or infanticide.3–5 deprived rodents.17–19 In another study, the results have demonstrat- Rapid decline in hormone levels, in particular sex hormones, ed a relationship between the severity of depressive symptoms and happens following delivery. Based on previous studies, withdrawal decreased serum Zn concentrations in humans with PPD.20 of progesterone has been proposed as a trigger for PPD symptoms Mg is a trace element that acts primarily as an intracellular ion and recent attention has been given to the possible mood effects of influencing the nervous system by its effects on the release and neuroactive metabolites and precursors of progesterone. Because metabolism of neurotransmitters.21,22 Mg has been proposed to depression is often accompanied by enhanced anxiety, chronic ex- participate in biochemical dysregulation that contributes to psy- posure to progesterone, followed by its withdrawal increases anxi- chiatric disorders. The results of several studies indicate that Mg ety.6–10 It is possible that complex interactions between hormones induces antidepressant and anxiolytic-like effects in mice without and neurotransmitters are involved; because of this, alterations in development of tolerance to these actions, which is suggestive of ovarian steroids are associated with debilitating psychiatric and its potential antidepressant and anxiolytic activity.9,23 The fetus and Authors’ Affiliations: 1Department of Physiology, School of Medicine, Tehran placenta absorb huge amounts of nutrients, particularly Mg, from University of Medical Sciences, Tehran, Iran,2Department of Midwifery, Shahid the mother and loss of Mg is hypothesized to be a contributing fac- Beheshti University of Medical Sciences, Tehran, Iran,3Department of Neurosci- tor in the development of PPD.24 ence, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran. Thiamine (Vit B1) de •Corresponding author and reprints: Hamid Reza Sadeghipour PhD, Depart- and hyperemesis gravidarium. This condition shows a high per- ment of Physiology, Tehran University of Medical Sciences, Poorsina Ave., Teh- centage of aggressiveness, confusion, memory impairments, and ran, Iran. Tel: +98 21 64053281, Fax: +98 2166570435, E-mail: [email protected]. depressive behaviors in animal models of Vit B1 deficiency where Accepted for publication: 7 September 2011 antidepressants such as imipramine can suppress this depressive

306 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Zn, Mg and Thiamine in PPD

Figure 1. Percentage of time spent in open arms (A) and number of entries (%) into open arms (B) of the elevated plus-maze (EPM) measured during 5 minutes. 1: Saline, 2: Sesame oil, 3: PWD, 4:

Zn+Mg, 5: Zn+Vit B1, 6: Mg+Vit B1, and 7: Zn+Mg+Vit B1. Treatment doses are as follows: saline (2

ml/kg); sesame oil (2 ml/kg); progesterone (5 mg/kg); Zn: (30 mg/kg); Mg (30 mg/kg); Vit B1 (50 mg/ kg). Columns represent the mean±SEM (n=10 per group). P<0.001 compared to the PWD group: It is common in original articles about figures of EPM and FST.

behavior.25,26 free access to food and water. Animals received food pellets that Oxidative stress is the imbalance between oxidative and antioxi- contained 18.7% protein, 3% fat, 0.65% calcium, 0.68% phospho- dative systems in favor of the former and has been implicated in rus, and 2600 Kcal/Kg with supplementary vitamins and minerals the pathophysiology of several neuropsychiatric diseases, includ- adequate for daily requirements. All behavioral experiments were ing major depressive disorder. A measurement of total antioxidant conducted during 12:00 and 18:00. Mice were housed in a tem- capacity (TAC) can provide information about overall antioxidant perature controlled room (21 ± 1°C). Throughout each experiment, status which may include those antioxidants not yet recognized or mice were maintained on a 12 hour light, 12 hour dark cycle. All not easily measured.27,28 procedures were carried out in accordance with the Guidelines for Despite the high prevalence of PPD, up to half of the cases of Animal Care and Use at Tehran University of Medical Sciences. postpartum disorders remain undiagnosed or untreated.29 Although All mice were allowed to adapt to their caging environment for at women with PPD may seek psychotherapy as an initial treatment, least one week prior to the induction of PPD. it is not always effective. Those with severe symptoms may need antidepressant therapy, but the high cost and side effects of antide- Experimental design pressant drugs remain important treatment obstacles for many.30,31 PPD was conducted according to the protocol by Beckley and Many women choose nonpharmacological interventions, due to Finn.6 For this purpose, 50 animals were divided equally into 5 the potential transmission of drugs into breast milk and fear of ad- groups (n = 10) of progesterone withdrawal (PWD) and treatment 32 diction or drug dependence. As mentioned above, a single admin- (Zn + Mg, Zn + Vit B1, Mg + Vit B1 and Zn + Mg + Vit B1). All istration of Zn and Mg improves depression and anxiety-related animals received daily injections of progesterone for 5 days after behavior. In addition, based on the literature and our pilot study, which progesterone was withdrawn for 3 days.

Vit B1 has been shown to have antidepressant and anxiolytic ef- In a preliminary study to confirm the effect of PWD, 2 groups, fects. Therefore, the aim of the present study was to evaluate the which received saline and sesame oil instead of progesterone therapeutic effects of different combinations of Zn, Mg, and Vit served as the control groups. Various combinations of ZnCl2,

B1 on an animal model of PPD. We assessed depressant-like and MgCl2 and thiamine-HCl in the corresponding groups were ad- anxiety-like behaviors, as well as TAC. ministered on the 8th day at 30 minutes before the open field, elevated plus-maze (EPM) and forced swimming tests (FST) in Materials and Methods the treatment groups.12,33,34 After the last test, mice were decapi- tated under deep anesthesia and approximately 1 ml of blood was Experimental animals quickly collected. After centrifugation for 3 minutes at 3000 rpm, Female albino NMRI inbred mice, weighing 25 – 30 g and 6 – 8 serum was collected in a test tube and stored at -70°C for mea- weeks old were used. Animals were housed in groups of 4 – 5 with surement of TAC.

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 307 S. Nikseresht, S. Etebary, M. Karimian, et al.

Figure 2. Immobility time in the forced swim test (FST) of 7 groups of mice. Immobility time was measured over 4 minutes. 1: Saline, 2: Sesame oil, 3: PWD, 4: Zn+Mg, 5: Zn+Vit B1, 6: Mg+Vit B1, and 7: Zn+Mg+Vit B1. Treatment doses are as follows: saline (2 ml/kg), sesame oil (2 ml/kg), progesterone (5 mg/kg), Zn (30 mg/kg), Mg (30 mg/kg), and Vit B1 (50 mg/kg). Columns represent the mean±SEM (n=10 per group). P<0.001 compared to PWD group.

Behavior was analyzed by 2 experienced raters blinded to the drug Drugs and treatments treatments. Each mouse was judged to be immobile when it ceased

Progesterone, ZnCl2, MgCl2, and thiamine-HCl (Sigma, St. Lou- struggling and remained floating motionless in the water, making is, MO, USA) were used in the study. Progesterone was dissolved only those movements necessary to keep its head above the water. in sesame oil (2.5 mg/ml) and injected intraperitoneally (5 mg/kg). The duration of immobility was recorded during the last 4 minutes 38,39 ZnCl (30 mg/kg), MgCl2 (30 mg/kg), and thiamine-HCl (50 mg/ of the test. kg) were dissolved in saline. All solutions were prepared immediately before the experiments and all injections were administered Evaluation of total antioxidant capacity (TAC) intraperitoneally with the exception of thiamine-HCl which was The assay is based on the incubation of [2, 20-azino-di-(3-ethyl- administered subcutaneously. Drugs were administered in a vol- benzthiazoline-6- sulphonic acid) (ABTS)] with peroxidase (met- ume of 2 ml/kg. myoglobin) and H2O2 to produce the radical cation ABTS•+ which has a relatively stable blue-green color, the absorbance of which Open field locomotor activity can be measured at 734 nm. When the colored ABTS•+ is com- First, we assessed the ambulatory behavior of mice in an open bined with an antioxidant substance, it is reduced to its original field test to ensure that alterations in the duration of immobility colorless ABTS form. Antioxidants in the added sample cause sup- did not result from the changes that occurred in motor activity. The pression of this color production to the degree that is proportional apparatus consisted of a wooden box that measured 40 × 60 × 50 to their concentration. Bovine serum albumin, the Trolox equiva- cm. The floor of the arena was divided into 12 equal squares. The lent antioxidant activity, was used as a standard.40,41 animals were gently placed in the center of the field and the num- Statistical analysis ber of squares crossed with all paws (crossing) was counted in a Data were expressed as mean ± SEM and comparisons between 6-min session.35 treatment and PWD groups were performed by one-way ANOVA. When appropriate, post-hoc analyses were performed using the Elevated plus-maze test (EPM) Tukey’s test following ANOVA. A value of P < 0.05 was consid- The plus-maze apparatus was made of Plexiglas and consisted ered significant. of 2 open (30 × 5 cm) and 2 enclosed (30 × 5 × 15 cm) arms. The arms extended from a central platform of 5 × 5 cm. The apparatus Results was mounted on a Plexiglas base which was raised 38.5 cm above the floor and illuminated by a red light. For the test, we placed a Spontaneous locomotor activity mouse in the center of the apparatus (facing an enclosed arm) and In all of the treatment groups, the number of squares entered was allowed it to explore freely. The number of entries into the open not more than the PWD group (data not shown). arms and the time spent in these arms were scored for a 5-minute test period. An entry was defined as the placement of all 4 paws Elevated plus-maze (EPM) within the boundaries of the arm. The following measures were The inter-rater reliability coefficient for the 2 observers that calculated from the test: percentage of entries into the open arms, scored the EPM behavior was 0.87 for the open arm time (P < 0.05). and time spent in the open arms, expressed as a percentage of the Figure 1A shows the percentage of time spent in the open arms time spent in both the open and enclosed arms. Anxiolytic activity among the experimental groups. ANOVA followed by Tukey‘s test was determined by increases in time spent in the open arms or in showed significant differences in the experimental groups with re- the number of open arm entries.36,37 gards to the percentage of time spent in the open arms. The saline and sesame oil groups spent significantly more time in the open Forced swimming test (FST) arms than the PWD group (P < 0.05). All treatment groups had Mice were individually placed in an open cylindrical container statistically significant increases in the time spent in the open arms (diameter 10 cm, height 25 cm), filled to 19 cm with water at a tem- compared to the PWD group (P < 0.05). The highest percentage of perature of 23 ± 1°C. Mice were allowed to swim for 6 minutes. the time spent in the open arms was noted for the Zn + Mg + Vit

308 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Zn, Mg and Thiamine in PPD

Table 1. Plasma total antioxidant capacity (TAC) levels Groups TAC (nmol/mg protein) Salineª 208 ± 0.032 Sesame oilª 207 ± 0.021 Progesterone b 169 ± 0.054 Zn+Mg c 195 ± 0.052 d Zn+Vit B1 184 ± 0.047 d Mg+Vit B1 181 ± 0.043 a Zn+Mg+Vit B1 206 ± 0.071 Data are expressed as mean±SEM (n=10 per group). a-d: Different letters have statistically significant differences (P<0.05). TAC: Total antioxidant capacity.

B1 group, whereas the least was seen in the PWD group. (F6, 69 Mg + Vit B1 group. Our results showed the most increase in time = 22.72, P < 0.05). Figure 1B shows the percentage of entries into spent in the open arms and the highest number of open arm entries the open arms by mice in each experimental group. was in the same group, which confirmed the synergistic effects of The saline and sesame oil groups had significantly more open these components. arm entries when compared with the PWD group (P < 0.05). In Previous studies have shown that Zn decreases immobility time addition, there were significant differences in the treatment groups in the FST.17,44 Interactions of inhibitory and excitatory amino acid compared with the PWD group (P < 0.05). The highest percentage neurotransmitters with Zn are well known.45 Zn supplementation of open arm entries belonged to the Zn+Mg+Vit B1 group and the can potentiate the effects of antidepressant drugs and it has been least to the PWD group (F6,69 = 19.33, P < 0.05). demonstrated that depression is possibly accompanied by lower serum Zn concentrations.18,46 The antidepressant-like effects of Zn Forced swimming test (FST) have been shown in an animal model of depression, as assessed The inter-rater reliability coefficient for the 2 observers who by the tail suspension test.47 Zn deprivation is linked to an increase scored the behaviors in the FST was 0.86 (P < 0.05). The results in anxiety-like behavior. 19 Zn may play a role in synaptic neuro- depicted in Figure 2 show that the saline and sesame oil groups transmission in the mammalian brain and serves as an endogenous spent significantly less time immobile than the PWD group P ( neuromodulator of several important receptors, channels, and en-

< 0.05). All treatment groups spent significantly less time in the zymes. For example, Zn inhibits NMDA, GABAA receptors and immobile state when compared with the PWD group (P < 0.05). nitric oxide synthase (NOS) which are believed to be important

Combined administration of Zn + Mg + Vit B1 caused the greatest molecular targets for antidepressants. Zn also augments α-amino- reduction in immobility time (F 6, 69 = 193. 8, P < 0.05). 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and ATP- 16,44,46,48 sensitive potassium (KATP) channel activity. Total antioxidant capacity (TAC) Based on other studies, Mg has antidepressant and anxiolytic As shown in Table 1, significant differences existed in TAC levels activity; activation of the NMDA receptor ion channel is blocked among the saline, sesame oil, and all treatment groups compared to by Mg in a voltage-dependent manner.9,23 Mg is a natural calcium the PWD group. (F6, 69 = 33.73, P < 0.05). channel blocker necessary for relaxation and appropriate nerve function. Calcium stimulates nerves and Mg relaxes them. These Discussion systems have been reported to be involved in the pathophysiology of depression. Mg also suppresses the Ca++-protein kinase C re- The aim of the present study was to determine whether acute lated neurotransmission and stimulates Na-K-ATPase.45,49 The NMDA class of glutamate receptors and NO signaling path- combined administration of Zn, Mg and Vit B1 improves depressive symptoms, as evaluated by immobility time in the FST and way are involved in the pathophysiology of major depression.50 anxiety-like behaviors of PPD in mice. We observed a significant The presence of NOS in regions such as the hypothalamus, amyg- decrease in immobility in the FST and a significant increase in dale, and hippocampus is associated with anxiety. Acute inhibi- percentages in the open-arm entry and open-arm time spent in the tion of NO synthesis by the use of a variety of antagonists has led EPM in all treatment groups. Despite the decrease in immobility to anxiolytic or anxiogenic effects depending on the animal and time in FST, the open field test showed no augmentation in loco- the method of anxiety evaluation.51 In this manner, dysfunctions in motor activity, which suggested that the results of the FST were GABAA receptor regulation during pregnancy and the postpartum not affected by our treatments. The TAC after administration of Zn, period may causedepression-like and anxiety-like behaviors during postpartum. However the differential actions of neurosteroids Mg, and Vit B1 significantly increased. Reports of several studies have supported the hypothesis that a such as progesterone are dependent on anatomical connections and 8,52 significant increase in depression-like behavior is detectable at GABAA receptor distribution. least 3 days after delivery.6,42 In the present study, we showed that In animal models, thiamine-deficient (TD) mice show increased at 3 days of PWD, along with acute administration of various com- duration of immobility in the FST swimming test. NMDA receptor antagonists provide significant neuroprotection in some of the binations of Zn, Mg, and Vit B1 there was antidepressant and anx- 26 iolytic-like behavior in mice as seen by the FST and EPM in the brain areas susceptible to Vit B1 deficiency. The results of this treatment groups. Our experiment showed anxiogenic-like behav- study have indicated that the time spent in the open arms and the ior at 3 days of PWD, while Bitran and Smite have demonstrated numbers of open arm entries in the Zn + Mg + Vit B1 group were anxiogenic-like behavior one day following PWD.43 According to more than those of the Zn + Mg group. This increase might be our results, the greatest reduction in immobility was in the Zn + mediated by Vit B1.

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 309 S. Nikseresht, S. Etebary, M. Karimian, et al.

Oxidative stress occurs as a consequence of an imbalance be- with serum leptin and interleukin-6 levels at delivery: A nested case– tween the formation of oxygen-free radicals and inactivation of control study within the UPPSAT cohort. Psychneuroendocrinology. 53 2009; 34: 1329 – 1337. these species by an antioxidant defense system. Oxidative stress 2. Steiner M, Dunn E, Born L. Hormones and mood: From menarche to has been found in pregnant mothers. It is well known that preg- menopause and beyond. J Afective Disord. 2003; 74: 67 – 83. nancy is itself a state of oxidative stress arising from the increased 3. Green AD, Barr AM, Galea LAM. Role of estradiol withdrawal in metabolic activity in placental mitochondria and the reduced scav- ‘anhedonic’sucrose consumption: A model of postpartum depression. 54 Physiol Behav. 2009; 97: 259 – 265. enging power of antioxidants. Reactive oxygen species are im- 4. Klainin P, Arthur DG. Postpartum depression in Asian cultures: A lit- plicated in the pathogenesis of various neuropsychiatric disorders, erature review. Int J Nurs Stud. 2009; 46: 1355 – 1373. including major depression.55 Major depression is associated with 5. Spinelli MG. Maternal infanticide associated with mental illness: Pre- increased levels of serum superoxide dismutase (SOD), serum, vention and the promise of saved lives. Am J Psychiatry. 2004; 161: 1548 – 1557. and erythrocyte malondialdehyde (MDA), and decreased levels of 6. Beckley EH, Finn DA. Inhibition of progesterone metabolism mimics plasma ascorbic acid.56,57 Changes in antioxidative parameters can the effect of progesterone withdrawal on forced swim test immobility. serve as a characteristic element of depression and help to assess Pharmacol, Biochem Behav. 2007; 87: 412 – 419. 58 7. Gulinello M, Gong QH, Smith SS. Progesterone withdrawal increases the effects of pharmacological treatment. the anxiolytic actions of gaboxadol: Role of [alpha] 4 [beta][delta] Antioxidant capacity can be defined as the ability of a compound GABAA receptors. Neuroreport. 2003; 14: 43. to reduce pro-oxidant activity. It appears that TAC is tightly regu- 8. Maguire J, Mody I. GABAAR plasticity during pregnancy: Relevance lated in serum or plasma in neurological disorders, however, some to postpartum depression. Neuron. 2008; 59: 207 – 213. 9. Singewald N, Sinner C, Hetzenauer A, Sartori SB, Murck H. Magne- studies have failed to demonstrate this. Sofic and colleagues did not sium-deficient diet alters depression-and anxiety-related behavior in find significant differences in total serum antioxidant capacity in mice—influence of desipramine and hypericum perforatum extract. patients with Parkinson’s and Alzheimer’s diseases, amyotrophic Neuropharmacology. 2004; 47: 1189 – 1197. lateral sclerosis (ALS), depression and schizophrenia when com- 10. Zonana J, Gorman JM. The neurobiology of postpartum depression. Int 59 J Neuropsychiatric Med. 2005; 10: 792 – 799. pared to healthy control subjects. In agreement with our results, 11. Bäckström T, Andersson A, Andree L, Birzniece V, Bixo M, Björn I, Cumurcu and colleagues have reported that the serum total oxidant et al. Pathogenesis in menstrual cycle-linked CNS disorders. Ann N Y status (TOS) and oxidative stress index (OSI: ratio of TOS to TAC) Acad Sci. 2003; 1007: 42 – 53. were significantly higher along with a significantly lower TAC in 12. Cardoso CC, Lobato KR, Binfaré RW, Ferreira PK, Rosa AO, Santos ARS, et al. Evidence for the involvement of the monoaminergic system the pre-treatment stage in major depressive disorder (MDD) pain the antidepressant-like effect of magnesium. Prog Neuro-Psycho- tients compared to the healthy control group. Serum TOS and OSI pharmacol Biol Psychiatry. 2009; 33: 235 – 242. significantly decreased, whereas TAC significantly increased in the 13. Groer MW, Morgan K. Immune, health and endocrine characteristics post-treatment stage compared to the pre-treatment stage in MDD of depressed postpartum mothers. Psychoneuroendocrinology. 2007; 27 32: 133 – 139. patients. 14. Szewczyk B, Poleszak E, Wla P, Wr bel A, Blicharska E, Cichy A, et Oxidative stress conditions can also induce excessive NO pro- al. The involvement of serotonergic system in the antidepressant ef- duction by activating inducible NOS activity. NO reacts rapidly fect of zinc in the forced swim test. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009; 33: 323 – 329. with reactive oxygen species (ROS) leading to protein nitration 15. Nowak G, Szewczyk B, Pilc A. Zinc and depression. An update. Phar- 60 and vascular cell injury. macol Rep. 2005; 57: 713 – 718. PPD and anxiety are important concerns for the mother, infant, 16. Takeda A. Movement of zinc and its functional significance in the and family. Based on our findings, acute administration of com- brain. Brain Res Rev. 2000; 34: 137 – 148. 17. Kroczka B, Branski P, Palucha A, Pilc A, Nowak G. Antidepressant- bined Zn, Mg, and Vit B1 3 days after delivery improved depres- like properties of zinc in rodent forced swim test. Brain Res Bull. 2001; sive symptoms and anxiety-like behavior. Our findings in the eval- 55: 297 – 300. uation of TAC have confirmed this hypothesis. However we have 18. Nowak G, Szewczyk B, Wieronska JM, Branski P, Palucha A, Pilc A, investigated only TAC while more tests, such as SOD and MDA et al. Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats. Brain could have been performed to better analyze the changes in the Res Bull. 2003; 61: 159 – 164. antioxidant system. We suggest that oral administration of these 19. Takeda A, Tamano H, Kan F, Itoh H, Oku N. Anxiety-like behavior elements along with other trace elements and vitamins should be of young rats after 2-week zinc deprivation. Behav Brain Res. 2007; investigated in future studies. The dosages in this study are for 177: 1 – 6. ,Wَjcik J, Dudek D, Schlegel-Zawadzka M, Grabowska M, Marcinek A .20 mice and their appropriateness for humans should be examined. Florek E, et al. Antepartum/postpartum depressive symptoms and se- Possible pharmacokinetic interactions between Zn, Mg, and Vit B1 rum zinc and magnesium levels. Pharmacol Rep. 2006; 58: 571 – 576. need to be further investigated for safety considerations. 21. Imada Y, Yoshioka S, Ueda T, Katayama S, Kuno Y, Kawahara R. Re- lationships between serum magnesium levels and clinical background factors in patients with mood disorders. Psychiatry Clin Neurosci. Acknowledgments 2002; 56: 509 – 514. 22. Loyke HF. Effects of elements in human blood pressure control. Biol The authors wish to express their appreciation to Drs. Shadan, Trace Elem Res. 2002; 85: 193 – 209. 23. Poleszak E, Szewczyk B, K dzierska E, Wla P, Pilc A, Nowak G. An- Beckley, Dehpour, and Zandieh, in addition to Ms. Zaree and Ms. tidepressant-and anxiolytic-like activity of magnesium in mice. Phar- Fatehi for their kind help and Dr. Nategh for his cooperation. This macol, Biochem Behav. 2004; 78: 7 – 12. study was supported by a grant from Tehran University of Medical 24. Eby GA, Eby KL. Rapid recovery from major depression using mag- Sciences, Tehran, Iran. nesium treatment. Med Hypotheses. 2006; 67: 362 – 370. 25. Nakagawasai O, Murata A, Arai Y, Ohba A, Wakui K, Mitazaki S, et al. Enhanced head-twitch response to 5-HT-related agonists in thiamine- References deficient mice.J Neural Transm. 2007; 114: 1003 – 1010. 26. Nakagawasai O, Yamadera F, Iwasaki K, Asao T, Tan-No K, Niijima F, et al. Preventive effect of kami-untan-to on performance in the forced 1. Skalkidou A, Sylvén SM, Papadopoulos FC, Olovsson M, Larsson A, swimming test in thiamine-deficient mice: Relationship to functions of .Sundstrِm-Poromaa I. Risk of postpartum depression in association catecholaminergic neurons. Behav Brain Res. 2007; 177: 315 – 321

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Original Article Microbial Susceptibility, Virulence Factors, and Plasmid Profiles of Uropathogenic Escherichia coli Strains Isolated from Children in Jahrom, Iran

Shohreh Farshad PhD•1, Reza Ranjbar PhD2, Aziz Japoni PhD1, Marziyeh Hosseini MSc1, Mojtaba Anvarinejad MSc1, Reza Moham- madzadegan PhD3

Abstract Background: Urinary tract infections (UTIs), including cystitis and pyelonephritis, are the most common infectious diseases in childhood. Escherichia coli (E. coli) accounts for as much as 90% of the community-acquired and 50% of nosocomial UTIs. Therefore, identification of E. coli strains is important for both clinical and epidemiological implications. Understanding antibiotic resistance patterns and molecular characterization of plasmids and other genetic elements is also epidemiologically useful. Methods: To characterize uropathogenic strains of E. coli, we studied 96 E. coli strains recovered from urine samples of children aged 1 month to 14 years with community-acquired UTIs in Jahrom, Iran. We assessed virulence factors (VFs), drug sensitivities, and plasmid profiles. Results: Drug sensitivities of the isolates were: 19.8% (ampicillin), 24% (trimethoprim-sulfamethoxazole), 29.2% ( tetracycline), 75.5% (nalidixic acid), 80.4% (cefixime), 84.6% (gentamicin), 91.4% (ciprofloxacin), 96.8% (nitrofurantoin), 96.8% (amikacin) and 100% (imipenem). Totally, 76 isolates harbored plasmids with an average of 5.5 plasmids (range: 1 – 10) in each strain. Plasmid profiling distinguished 22 different E. coli genotypes in all isolates that ranged in similarity from 50% to 100%. PCR showed that the prevalence of virulence genes ranged from 15.62% for hly to 30.2% for pap. Conclusion: These data mandate local monitoring of drug resistance and its consideration in empirical therapy of E. coli infections. Plasmid analysis of representative E. coli isolates also demonstrates the presence of a wide range of plasmid sizes, with no consistent relationship between plasmid profiles and resistance phenotypes. Plasmid profiles distinguished more strains than did the antimicrobial susceptibility pattern.

Keywords: E. coli, plasmid, UTI, virulence genes

Cite this article as: Farshad S, Ranjbar R, Japoni A, Hosseini M, Anvarinejad M, Mohammadzadegan R. Microbial Susceptibility, Virulence Factors, and Plasmid Profiles of Uropathogenic Escherichia coli Strains Isolated from Children in Jahrom, Iran.Arch Iran Med. 2012; 15(5): 312 – 316.

Introduction tions. Understanding antibiotic resistance patterns and molecular characterization of plasmids and other genetic elements is also scherichia coli (E. coli) is one of the most important causes epidemiologically useful. Antibiotic susceptibility is reported to be of community-acquired and human nosocomial infections. dynamic in bacteria, and it differs according to time and environ- EThe organism is therefore of clinical importance and can be ment.7 Therefore, there is a need for periodic screening of com- isolated from various clinical specimens.1 Urinary tract infections mon bacterial pathogens to determine their antibiotic susceptibil- (UTIs), including cystitis and pyelonephritis, are the most common ity profiles in different communities.1 Comparing plasmid profiles infectious diseases in childhood. E. coli accounts for as much as is a useful method to assess the possible relatedness of individual 90% of the community-acquired and 50% of the nosocomial clinical isolates of a particular bacterial species for epidemiologi- UTIs.2,3 cal studies.8 The pathogenic potential of E. coli strains is thought to be depen- The present study isolated E. coli strains from clinical samples of dent on the presence of virulence factors (VFs),4 which are located patients with UTIs who resided in Jahrom, a city in southern Iran. on large plasmids and/or in particular regions, called ‛pathogenic- Strains were isolated by culture methods and characterized by the ity islands’ (PAIs), on the chromosome.5,6 Identification of E. coli appropriate biochemical, serological, and antibiogram tests. In this strains is important for both clinical and epidemiological implica- study, we performed molecular techniques such as plasmid profile analysis and PCR. This study also investigated the reliability of Authors’ Affiliations: 1Alborzi Clinical Microbiology Research Center, Shiraz drug sensitivity patterns and plasmid profiles in the discrimination 2 University of Medical Sciences, Shiraz, Iran, Molecular Biology Research Cen- of E. coli strains isolated from UTI epidemics. ter, Baqiyatallah University of Medical Sciences, Tehran, Iran,3Interdisciplinary Nanoscience Center (INANO), Århus University, Århus, Denmark •Corresponding author and reprints: Shohreh Farshad PhD, Alborzi Clinical Materials and Methods Microbiology Research Center, Shiraz University of Medical Sciences, Nemazee Hospital, Shiraz 71937-11351, Iran. Tel: +98 711 6474294, Fax: +98 711 6474303, E-mail:[email protected] Patients and bacterial isolation Accepted for publication: 14 September 2011 E. coli strains were isolated from urine samples of children aged l month to 14 years, who presented at Motahari Hospital, Jahrom,

312 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Molecular characterization of E. coli

Table 1. Antibiotic sensitivity of E. coli strains isolated from children with UTI

Antibiotic Sensitivity n (%) Ampicillin 19 (19.8) Trimethoprim- Sulfamethoxazole 23 (24) Tetracycline 28 (29.2) Nalidixic acid 72 (75.5) Cefixim 77 (80.4) Gentamicin 81 (84.6) Ciprofloxacin 88 (91.4) Nitrifurantoin 93 (96.8) Amikacin 93 (96.8) Imipenem 96 (100)

Table 2. Prevalence of virulence genes in E. coli strains isolated from different groups of children with UTI.

Clinical findings (%) Kidney ultrasound (%) Sex (%) Virulence genes Pyelonephritis Cystitis Normal Abnormal Male Female + (%) 66.7 33.3 62.5 37.5 41.7 58.3 pap - (%) 46.5 53.5 54.5 45.5 33.3 66.7 + (%) 62.5 37.5 33.3 66.7 33.3 66.7 sfa - (%) 50 50 59.3 40.7 35.9 64.1 + (%) 63.6 36.4 16.7 83.3 35 65 cnf-1 - (%) 48.7 51.3 72.4 27.6 35.7 64.3 + (%) 85.7 14.3 100 0 50 50 h ly - (%) 47.1 52.9 61.8 38.2 333.3 66.7

Iran. E. coli isolates were identified by standard methods.9 The al. using a thermal cycler (Eppendorf, Germany).12 Negative con- exclusion criteria were recent antibiotic use during the past 28 trol reactions with distilled water were performed with each batch days and nosocomial infections, defined as infections 48 h post- of amplification to exclude the possibility of any contamination. admission or within 4 weeks following a previous discharge. Posi- Expected sizes of the amplicons were ascertained by electrophore- tive urine cultures were defined by the growth of a single colony sis in 1.5% agarose gel with an appropriate molecular size marker morphotype with counts > 105 colony forming unit/ml. (100 bp DNA ladder, MBI, Fermentas, Lithuania).

Susceptibility testing Plasmid DNA extraction Susceptibility of all the isolates to different antibiotics was de- Plasmid DNA was extracted from E. coli strains according to the termined by the disk diffusion method, as recommended by the alkaline lysis method by Brinboim and Doly (1979).13 Extracted National Committee for Clinical Laboratory Standards.10 Com- plasmid DNA was separated by horizontal electrophoresis in an mercial antimicrobial disks (Mast Co., UK) used in this study 0.8% agarose slab gel in tris-acetate EDTA (TAE) buffer at room were: ampicillin (10 µg), nalidixic acid (30 µg), cefixime (5 µg), temperature at 60 V for 4 h. Using ethidium bromide, the gel was gentamicin (10 µg), nitrofurantoin (300 µg), ciprofloxacin (5 µg), stained after electrophoresis and video images were prepared by a amikacin (30 µg), and imipenem (10 µg). E. coli ATCC 25922 was gel documentation system. The molecular mass of the unknown used for quality-control purposes. plasmid DNA was assessed by comparing plasmid mobilities with the known supercoiled DNA ladder (Gibco-BRL, England). The Preparation of bacterial DNA Photo Capt Mw program was used to determine the molecular DNA to be amplified was extracted from the whole organisms weight of plasmid bands and analyze plasmid profiles. by boiling. Bacteria were harvested from 1.5 ml of an overnight Luria-Bertani broth culture, suspended in sterile distilled water, Analysis of similarity among strains and construction of a dendro- and incubated at 95oC for 10 min. Following centrifugation of gram the lysate, the supernatant was stored at -20oC as a template DNA Similarities among the isolates as based upon plasmid profiles stock. DNA from uropathogenic E. coli strain J96 was extracted were analyzed by Numerical Taxonomy and Multivariate Analysis and used as a positive control in our PCR reaction. System software (NTSYS-PC ver. 2.02) for dendrogram construction. The matrix of similarity of coefficients was subjected to un- Detection of virulence factors (VFs) weighted pair-group method analysis (UPGMA) to generate den- Detection of pap, sfa, cnf-1, and hly genes was performed by drograms using the average linkage procedure. gene amplification using Multiplex-PCR. The primer sequences were previously reported11 and obtained from TIB MOLBIOL Statistical analysis Syntheselabor GmbH (Berlin, Germany). Descriptions and se- Statistical analysis was performed using SPSS software for Win- quences of the PCR primers used in this study are presented in dows, ver.15 (SPSS, IBM, USA). Chi-square was used to evaluate Table 1. Other enzymes and chemicals were provided by Cinna- the variables correlation. P values less than 0.05 were considered gen Chemical Company (Tehran, Iran). The amplification steps significant. were accomplished based on methods described by Yamamoto et

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 313 S. Farshad, R. Ranjbar, A. Japoni , et al.

Results the most frequent plasmids, and were seen in about 28.94% of the isolates, while plasmids of 11 – 12 kb, 21 – 22 kb, 26 – 27 kb, and Patients and E. coli strains 29 – 30 kb were detected in only 1.31% of the isolates. Totally, 96 strains of E. coli were isolated from children with UTI, aged 1 month to 14 years (mean 21.8 ± 26.9 months). There were 60 females (62.5%) and 36 males (37.5%). Among patients, Genetic similarity among the isolates 46.6% had cystitis and 53.3% were diagnosed with acute pyelo- The genetic similarities among the 76 E. coli strains based on nephritis, which was more prevalent in girls (63.2% vs. 36.4%, p their plasmid patterns are represented by the dendrogram shown = 0.04). Only 37 patients underwent kidney sonography. Fourteen in Figure 2. cases had abnormal findings that included reflux, UPJ stenosis, multicystic kidney, and single kidney. Discussion

Antibiotic susceptibility analysis Frequent irrational use of antibiotics changes the intestinal flora, As shown in Table 1, drug sensitivities of the isolates were: leading to bacterial resistance.14 In this study we observed a high 19.8% (ampicillin), 75.5% (nalidixic acid), 80.4% (cefixime), incidence of antibiotic resistance among the uropathogenic Esch- 84.6% (gentamicin), 91.4% (ciprofloxacin), 96.8% (nitrofuran- erichia coli strains. Although resistance to tetracycline was high toin), and 96.8% (amikacin). Sensitivity to imipenem was 100%. (70.8%), ampicillin (80.2%) was the most resistant, followed by Multiple resistance to ampicillin, gentamicin, nalidixic acid, and trimethoprim-sulfamethoxazole (76%). High levels of resistance cefixime were seen in 2.1% of the isolates, but no case of multi- to tetracycline, ampicillin, trimethoprim-sulfamethoxazole, chlor- drug resistance to all drugs was detected. Only 12.5% of the strains amphenicol and sulphonamide have also been reported in other were susceptible to all tested antibiotics. The remaining strains studies.15–17 In a previous study in Shiraz, Iran, high levels of resis- were resistant to one or more antibiotics. tance to ampicillin (63%), trimethoprim-sulfamethoxazole (48%), and tetracycline (57%) were documented among E. coli strains ob- Detection of E. coli virulence genes by PCR assay tained from urine samples.18 However, the incidence of resistance PCR assay showed that the prevalence of virulence genes ranged to these antibiotics was higher in our UPEC strains compared to from 15.62% for hly to 30.2% for pap. Of the studied toxin coding the Shiraz study. As Jahrom is a small city located southeast of genes, cnf-1 (22.91%) was more prevalent than hly (15.62%). For Shiraz, the increase in antibiotic resistance observed in this study the adhesion coding genes, pap (30.2%) was more prevalent than could be due to an irrational consumption of antibiotics and food sfa (18.75%). There were 67 (69.8%) strains that were negative from animals that have received antibiotics, transmission of resis- for the virulence genes. tant isolates among people, self-medication, and noncompliance with medication. No resistance to imipenem was observed in the studied isolates. A high sensitivity of E. coli strains to imipenem has been previously reported.16,18–21 It seems this antibiotic can serve as a medication of choice for the treatment of UTI caused by E. coli. However, it should be noted that unlimited use of a medicine can gradually lead to rising antibiotic resistance. Resistance to nalidixic acid and chloramphenicol in our isolates was lower than that observed in studies performed in other parts of the world.16,17 In the present study, it has also been shown that resistance to ciprofloxacin (8.3%), norfloxacin (8.3%), nitrofurantoin (3.1%), and amikacin (3.1%) was low among the UPEC isolates. Shao et al.22 have shown that amikacin and nitrofurantoin are the most effective treatments in children with UTI in China, which could be explained by the low numbers of prescriptions of these antibacterial agents for UTI. Thus, they could be used as effective therapy for children in our area. A high incidence of multidrug resistant (MDR) strains was also detected among the present isolates. About 77% were resistant to 3 or more tested antibiotics. The level of MDR among UTI isolates varies from country to country. For example, it was reported to be Figure 1. Plasmid patterns of some representative uropathogenic E. coli 24,25 strains. 7.1% in the USA, while 42% of the UPEC isolates in Slove- nia in 2006 were MDR.17 MDR causes major consequences such Plasmid profile analysis as empirical therapy of E. coli infections as well as possible co- Analysis of plasmid DNA revealed that, totally, 76 isolates har- selection of antimicrobial resistance mediated by MDR plasmids. bored plasmids with an average of 5.5 plasmids (range from 1 – The WHO guidelines recommend trimethoprim-sulfamethoxazole 26 10) in each strain. Figure 1 shows the plasmid patterns of some and ampicillin as the first choice for UTI treatment. In contrast, representative strains of the isolates. Plasmid sizes ranged from 1 as revealed in the present study, these two antibiotics cannot serve to 33 kb in the isolates. The plasmids with the sizes of 4-5 kb were as treatment of choice in our region.

314 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Molecular characterization of E. coli

Figure 2. Genetic similarities among 76 E. coli strains based on their plasmid patterns.

Antibiotic resistance among bacteria can occur via plasmids. teria should be performed. Similarity among isolates on the basis Transmission of specified characterization through plasmids (ver- of the plasmid profile was also analyzed by NTSYS-PC ver. 2.02K tical and horizontal) is better than that through a particular bacte- software (Figure 2). As seen in the dendrogram, similarities ranged rial clone. In this research, to reveal the clonality of UPEC strains from 50% to 100%. Plasmid profiling could distinguish 22 differ- isolated from community-acquired UTIs, the plasmid patterns of ent E. coli genotypes in all isolates named A1-A22. Pattern A1 has the isolates were investigated. included 31 isolates with 100% similarity and pattern A2 has 14 The results showed that 76 (79%) of the isolates harbored an av- isolates with 100% similarity. It seems that patients with E. coli erage of 5.5 plasmids. Other reported results agreed with our study. strains with each of these two models of plasmid patterns are likely Woo-Joo et al. have reported that 87.5% and 72% of UPEC strains to obtain the sources of the bacteria from a clone with a high inci- carried plasmids.27 In another study undertaken by Fluit, the preva- dence of bacterial gene transfer in the community. According to the lence of plasmid in the isolates was 81%, which was also similar data shown in Table 2, plasmid profiles distinguished more strains to our results.28 than did the antimicrobial susceptibility pattern. In the present study, the range of plasmids was 1-10 while Mal- Saif and Umolu reported a high prevalence of plasmids in anti- kawi has reported the numbers of plasmids to be approximately biotic resistant E. coli strains isolated from animals.1,32 In Jahrom, 1 – 6 in E. coli strains.29 most people are in close contact with animals, thus it could be sug- Molecular weights of the plasmids were between 1-33 kb. In a gested that animals may be a source for antibiotic resistant gene research conducted by Malkawi, the plasmid sizes were from 1.5 dissemination. – 54 kb.29 Tsen has reported a range of 2 – 22 kb for plasmid In an attempt to investigate the prevalence of 4 important VFs, sizes.30 Danbara et al. have also reported plasmid size variations cnf-1, sfa, pap and hly, in resistant compared to susceptible uro- between 3.9 kb and 50 kb in E. coli strains.31 We detected plas- pathogenic E. coli strains isolated from urine samples of children mid weight ranges of 11 – 12 kb, 21 – 22 kb, 26 – 27 kb, and with UTI, we found that pap operon was, as expected, the most 29 – 30 kb in only 1.31% of the isolates. Those with 4-5 kb were prevalent virulence factor identified. Regardingpap , pooled results the most frequent plasmids, seen in about 28.94% of the isolates with the present data indicated a crucial role of this virulence fac- and among the strains resistant to the medicines under the study. tor in E. coli-associated UTI.33,34 It has recently been shown that These data show that the former plasmids have a lower stability the transformation of E. coli with pap sequences is sufficient to in comparison with 4 – 5 kb plasmids. As ampicillin showed the convert it to a more potent host response inducer, with P fimbriae most resistance, therefore we have suggested that the gene coding lowering the significant bacteriuria threshold.35 The distribution of for ampicillin resistance could be located on this plasmid. On the the sfa operon found among studied strains was also similar to pre- other hand, 21% of our isolates have no plasmids, yet they were viously reported data. The prevalence of hly among the collected resistant to a large number of antibiotics. Possibly, some antibiotic clinical isolates also matched those reported by other investiga- resistance genes may not be located in the plasmid but may be tors.4,35 However, in our study, the cnf-1 operon was more preva- on the bacterial chromosome. In order to prove the relationship lent than in other studies.4,11,35 Possibly, the cnf-1 gene played an between the plasmid and its resistance, additional studies such as important role in UTI in our study. plasmid curing and transferring of the plasmid to other known bac- In conclusion, the high incidence of MDR strains detected among

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 315 S. Farshad, R. Ranjbar, A. Japoni , et al. the present isolates mandate local monitoring of resistance and its Agents Chemother. 2006; 50: 649 – 653. consideration in empirical therapy of E. coli infections, particularly 15. Mehr SS, Powell CV, Curtis N. Cephalosporin resistant urinary tract infection in young children. J Paedi Child Health. 2004; 40: 48 – 52. those which cause UTIs. We found that pap operon was, as expect- 16. Mathai E, Grape M, Kronvall G. Integrons and multidrug resistance ed, the most prevalent virulence factor identified. Plasmid analysis among Escherichia coli causing community acquired urinary tract in- of representative E. coli isolates also demonstrated the presence fection in southern India. APMIS. 2004; 112: 159 – 164. of a wide range of plasmid sizes, with no consistent relationship 17. Rijavec M, Starcic Ergivec M, Ambrozic Augustin J, Reissbrodt R, Fruth A, Krizan-Hergouth V, et al. High prevalence of multidrug re- between plasmid profiles and resistant phenotypes. A common sistance and random distribution of mobile genetic elements among large plasmid with a molecular size of 28 kb was responsible for uropathogenic Escherichia coli (UPEC) of the four major phylogenetic transferring partial resistance. In our study, plasmid profiles distin- groups. Curr Microbiol. 2006; 53: 158 – 162. guished more strains than the antimicrobial susceptibility pattern. 18. Japoni A, Gudarzi M, Farshad SH, Basiri E, Ziyaeyan M, Alborzi A, et al. Assay for integrons and pattern of antibiotic resistance in clinical Escherichia coli strains by PCR-RFLP in Southern Iran. Jpn J Infect Acknowledgments Dis. 2008; 61: 85 – 88. 19. Adwan K, Abu-hasan N, Adwan G, Jarrar N, Abu-shanab B, Al-masri M. Molecular epidemiology of antibiotic-resistant Escherichia coli iso- This work was supported by research grant #83-14 from Profes- lated from hospitalized patient with urinary tract infection in Northen sor Alborzi Clinical Microbiology Research Center, Shiraz Univer- Palestine. Pol J Microbiol. 2004; 53: 23 – 26. sity of Medical Sciences. The authors wish to thank Dr. Fatemeh 20. Tariq N, Jaffery T, Ayub R, Alam AY, Javid MH, Shafique S. Frequen- Emmamghorashi for her assistance with sample collection and Dr. cy and antimicrobial susceptibility of aerobic bacterial vaginal isolates. JCPSP. 2006. 16: 196 – 199. Hassan Khajehi for his editorial assistance. 21. Gulsun S, Oguzoglu N, Inan A, Ceran N. The virulence factors and antibiotic sensitivities of Escherichia coli isolated from recurrent urinary tract infections. Saudi Med J. 2005; 26: 1755 – 1758. References 22. Shao HF, Wang WP, Zhang XW, Li ZD (2004). Distribution and resistance trends of pathogens from urinary tract infections and impact on 1. Umolu Pdia, Okoli EN, Izomoh IM. Antimicrobial susceptibility and management. Internal. J. Antimicrob. Agents. 23: 2-5. plasmid profiles ofEscherichia coli isolates obtained from different hu- 23. Kawamori, F, Hiroi M, Harada T, Ohata K, Sugiyama K, Masuda T, man clinical specimens in Lagos – Nigeria. J Am Sci. 2006; 2: 70 – 76. et al. Molecular typing of Japanese Escherichia coli 0157:H7 isolates 2. Vila J, Simon K, Ruiz J, Horcajada JP, Velasco M, Barranco M, et al. from clinical specimens by multilocus variable number tandem repeat Are quinolone-resistant uropathogenic Escherichia coli less virulent? J analysis and PFGE. J Med Microbiol. 2008; 57: 58 – 63. Infect Dis. 2002; 186: 1039 – 1042. 24. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic 3. Svanborg C, Godaly G. Bacterial virulence in urinary tract infection. use for acute respiratory infections in the United States. Clin Infect Dis. Infect Dis Clin North Am. 1997; 11: 513 – 529. 2001; 33: 757 – 762. 4. Johnson JR. Virulence factors in Escherichia coli urinary tract infec- 25. Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluo- tion. Clin Microbiol Rev. 1991; 4: 80 – 128. roquinolone prescribing in the United States: 1995 to 2002. Am J Med. 5. Hacker J, Blum-Oehler G, Mühldorfer I, Tschäpe H. Pathogenicity is- 2005; 118: 259 – 268. lands of virulent bacteria: Structure, function and impact on microbial 26. Wolff O, Maclennan C. Evidence behind the WHO guidelines hospital evolution. Mol Microbiol. 1997; 23: 1089 – 1097. care for children: What is the appropriate empiric antibiotic therapy in 6. Farshad S, Emamghoraishi F, Japoni A. Association of virulent genes uncomplicated urinary tract infection in children in developing coun- hly, sfa, cnf-1 and pap with antibiotic sensitivity in Escherichia coli tries? J Trop Ped. 2007; 53: 150 – 152. strains isolated from children with community-acquired UTI. Iran Red 27. Woo-joo K, Hee-Lin J, Hyun-Jin P, Min-Ja K, Seung-Chull P. Appli- Cresc Med J. 2010; 12: 30 – 34. cation of ribotyping for molecular epidemiology study of Escherichia 7. Hassan SH. Sensitivity of salmonella and shigella to antibiotics and coli isolated from patients with urinary tract infection. Kor J Infect Dis. chemotherapeutic agents in Sudan. J Trop Med Hyg. 1985; 88: 243 1995; 27: 505 – 517. – 248. 28. Fluit AC, Janes ME. Antimicrobial resistance among UTI isolates in

8. Horcajada JP, Soto S, Gajewski A, Smithson A, Jiménez de Anta MT, Europe. Antonie van Leeuwenhoek. 2001; 77: 147 – 152. Mensa J, et al. Quinolone-resistant uropathogenic Escherichia coli 29. Malkawi HI, Youssef MT. Antibiotic susceptibility testing and plasmid strains from phylogenetic group B2 have fewer virulence factors than profile of Escherichia coli isolated from diarrhoeal patients. J Trop their susceptible counterparts. J Clin Microbiol. 2005; 43: 2962 – Ped. 1998; 44: 128 – 132. 2964. 30. Tsen HY, Chi WR. Plasmid profile analysis for enterotoxigenic Esch- 9. Farmer JJ. Enterobacteriaceae: Introduction and identification. In: erichia coli and detection for heat stable enterotoxin I (ST1) gene by Murray PR, Baron EJ, Phaler MA, Tenover FC, Yolken RH, eds. Man- polymerase chain reaction. J Food Drug Analysis. 1996; 4: 215 – 222. ual of Clinical Microbiology. Washington: ASM Press; 1999: 438. 31. Danbara H, Komase K,Yasuyuki Kirii K, Shinohara M, Arita H, Maki- 10. National Committee for Clinical Laboratory Standards. Performance no S, et al. Analysis of the plasmids of Escherichia coli 0148:H28 from standards for antimicrobial susceptibility testing. Eighth informational travelers with diarrhoea. Microbial Patholog. 1987; 3: 269 – 278. supplement Villanova, PA, 2000. Approved standard M2 A7. 32. Al-Bahry Saif N, Al-Mashani Basma M, Elshafie Abdulkadir E, 11. Arisoy M, Aysev D, Ekim M, Özel D, Kose SK, Özsoy ED, et al. Pathare N, Al-Harthy Asila H. Plasmid profile of antibiotic resistant Detection of virulence factors of Escherichia coli from children by Escherichia coli isolated from chicken intestines. J Ala Acad Sci 2006; multiplex polymerase chain reaction. Inter J Clini Pract. 2006; 60: 77: 152. 170 – 173. 33. Garcia M, Le Bouguénec C. Role of adhesion in pathogenicity of hu- 12. Yamamoto S, Terai A, Yuri K, Kurazono H, Takeda Y, Yoshida O, et man uropathogenic and diarrhoeogenic Escherichia coli. Bulletin de al. Detection of urovirulence factors in Escherichia coli by multiplex l’Institute Pasteur. 1996; 94: 201 – 236. polymerase chain reaction. FEMS Immunol Med Microbiol. 1995; 12: 34. Usein C, Damian M, Tatu-Chitoiu D, Capusa C, Fagaras R, Tudorache 85 – 90. D, et al. Prevalence of virulence genes in Escherichia coli strains iso- 13. Birnboim H, Doly J. A rapid alkaline extraction procedure for screen- lated from Romanian adult urinary tract infection cases. J Cell Mol ing recombinant plasmid DNA. Nucleic Acids Res. 1979; 7: 1513 – Medi. 2001; 5: 303 – 310. 1523. 35. Wullt B. The role of P fimbriaefor Escherichia coli establishment and 14. Soto S, Jimenez de Anta M, Vila J. Quinolones induce partial or to- mucosal inflammation in the human urinary tract. Inter J Antimicrob tal loss of pathogenicity islands in uropathogenic Escherichia coli by Agents. 2003; 21: 605 – 621. SOS-dependent or-independent pathways, respectively. Antimicrob

316 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Injuries Sustained in Iran Air Flight 277

Brief Report A Report of the Injuries Sustained in Iran Air Flight 277 that Crashed near Urmia, Iran

Ahmadreza Afshar MD•1, Majid Hajyhosseinloo MD2, Ali Eftekhari MD2, Mir Bahram Safari MD1, Zahra Yekta MD3

Abstract Background: On January 9, 2011 Iran Air Flight 277 crashed during approach to Urmia, Iran. Out of 105 passengers, 27 survived. This brief report presents a perspective of the passengers’ sustained injuries. Methods: We reviewed the recorded injuries of all passengers as provided by the Legal Medicine Organization authorities. The Injury Severity Score (ISS), an anatomical scoring system, was used to provide an overall code for those who survived with multiple anatomical injuries. Results: There were a total of 96 ISS body region injuries among those who survived. Facial injuries (83%) were the most frequent injuries noted among fatalities, which was statistically significant (P = 0.000). In those who survived, injuries to the head and neck (37%) and facial (33%) regions were relatively less frequent than other anatomical regions. The most serious injuries among survivors belonged to the extremity (85%) region, particularly lower limb fractures (62%). Differences in extremity injuries between the survivors and fatalities were not statistically significant. Conclusion: The findings of this study were similar to other studies where the most frequent serious injuries were fractures of the extremities, particularly the lower limbs.

Keywords: Abbreviated injury scale, airplane crash during approach, injury severity score, mass casualty incidents

Cite this article as: Afshar A, Hajyhosseinloo M, Eftekhari A, Safari MB, Yekta Z. A Report of the Injuries Sustained in Iran Air Flight 277 that Crashed near Urmia, Iran. Arch Iran Med. 2012; 15(5): 317 – 319.

Introduction legal medicine authorities examined all passengers and recorded their injuries. ‛ irplane crash during approach’ is defined as an emergency Autopsies were performed on the 3 cockpit crew who perished. Alanding under circumstances where a normal landing is However, passengers who died were not autopsied and X-ray ex- impossible. Usually the airplane is damaged, the circum- aminations were not performed to detect occult skeletal fractures. stances are not under the pilot’s control and a runway is not avail- The examinations of those killed were limited to the clinical ap- able.1,2 Usually, because of extensive damage and fire, airplane pearance and obvious external body region injuries. Death cer- crash accidents do not lend themselves to an extensive analysis of tificates were issued because of multiple injuries. Injuries of the the occupants’ injuries. Therefore there is limited detailed analysis survivors were registered according to hospital in-patient records. of such accidents.3–6 We reviewed the documented examinations from the legal med- On January 9, 2011 Iran Air Flight 277, a Boeing 727, crashed icine authorities for all passengers. We used the Injury Severity during approach about 5 miles from the Urmia airport runway at Score (ISS), which is an anatomical scoring system, to provide an 19:40 pm local time. Fortunately, the airplane did not catch on fire; overall code for patients with multiple anatomical injuries. The thus, this facilitated the identification and examination of victims. ISS is a process by which complex and variable patient data is re- However, heavy snow and thick fog made the rescue activities dif- duced to a single number. To calculate an ISS for an injured person, ficult (Figure 1). the body is divided into 6 ISS body regions, which are: head and This brief report presents a perspective of the flight passengers’ neck (including cervical spine); face (including the facial skeleton, sustained injuries. nose, mouth, eyes and ears); chest (including thoracic spine and diaphragm); abdomen or pelvic area (including abdominal organs Materials and Methods and lumbar spine); extremities or pelvic girdle (including pelvic skeleton); and external (skin). Each injury in the body region is Of the 105 passengers on this flight, 27 survived and 78 died. The ranked according to the Abbreviated Injury Scale (AIS). AIS clas- sifies each injury according to its relative severity on a 6 ordinal Authors’ Affiliations: 1Department of Orthopedics, Urmia University of Medi- scale: 1 (minor), 2 (moderate), 3 (serious), 4 (severe), 5 (critical), 2 cal Sciences, Urmia, Iran, Legal Medicine Organization, West Azarbaijan, Ur- and 6 [maximal (currently untreatable)]. We used only the highest mia, Iran, 3Department of Community Medicine, Urmia University of Medical Sciences, Urmia, Iran. AIS number for each body region. To calculate a final ISS code, •Corresponding author and reprints: Ahmadreza Afshar MD, Urmia Univer- the 3 most severely injured ISS body regions have their AIS score sity of Medical Sciences, Department of Orthopedics, Imam Khomeini Hospital, squared and added together to produce the ISS code. The ISS Modaress Street, Ershad Boulevard, Urmia, Iran. Tel: +989123131556, Fax: +984413469939, E-mail: [email protected]. ranges from 1 to 75. Severity of each patient’s injuries is classified Accepted for publication: 7 September 2011 according to the ISS code: 1 – 8 (minor), 9 – 15 (moderate), and 16

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 317 A. Afshar, M. Hajyhosseinloo, A. Eftekhari, et al.

Figure 1. Cockpit of the Boeing 727 that crashed near Urmia on January 9, 2011. and above (serious).7–9 intra-abdominal, intra-thoracic, brain contusion and concussion in- Fisher’s exact test was used to for data analysis and P values less juries were not recorded. Therefore comparative analyses for these than 0.05 were considered statistically significant. body regions were not an accurate reflection of this difference. The 3 cockpit crew sustained the most severe and extensive injuries in Results all 6 ISS body regions.

There were 27 survivors, of which all were adults. There were no Discussion pre-or in-hospital deaths. All passengers (survivors and fatalities) sustained multiple anatomical region injuries. Table 1 presents the In airplane crashes, injuries are produced by horizontal, vertical, AIS (range: 1 to 6) of the 6 ISS body regions and the ISS codes of and transverse force axes. Head, neck, facial, and thoracic injuries the 27 survivors. Except for one individual, all survivors sustained occur when the transmitted horizontal deceleration force exceeds more than one ISS body region injury and a total of 96 ISS body the limits of the human body’s tolerance to abrupt deceleration. region injuries were recorded. The mean ISS code was 23 (1 to 41). The vertical deceleration force produces spinal fractures. Bending Among survivors, 18 (67%) had severe injuries, 7 (27%) had and torsional forces produce fractures in the extremities. However, moderate, and 2 (7%) had minor injuries according to the severity combinations of different forces in 3-dimensional space produce of the ISS codes. many complex mechanisms for injuries.4 Of those who died, 65 (83%) out of 78 had facial injuries which In 1968 Zanca reported an airplane crash accident in which 21 were the most frequent obvious injuries. The difference in facial of 66 occupants survived. In that accident the registered injuries region injuries between survivors (33%) and fatalities (83%) was among survivors in order of frequency were: abrasions, wounds statistically significant P( = 0.000). Among survivors, injuries to and contusions, fractures, shock or impending shock, internal inju- the head and neck (37%) and facial (33%) regions were relatively ries, and concussions. Most fractures occurred in the lower limbs.6 less frequent than other anatomical regions. The most frequent Carter et al., in 1973, reported a total number of 203 injuries for injuries among survivors were external (100 %) and extremities all passengers of an airplane crash. Fractured extremities, which (85%) body regions. However the external injuries consisted of comprised 79 (39%) out of 203 total injuries, were the most fre- swellings, bruises, abrasions, and superficial lacerations, all of quent seen among victims.4 which were minor injuries (AIS 1) that did not substantially impact On February 25, 2009 Turkish Airline Flight 1951 crashed during the final ISS codes. From 27 survivors, 17 (62%) sustained lower approach to Schipol Airport, Amsterdam. Of the 135 passengers, limb fractures which were the most frequent site for extremities 9 including the 3 cockpit crew died, 11 had serious injuries, 22 had injuries. The difference in extremity body region injuries between moderate injuries, 87 had minor injuries, and 6 were uninjured. A the survivors and fatalities was not statistically significant. Among total of 297 ISS body region injuries were recorded, of which most survivors, 16 (59%) out of 27 sustained fractures to their spinal were to the head, face, spine, and extremities.3,5 columns, which were at different levels. Spinal injuries were in- The findings of the current study were similar to previous reports cluded in the head and neck, abdominal, and thoracic ISS body on survivors3–6 in which the most frequent serious injury was frac- regions. ture of the extremities, especially in the lower limbs. Only 4 out of the 27survivors sustained internal injuries to their In the current study, the cockpit crew who perished sustained abdominal organs. extensive injuries in all 6 ISS body regions, which was similar The 4 recorded abdominal injuries consisted of the 3 cockpit to other reports.3–6 It seems that the cockpit crew are at the most crew who were autopsied and one passenger who had extruded endangered position. Therefore, improvements in cockpit design abdominal organs. Since fatalities were not autopsied, some fatal might reduce and protect the crew from extensive injuries.

318 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Injuries Sustained in Iran Air Flight 277

Table 1. AIS of 6 ISS body regions and final ISS codes in survivors. ISS body regions Cases Number Head and neck Face Chest Abdomen Extremity External ISS code 1 3 0 0 0 0 1 10 2 0 0 0 0 3 1 10 3 0 0 0 3 3 1 19 4 2 1 0 3 4 1 29 5 0 0 0 0 3 1 10 6 0 0 4 4 3 1 41 7 0 1 3 0 3 1 19 8 0 1 3 3 4 1 34 9 2 0 3 0 4 1 29 10 0 0 0 0 0 1 1 11 4 1 3 3 0 1 34 12 0 0 3 0 4 1 26 13 0 0 4 3 3 1 34 14 0 0 0 0 3 1 10 15 3 0 0 0 0 1 10 16 0 0 4 3 3 1 34 17 0 0 0 0 2 1 5 18 2 0 3 0 3 1 22 19 1 2 4 4 3 1 41 20 3 0 3 0 4 1 34 21 0 1 0 3 4 1 26 22 4 0 3 3 4 1 41 23 0 0 0 0 3 1 10 24 0 1 0 3 4 1 26 25 4 3 4 3 3 1 41 26 0 0 0 3 2 1 14 27 0 1 0 3 3 1 19 AIS: Abbreviated Injury Scale (1- minor; 2- moderate; 3- serious; 4- severe; 5- critical; 6- maximal); ISS: Injury Severity Score

In the current study we did not evaluate the relation between seat Conflict of interest locations, severity of the incurred injuries, and death because the seating positions of all occupants were not officially available to All data in this study was provided by the Legal Medicine Orga- the authors of this study. In addition, since about two-thirds of seats nization in Urmia, West Azarbaijan, Iran. were occupied, it was probable that some passengers had changed their seats during the flight and did not occupy their assigned seats. References A major flaw of this study was that examinations of passengers who perished was limited to clinical appearance and obvious ex- 1. Emergency landing. Available from URL: http://en.wikipedia.org/ ternal injuries of the anatomical body regions. Therefore we were wiki/Emergency-landing. (Accessed: 25 June 2011). 2. Crash landing. Available from URL: http://www.thefreedictioanry. unable to compare the true differences between the head and neck, com/crash+landing . (Accessed: 25 June 2011). abdomen, and chest ISS body region injuries among survivors and 3. Crashed during approach, Boeing737-800, near Amsterdam Schiphol fatalities. Doubtlessly those who perished had undetected intra-ab- Airport, 25 February 2009. Available from URL: www.ntsb.gov/avia- dominal, intra-thoracic, and cranial injuries which were more than tion/Netherlands/DSB_ENG_Report.pdf. (Accessed: 25 June 2011). 4. Carter JH, Burdge R, Powers SR Jr, Campbell CJ. An analysis of 17 their registered injuries. Evaluations of skeletal injuries would have fatal and 31 nonfatal injuries following an airplane crash. J Trauma. been completed and the number of skeletal fractures increased if 1973; 13: 346 – 353. X-rays had been taken from the bodies of those who died. There- 5. Winkelhagen J, Bijlsma TS, Bloemers FW, Heetveld MJ, Goslings JC. fore, it might be reasonable to suggest that in such accidents autop- Airplane crash near Schiphol Airport 25 February 2009: Injuries and casualty distribution. Ned Tijdschr Geneeskd. 2010; 154: A1064. sies should be regularly performed on those who expired. 6. Zanca P. Types of injuries in air plane crash survivors. South Med J. This study might hopefully provide an understanding of the sur- 1968; 61: 1219 – 1222. vival aspect of airplane crash accidents that occur during approach. 7. Injury Severity Score. Available from URL: http://en.wikipedia.org/ A study of these types of injuries may provide a resource for subse- wiki/Injury_Severity_Score. (Accessed: 2 July 2011). 8. Baker SP, O’Neill B, Haddon W Jr, Long WB. The Injury Severity quent research and assist investigators to make recommendations Score: A method for describing patients with multiple injuries and eval- that reduce the occurrence of similar injuries. uating emergency care. J Trauma. 1974; 14: 187 – 196. 9. Baker SP, O’Neill B. The Injury Severity Score: An update. J Trauma. 1976; 16: 882 – 885.

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Report Advocacy Strategies and Action Plans for Reducing Salt Intake in Iran

Noushin Mohammadifard MSc1, Saman Fahimi MD MPhil2,3, Alireza Khosravi MD1, Hamed Pouraram PhD4, Sima Sajedinejad MD5, Paul Pharoah MD PhD3, Reza Malekzadeh MD2, Nizal Sarrafzadegan MD•6

Cite this article as: Mohammadifard N, Fahimi S, Khosravi A, Pouraram H, Sajedinejad S, Pharoah P, et al. Efficacy Advocacy strategies and action plans for reducing salt intake in Iran. Arch Iran Med. 2012; 15(5): 320 – 324.

Key words: Iran, national program, non-communicable diseases, salt reduction

Introduction reduction in 24-hour urinary excretion of sodium, there was 3.99 mmHg reduction in systolic blood pressure (95% CI: 2.93 – 5.05) t has been estimated that in 2008, non-communicable dis- and 1.92 mmHg reduction for diastolic blood pressure (95% CI: 11 eases (NCDs) accounted for 36 million death worldwide, 1.26 – 2.59). The increase in blood pressure leads to an increased 12,13 I contributing to 63 percent of all-cause global mortalities.1 risk of cardiovascular disease. In a meta-analysis of 19 inde- Without any serious action, the NCD epidemic is projected to kill pendent cohort samples from 13 studies, with 177,025 participants 52 million people annually by 2030.2,3 High blood pressure has and average follow up of 3 years (5 – 19 years) and over 11,000 been reported as the leading underlying cause of as many as 7.6 vascular events, a higher salt intake was associated with a greater million premature global deaths and 92 million disability adjusted risk of stroke (pooled relative risk 1.23, 95% confidence interval life years (DALYs) in 2001.4 Globally, 51 percent of deaths due to 1.06 – 1.43, P = 0.007) and cardiovascular disease (pooled relative 14 stroke (cerebrovascular disease) and 45 percent of deaths due to risk 1.14, 95% confidence interval 0.99 – 1.32, P = 0.07). There ischemic heart disease are attributable to high systolic blood pres- is also substantive evidence suggesting that excessive salt intake 15 sure. At any given age, the risk of dying from high blood pressure is also causally associated with increased risk of gastric cancer. in low- and middle-income countries is more than double that in The UN high level meeting on NCD urged member states to high-income countries. In the high-income countries, only 7 per- adopt urgent preventive actions to tackle the NCD’s rapidly ris- 16 cent of deaths caused by high blood pressure occur under age 60; ing burden. It has been estimated that reducing dietary salt in- in the African Region, this figure increases to 25 percent.5 Nearly take across populations, as a single, inexpensive, cost effective 80 percent of current deaths due to non-communicable diseases measure, can hugely reduce the burden of cardiovascular disease 17–19 occur in low- and middle-income countries, disproving the myth (CVD). According to the World Health Organization (WHO), that non-communicable diseases are mostly affecting affluent soci- reducing populations’ salt intake is by far the most effective pre- 20 eties.6 ventive approach for all countries and in all settings. It has been There is abundant evidence on a causal relation between salt estimated that reducing the salt intake at a population level can re- intake and high blood pressure.7–10 In a meta analysis of salt reduce total mortality rate, on average, by 1 – 2 percent and increase 21 duction randomized clinical trials with the median duration of mean life expectancy by 1.6 months. 5 weeks (ranging from 4 weeks to 3 years), for each 100 mmol Iran is undergoing epidemiological transition and is facing a rapid increase in the burden of NCDs.22 Based on a WHO report, Authors’ Affiliations: 1Department of Nutrition, Hypertension Research Center, NCDs are estimated to account for 72 percent of all deaths in Iran, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sci- 23 ences, Isfahan, Iran,2 Digestive Diseases Research Institute, Tehran University of 24 percent of which happens under age 60. The estimated age Medical Sciences, Tehran, Iran,3 Department of Public Health and Primary Care, standardized prevalence of hypertension was 34 percent in the University of Cambridge, Cambridge, UK,4 Department of Nutrition, Under Sec- adult population (36 percent in men and 32 percent in women). It retary for Health, Ministry of Health & Medical Education, Tehran, Iran,5 National Professional Officer, World Health Organization Office in Iran, Tehran, Iran, 6 Is- has been estimated that the circulatory system diseases contributed fahan Cardiovascular Research Center, Isfahan Cardiovascular Research Institute, to about 1,500,000 Disability Adjusted Life Years Lost (DALYs) Isfahan University of Medical Sciences, Isfahan, Iran. in Iran in 2003.22 Cardiovascular diseases were responsible for 45 •Corresponding author and reprints: Nizal Sarrafzadegan MD, Isfahan Car- diovascular Research Center, Isfahan Cardiovascular Research Institute, Isfahan percent of total national mortality, while communicable diseases, University of Medical Sciences, Isfahan, Iran, Cardiovascular Research Center, maternal, perinatal, and nutritional conditions together contributed Isfahan Cardiovascular Research Institute, Sedigheh Tahereh Research Center, to 13 percent of total mortality in Iran in 2008.23 So far, compared Khorram St., Isfahan, Iran, P. O. Box: 81465-1148 . Tel: +98 311 3359696, Fax: +98 311 3373435, Email: [email protected] to infectious diseases, chronic diseases have received less attention Accepted for publication: 26 March 2012 in the Iranian health care system.24 However, recently the Iranian

320 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Advocacy Strategies and Action Plans for Reducing Salt intake in Iran

Table 1. Twenty-four hour urinary salt equivalent excretion values based on 24-hour urinary sodium excretion studies in Isfahan

Equivalent 24-hour salt Sample Age range excretion based on 24- Equivalent salt Year Source population Sampling method size (years) hour urinary excretion intake (g/d) * values (g/d)

1999–2000 General urban adult population 1059 20–60 Multistage random sampling 8.2 9.1

2001–2002 General urban adult population 374 +19 Multistage random sampling 12.5 13.9

2007 General urban adult population 806 +19 Multistage random sampling 10.6 11.8

*Assuming that 90 percent of sodium intake is excreted into the urine ministry of health has acknowledged tackling NCDs as one of its intake.26 priorities.25 A road map for reducing salt intake in Iran was pro- Table 1 provides further details of the 24-hour urinary sodium posed in the previous issue of this journal.26 Here, we present the excretion studies in the city of Isfahan. national advocacy strategies and action plans for implementing a There have also been dietary sodium studies that used food fre- nation-wide salt reduction program that was developed by Isfahan quency questionnaire to estimate the salt intake in the cities of Cardiovascular Research Institute (ICRI) and proposed to the Ira- Rasht and Sari and those residing in “Ilam province” according to nian Ministry of Health.27 which the average intake for the population aged 2 – 79 were 7.2, 7.7, and 10.3 g/d, respectively.30,31 There is a general consensus that Main steps in designing a comprehensive national salt reduc- the dietary estimation of salt intake considerably under-reports the tion plan true salt intake; data from these studies support the notion that the salt intake of Iranians is high. Creating a national salt reduction task force As a first step, and after initial considerations by ICRI experts, Setting a salt intake target a steering committee was formed in 2010 in order to set out the A joint WHO/FAO working group on Diet, Nutrition and the priorities and devising an action plan for reducing the salt intake Prevention of Chronic Disease suggested reducing salt intake in Iran. This committee encompassed a wide range of experts en- to less than 5.0 g/d.32 In the UK, the recommended salt intake is gaged with various aspects of NCD control in Iran and included to be less than 6 g/d in the British adult population.33 However, ICRI senior members with expertise in cardiovascular preventive more recently, the UK government’s health advisory agency, the strategies and nutrition sciences, representatives from the Health, National Institute for Health and Clinical Excellence (NICE), has and “Food and Drug” deputies of Isfahan University of Medical recommended that by the year 2025 the population’s salt consump- Sciences and Institute of Standard and Industrial Research of Is- tion should be reduced to less than 3 g/d.34 In the USA, it is cur- fahan province, Director General of Nutrition Department in the rently recommended salt intake should be reduced to less than 6 Ministry of Health, and food technologies of Isfahan University g/d for adults, with an even further reduction to less than 4 g/d of Technology, an officer from the NCD branch of WHO office in salt for those at higher risk of developing adverse effects including Tehran, and delegates from the food industry. In parallel an execu- African Americans, those with hypertension, diabetes or chronic tive committee was formed in 2010 in order to define target groups kidney disease, and all adults 51 years old and older.35 The recom- and key messages based on the decisions made by the steering mended daily salt intake in Iran was judged to be less than 5 g/d.27 committee. The executive committee encompassed members of ICRI with a wide variety of expertise including its executive direc- Getting lessons from the experiences of other countries tor and heads of nutrition group; education and training unit; evalu- With revived interest worldwide on the importance of salt re- ation, assessment and quality control group; and IT department. duction as a tool for reducing the burden of salt intake, various countries of the world are in the development stages of theirs salt Estimating the current salt intake in Iran reduction plan.26,36 Currently, only a few countries worldwide have The next step was to get the best estimate for current salt intake successful operational salt reduction plans in place. They include in Iran. Details of the best methods for the estimation of popula- countries such as the UK, Finland, and Canada. Such activities in tions salt intake and current estimates of salt intake in Iran, and the UK led to drop of about 10 percent in average populations salt its comparison to estimates from other countries was explained intake, from 9.5 g/d in 2000 to 8.6 g/d in 2008.37 Efforts were made elsewhere.26 In brief, there have been no studies that measured 24- to get the lessons from the experience of such countries as well as hour urinary sodium excretion in a nationally representative Ira- those of international action alliances such as World Action on Salt nian sample. However, there were three 24-hour urinary sodium and Health (WASH). excretion studies performed in representative adult population samples in the city of Isfahan. Equivalent 24-hour salt excretion Choosing the key target groups values based on 24-hour urinary sodium excretions, in the years Based on the experience from other countries and by considering 1999, 2002, and 2007, were 8.2, 12.5, and 10.6 g/d, respective- the role that individuals and groups can potentially play, four key ly.28,29 Assuming that about 90 percent of sodium intake is excreted target groups were identified: First group were those who were en- into the urine, they correspond to salt intakes of 9.1, 13.9, and 11.8 gaged in decision making processes; they included the legislative g/d. These values are in line with most of the countries around the authorities, policy makers, and the executive authorities. Engaging world, in which the intakes are higher than recommended daily with the above mentioned authorities would help ensuring that ap-

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Table 2. Targets groups with current or potential impacts on a national salt reduction plan Legislative Iranian parliament’s high council for health, food security and nutrition authorities Iranian parliament’s; high council for health, food security and nutrition; Minister of health; Vice-chancellors in health and treatment affairs of the ministry of health; Food and drug organization; Nutrition improvement office; Institute of standard and industrial research; Policy makers The ministry of agriculture; Ministry of industry, mining, and commerce; Governors of the provinces

Decision makers The ministry of Sciences; The welfare organization; The office for monitoring supply of flour and bread; The health, food and drug and treatment deputies of the Isfahan university of 1 medical sciences; The medical education development center of Isfahan university of medical Executive sciences; Institute of standard and industrial research of Isfahan province; The office for forces industries, mining, and commerce of Isfahan province; The office for agricultural of Isfahan province; Organizations that provide food for their employees; Food industries; The restaurant, bakeries sandwich, pizza shop and nuts unions

General Children; Adolescents; Adults; The elderly population

Individuals aged more than 40 years; Those suffering from high blood pressure, CVD, Primary High risk diabetes mellitus, renal disease, osteoporosis, or some types of cancer; First degree relatives 2 Beneficiaries groups of individuals with high blood pressure or suffering from CVD; Individuals with overweight or obesity

Medical universities; Health insurance agencies; Ministry of education; Welfare organization; Secondary Organizations that provide food for their employees

National Iranian broadcasting corporation; Religious authorities; Celebrities (actors, sportsmen); National and local media; Isfahan university of medical sciences; The Institute of standard and industrial research of Isfahan province; The office for agricultural of Isfahan 3 Partners province; The office for industries, mining, and commerce of Isfahan province; The office for monitoring supply of flour and bread; Health sector personnel; Non-governmental organizations

Potential Producers of processed foods with high salt content; Syndicate of restaurant owners; Syndicate 4 opposition of fast food shops; Syndicate of bakers; Individuals with wrong beliefs

Table 3. Core key messages and some of the secondary key messages for communicating salt intake reduction plan Core key messages High blood pressure is one of the leading causes of mortality and morbidity worldwide Excessive salt intake causes high blood pressure Reducing salt intake is the most cost-effective way for reducing blood pressure Iranian’s salt intake is more than twice recommended Up to two-thirds of salt intake of Iranians comes from processed foods , and salty snacks such as potato chips Secondary core messages* High blood pressure, usually has no symptoms and is therefore also called “ a silent killer” The recommended daily intake for salt is less than 5 grams ( less than one large teaspoon) High blood pressure is the most important risk factor for CVD in Iran Reducing salt intake will lower the blood pressure levels and decreases the chance of CVD, diabetes, osteoporosis, and some types of cancers Bread and cheese are the main sources of salt intake of the Iranians Currently, the Salt intake in Iranians is more than twice the recommended intake Those suffering from high blood pressure should reduce their salt intake to less than 4 grams per day * A selection of the secondary core messages, the full list of the messages can be accessed at http://www.icrc.ir/pdf/advocacy.pdf propriate legislations and regulations would be put into place to national media. The last group was those who may oppose the salt incentivize the food industry to reduce foods salt content. Second reduction plan. Table 2 presents the different target groups whose group were the beneficiaries engaged with salt which itself com- views and actions has potential impacts on the success of a national prised two major sub-groups: A primary beneficiary group which salt reduction plan. included : a) general population and b) the high risk groups and a secondary group that included institutions and organization such Holding meetings with key stake holders as universities of medical sciences, health insurance agencies, Several meetings were held with a subset of the target groups in ʻeducation and training organization’, and ʻwelfare and social se- order to understand to their viewpoints and assess their beliefs and curity organization’. The third target group consisted of those who help clarify the mutual needs and priorities. These meetings helped can potentially act as partners and included bodies like the Iranian identify the key messages for communicating the salt reduction broadcasting corporation, religious authorities, and local as well as plan.

322 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Advocacy Strategies and Action Plans for Reducing Salt intake in Iran

Table 4. Different methods for communication of salt reduction plan

1 Regular contacts and meetings with the stakeholders 2 Publication of booklets, pamphlets , and posters 3 Initiating volunteer salt reduction campaign groups 4 Holding debates on the health effects of salt on the national media 5 Holding training courses, conferences and seminars 6 Making documentaries, and animations on the importance of salt reduction 7 Engaging the public through partnerships with popular figures, sportsmen and celebrities

Table 5. Surveillance and monitoring plan for evaluation and assessment the Iranian national salt reduction program Stage of the intervention Elements to be assessed and monitored Existence and quality of educational programs and trainings provided through/at the time of: a) families attending health clinics b) attending mandatory continuing qualification courses for employees c) the meetings of “parents and teacher associations” d) TV programs Processes e) bulletins f) competitions g) emails h) text messages i) attending health clinics specially for those suffering from obesity or diabetes a) public awareness and attitude towards harmful effects of excessive salt intake b) level of salt intake per capita c) the extent to which prepared food are used Impacts d) prevalence of taking salty snacks e) Consuming fast foods f) using discretionary salt at table a) Prevalence of hypertension b) Prevalence of controlled hypertension c) Average blood pressure level Outcomes d) Incidence of cardiovascular disease e) Incidence of gastric cancer f) All-cause mortality rate g) Prevalence of obesity

Defining the key messages sidered in order to evaluate and assess the “processes”, their “im- A set of key messages were chosen, by trying to put in an Iranian pacts”, and “outcomes” in each of the target groups; according to dietary pattern, the scientific facts on the harmful effects of exces- which the plan would be reviewed and revised. Multiple indicators sive salt intake and the experience from other countries’ successful were defined for each type of evaluation and its target population, salt reduction programs. Accordingly, the messages were divided place, time and frequency were explained in the full report. For in- into those considered as “core key messages” and those regarded stance, the success of interventions at the general population level as “secondary key messages”. Table 3 presents the core key mes- will be assessed by: sages and some of the secondary key messages. a) Assessing and evaluating the “processes” through which the intervention is communicated with the public (e.g. by assessing Defining the methods for the communication of the national salt re- the existence and quality of education and training provided to the duction plan population on harmful effects of salt) Various methods for communication of the salt reduction plan were b) Assessing and evaluating their “impacts” on general popula- reviewed; Table 4 summarizes the different approaches proposed. tion by measures such as monitoring the trend in population’s salt intake Choosing the most appropriate key messages and their communica- c) Assessment and evaluation of the “outcomes”, for instance tion tools for different target groups by monitoring the reductions in the level of blood pressure at the The next task was to select and match those key messages (pre- population level. sented in Table 3) depending on the specific target groups (sum- Table 5 provides the details of the surveillance and monitoring marized in Table 2) by choosing the most effective communication plan for assessment of the success of the national salt reduction tools (listed in Table 4). For instance, the main key message in program in the general population. communications with the general public was chosen to be through communication of the health effects of salt through various media; Acknowledgments the cost-effectiveness of salt reduction planning could discussed in the meetings to be held with the authorities engaged in budget and The study was supported by a grant from the Nutrition Depart- health policy planning. ment of Iranian Ministry of Health and Medical Education and the Office of World Health Organization in Iran. We thank Drs. Man- Surveillance and monitoring sour Shiri, Katayoun Rabiei, Hasan Alikhasi Mohammad Badiei, Proper surveillance and monitoring is a vital element of any suc- and Soheila Kanani who cooperated in conducting this study. cessful intervention program. Therefore, various steps were con- Conflict of interest: None to declare

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19. Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic disease prevention: health effects and financial costs of strategies to References reduce salt intake and control tobacco use. Lancet. 2007; 370: 2044 – 2053. 1. Alwan A, Maclean DR, Riley LM, d’Espaignet ET, Mathers CD, Ste- 20. WHO forum on reducing salt intake in populations. Reducing salt in- vens GA, et al. Monitoring and surveillance of chronic non-communi- take in populations, report of a WHO forum and technical meeting, 5-7 cable diseases: progress and capacity in high-burden countries. Lancet. October 2006, Paris, France. 2007. 2010; 376: 1861 – 1868. 21. The effectiveness and costs of populatioin interventions to reduce salt 2. Daar AS, Singer PA, Persad DL, Pramming SK, Matthews DR, Bea- consumption, background paper prepared by Bruce Neal with assis- glehole R, et al. Grand challenges in chronic non-communicable distance from Wu Yangfeng and Nicole Li to the WHO froum and tech- eases. Nature. 2007; 450: 494 – 496. nical meeting on “Reducing Salt Intake in Populations” 5-7 october 3. The global burden of Disease, 2004 update. Geneva: World Health Or- 2006, Paris, France. 2006. ganization; 2008. 22. Naghavi M, Abolhassani F, Pourmalek F, Lakeh M, Jafari N, Vaseghi 4. Lawes CM, Vander HS, Rodgers A. Global burden of blood-pressure- S, et al. The burden of disease and injury in Iran 2003. Popul Health related disease, 2001. Lancet. 2008; 371: 1513 – 1518. Metr. 2009;7: 9. 5. Global health risks: mortality and burden of disease attributable to se- 23. World Health Organization. Noncommunicable diseases country pro- lected major risks. Geneva: WHO; 2009. files2011, WHO global report. 2012. 6. MacMahon S, Alderman MH, Lindholm LH, Liu L, Sanchez RA, 24. Sepanlou SG, Kamangar F, Poustchi H, Malekzadeh R. Reducing the Seedat YK. Blood-pressure-related disease is a global health priority. burden of chronic diseases: a neglected agenda in Iranian health care J Hypertens. 2008; 26(10): 2071 – 2072. system, requiring a plan for action. Arch Iran Med. 2010;13(4): 340 – 7. INTERSALT cooperative research group. Intersalt: an international 350. study of electrolyte excretion and blood pressure. Results for 24 hour 25. Iran stresses measures to prevent non-communicable diseases. Avail- urinary sodium and potassium excretion. Intersalt Cooperative Re- able from: URL: http://tehrantimes.com/index.php/health/2906-iran- search Group. BMJ. 1988; 297: 319 – 328. stresses-measures-to-prevent-non-communicable-diseases . 2011. 8. He FJ, MacGregor GA. Salt, blood pressure and cardiovascular dis- Tehran Times. ease. Curr Opin Cardiol. 2007; 22(4): 298 – 305. 26. Fahimi S, Pharoah P. Reducing salt intake in iran: priorities and chal- 9. Khaw KT, Bingham S, Welch A, Luben R, O’Brien E, Wareham N, et lenges. Arch Iran Med. 2012;15(2):110 – 112. al. Blood pressure and urinary sodium in men and women: the Norfolk 27. Mohammadifard N, Khosravi A, Sarrafzadegan N. Advocacy strate- Cohort of the European Prospective Investigation into Cancer (EPIC- gies and action plans for reducing salt intake in Iran (in Persian). Avail- Norfolk).[see comment]. American Journal of Clinical Nutrition. able from: URL: http://www.icrc.ir/pdf/advocacy.pdf . 2011. 2004; 80(5): 1397 – 1403. 28. Khosravi A, Kelishadi R, Sarrafzadegan N, Boshtam M, Nouri F, 10. Meneton P, Jeunemaitre X, de Wardener HE, MacGregor GA. Links Zarfeshani S, et al. Impact of a community-based lifestyle interven- between dietary salt intake, renal salt handling, blood pressure, and car- tion program on blood pressure and salt intake of normotensive adult diovascular diseases. Physiol Rev. 2005; 85(2): 679 – 715. population in a developing country. J Res Med Sci. 2012; 17(3):12. 11. He FJ, MacGregor GA. Effect of longer-term modest salt reduction on 29. Rafiei M, Boshtam ,M Sarraf-Zadegan N, Seirafian S. The relation be- blood pressure. Cochrane Database Syst Rev. 2004; 3: CD004937. tween salt Intake and blood pressure among Iranians. Kuwait Medical 12. Tuomilehto J, Jousilahti P, Rastenyte D, Moltchanov V, Tanskanen A, Journal. 2008;40(3):191 – 195. Pietinen P, et al. Urinary sodium excretion and cardiovascular mortality 30. Azizi F, Rahmani M, Allahverdian S, Hedayati M. Effects of salted in Finland: a prospective study. Lancet. 2001; 357: 848 – 851. food consumption on urinary iodine and thyroid function tests in two 13. Cook NR, Obarzanek E, Cutler JA, Buring JE, Rexrode KM, Ku- provinces in the Islamic Republic of Iran. Eastern Mediterranean manyika SK, et al. Joint effects of sodium and potassium intake on Health Journal . 2001;7: 115 – 20. subsequent cardiovascular disease: the Trials of Hypertension Preven- 31. Rahmani M, Koohkan A, Allahverdian S, Hedayati M, Azizi F. Com- tion follow-up study. Arch Intern Med. 2009;169(1): 32 – 40. parison of dietary iodine intake and Urinary excretion in urban and 14. Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, rural Households of Ilam in 2000 (in Persian). Iranian Journal of En- and cardiovascular disease: meta-analysis of prospective studies. BMJ. docrinology and Metabolism. 2000; 2: 1 2009;339: b4567. 32. Diet,nutrition and the prevention of chronic diseases; Report of a joint 15. World Cancer Research Fund / American Institute for Cancer Re- WHO/FAO expert consultation group, Geneva. 2003. search. World Cancer Research Fund / American Institute for Cancer 33. Medical Research Council Human Nutrition Research CU. Why 6g? A Research. Food, Nutrition, Physical Activity, and the Prevention of summary of the scientific evidence for the salt intaketarget. 2005. Cancer: a Global Perspective. Washington DC: AICR. 2007. 34. National Institute of Clinical Excellence. Guidance on the prevention 16. UN High-Level Meeting puts NCDs on the map, falls short of setting of cardiovascular disease at the population level. 2011. goals or targets. Available from : URL: http://www.ncdalliance.org/ 35. Dietary Guidelines for Americans, 2010. US Department of Agricul- node/3517 . 2011. ture 2010Available from: URL: http://www.cnpp.usda.gov/Dietary- 17. Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J+, Murray CJL, Guidelines.htm et al. The Preventable Causes of Death in the United States: Compara- 36. Dropping the salt; Practical steps countries are taking to prevent chron- tive Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors. ic non-communicable diseases through population-wide dietary salt re- PLoS Med. 2009; 6(4): 1000058. duction. 2009. 18. Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, Lightwood 37. Consensus Action on Salt and Health, July 2009-10 Annual Report. JM, Pletcher MJ, et al. Projected effect of dietary salt reductions on 2010. future cardiovascular disease. N Engl J Med. 2010;362(7): 590 – 599.

324 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 GIST

Case Report A Rare Case of Perforated Meckel’s Diverticulum Presenting as a Gatrointestinal Stromal Tumor

Selim Sozen MD•1, Ömer Tuna MD1

Abstract Meckel’s diverticulum is located on the antimesentric border of the ileum, approximately 45 to 60 cm proximal to the ileocecal valve, and results from incomplete closure of the omphalomesentric or viteline duct. Common complications presenting in adults include bleeding, obstruction, diverticulitis, and perforation. Tumors within Meckel’s diverticulum are a rare, but recognized complication. A 62year-old woman presented with peri-umbilical pain that had localized to the right iliac fossa. On examination, she was tender in the right iliac fossa, with localized peritonism. At surgery,a perforated Meckel’s diverticulum was found that was associated with free intra-abdominal fluid and hemorrhage. A 25 mm nodule was found at the apex of Meckel’s diverticulum.We resected 100 mm of the small bowel and a primary anastamosis was performed.Histopathological examination of the resected lesion revealed a mesenchymal tumor categorized as a gastrointestinal stromal tumor (GISTs). GISTs arising from Meckel’s diverticulum are an extremely rare, but recognized complication. Surgery is considered the standard treatment for non-metastatic GISTs with enbloc resection and clear margins.

Keywords: Complications, gastrointestinal stromal tumor, Meckel’s diverticulum

Cite this article as: Sozen S, Tuna O. A Rare Case of Perforated Meckel’s Diverticulum Presenting as a Gatrointestinal Stromal Tumor. Arch Iran Med. 2012; 15(5): 325 – 327.

Introduction of 114000/mL. Her Hiser white cell count was 15.2 × 109 (neutro- phils 12.1 × 109).On physical examination, there was abdominal eckel’s diverticulumis located on the antimesentric border tenderness, rebound, and increased bowel sounds in all quadrants. of theileum, approximately 45 to 60 cm proximal to the Plain abdominal X-rays were first obtained whenthe patient had M ileocecalvalve, and results from incomplete closure of the acute symptoms, which revealed air-fluid levels that suggested in- omphalomesentricor viteline duct.1Common complications pre- testinal obstruction(Figure 1). A palpable mass in the right lower sentingin adults include bleeding, obstruction, diverticulitis, and- quadrant was present.The patientunderwent surgery with a diagno- perforation. Tumors within a Meckel’s diverticulum are a rare but sis of plastrone appendicitis. A McBurney incision in the abdomen recognized complication. Meckel’s diverticulumis surgically re- was made;the appendix was normal. During surgery, a perforated moved only when a complication arises ora neoplasia develops. Meckel’s diverticulum was found, which was associated with free The tumors are infrequent andobserved only in 0.5% – 3.2% of the intra-abdominal fluid and hemorrhage (Figure 2). A 25 mm nodule Meckel’s diverticula.Of thesetumors, 12% are gastrointestinal was found at the apex of Meckel’s diverticulum. Theperforation stromal tumors(GISTs).2 of the diverticulum was also not associatedwith the tumor nodule. GISTs occurs predominantly in adults at a median age of58 years. At the subsequent laparotomy, 100 mm of small bowel was re- The majority of GISTs (60% to 70%) have been reported to arise sected and primary anastamosis performed. Histology confirmed in the stomach, whereas 20% to 30% originate in the small intes- a Meckel’s diverticulum with a 12 mm area of perforation. The tine, and less than 10% in the esophagus, colon, and rectum. GISTs histopathological examination of the resected lesion revealed a also occur in the extra-intestinal abdominopelvic sites such as the mesenchymal tumor which was categorized as a GIST tumor. The omentum, mesentery, andretroperitoneum.3,4 GISTs arising from stromal tumor demonstrated whirling sheets of spindle cells with Meckel’s diverticulum are extremely rare.5 a moderate level of pleomorphism and mitotic activity (6 – 7 mi- toses/50 HPF; H&E stain). No necrosis was observed. Immuno- Case Report histochemical staining for CD117, a-smooth-muscle actin (SMA), and S-100 protein was positive, whereas staining for desmin and A 62-yearold woman presented with peri-umbilical pain that had CD34 was negative(Figure 3). The labeling index for MIB-1, de- localized to the right iliac fossa. On examination, she was tender termined by counting positively stained nuclei, was about 5%.The in the right iliac fossa with localized peritonism. Hematologic tests postoperative period was unremarkable and she was discharged in showed decreased hematocrit (Ht: 22%) and a platelet (PLT) count good general condition.

Authors’ Affiliations: 1Kayseri Training and Research Hospital, Department of Discussion General Surgery. •Corresponding author and reprints: Selim Sozen MD, Kayseri Training and Research Hospital Department of General Surgery, Kayseri /Turkey. Meckel’s diverticulum is the most commonly encountered con- E-mail: [email protected]. genital anomaly of the small intestine, occurring in approximately Accepted for publication: 14 September 2011

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 325 S. Sozen, Ö. Tuna

Figure 1. Plain abdominal X-rays were first obtained in patient with acute Figure 2. A 25 mm nodule was found at the apex of Meckel’s diverticulum. symptoms, which revealed air-fluid levels suggestive of intestinal obstruction.

Figure 3. Immunohistochemical staining for CD117, a-smooth-muscle actin (SMA), and S-100 protein was positive, whereas staining for desmin and CD34 was negative.

2% of the population.6,7 GISTs, which arise primarily in the gut diverticula in adults to be bleeding (38%), obstruction (34%), di- wall, are uncommon mesenchymal,malignant, or potentially ma- verticulitis (28%) and perforation (10%).11 GISTs arise from the lignant tumors affecting the gastrointestinal tract. GISTs are the interstitial cells of Cajal, the pacemaker cells of the gastrointestinal most commonnon-epithelial tumors of the digestive tract, account- tract.8 GISTs strongly expresses the KIT (CD 117) protein and may ing for only 1% of all gastrointestinal malignancies.8,9 Primary harbor mutations of the type III tyrosine kinase receptorgene (either GISTs may occur anywhere along the gastrointestinal tract from KIT or PDGFRA).12 For many patients, detection of GISTs may be the esophagus to the anus.10 The most frequent site is the stom- an incidentalfinding during evaluation of nonspecific symptoms. ach (55%), followed by the duodenum and small intestine (30%), Symptoms tend to arise only when tumors reach alarge size or are esophagus (5%), rectum (5%), colon (2%), and rare other loca- in a critical anatomic location. Most symptomaticpatients present tions.The incidence of tumors within Meckel’s diverticulm is 0.5% with tumors larger than 5 cm inmaximal dimension. Symptoms to 3.2%.2 Most are commonly benign tumors such as leiomyomas, at presentation mayinclude abdominal pain, abdominal mass, nau- angiomas, and lipomas. Malignant neoplasms include adenocarci- sea, vomiting,anorexia, and weight loss. There are little prognostic noma (which commonly originate from the gastric mucosa), sar- data regarding GISTs and current prognostic indicators are based coma, carcinoid tumor, and GISTs. on consensus guidelines. The most important adverse factors are The most common presentation of GISTs is acute or chronic gas- thought to be a tumor diameter of greater than 5 cm and a high mi- trointestinal bleeding. They often present with nausea, vomiting, totic count exceeding 5 mitotic figures per 50 high powered fields abdominal pain, metastatic disease, and bowel obstruction. In our on light microscopy.12,13 Other suggested factors indicative of poor case, the patient presented with bowel obstruction and perforation. prognosisinclude tumor perforation, tumor necrosis, high cellular- In a large series of 1476 cases at the Mayo Clinic, Park et al. have ity, and marked pleiomorphism.12 reported the most common presentations of symptomatic Meckel’s Surgery is considered the standard treatment for non-metastatic

326 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 GIST

GISTs with enbloc resection and clear margins. The treatment of 353 – 357. choice is the complete resection of the tumour. The surgeon’s ap- 2. Yahchouchy E, Marano A, Etienne J, Fingerhurt A. Meckel’s diverticulum. J Am Coll Surg. 2001; 192: 658 – 662. proach in an actual case depends on factors such as: the exact ana- 3. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan tomical site of the GISTs, the characteristics of the individual pa- MF.Two hundred gastrointestinal stromal tumors: Recurrence patterns tient’s particular situation, and the specific location of the tumour and prognostic factors for survival. Ann Surg. 2000; 231: 51 – 58. relative to the blood supply of the involved organ. There is little ev- 4. Miettinen M, Lacosta J.Gastrointestinal stromal tumors definition, clinical, histological, immunohistochemical and molecular genetic idence to support local/regional lymphadenectomy as GISTs rarely features and differential diagnosis. Arch Pathol Lab Med. 2006; 130: metastasize to lymph nodes.12 Targeted therapy with imantinib, a 1466 – 1478. KIT tyrosine kinase inhibitor, is considered the standard treatment 5. Hager M, Maier H, Eberwein M, Klingler P, Kolbitsch C, Tiefenthaler for metastatic GISTs.12 In our case, the outcome has shown that W, et al. Perforated Meckel’s diverticulum presenting as a gastrointestinal stromal tumor:A case report. J Gastrointest Surg. 2005; 9: 809 the location is very important in determining the prognosis. Pa- – 811. tients with a small bowel localization do worse than those with 6. Haber JJ.Meckel’s diverticulum. Am J Surg.1947; 73: 468 – 485. stomach GISTs as reported by DeMatteo et al.14 In a case of a MD 7. Harkins HN.Intussusception due to invaginated Meckel’s diverticulum. Ann Surg.1933; 98: 1070 – 1095. (Meckel diverticulum) localization, treatment with imatinib me- 8. Nowain A, Bhakta H, Pais S, Kanel G, Verma S. Gastrointestinal stro- 15 sylate has been reported by Khoury et al., but the impact on the mal tumors: Clinical profile, pathogenesis, treatment strategies and clinical behavior of the disease has not been described. The case prognosis. J Gastroenterol Hepatol. 2005; 20: 818 – 824. reported by us has a low risk of recurrence based on characteristics 9. Eisenberg BL, Judson I. Surgery and imatinib in the management of GIST: Emerging approaches to adjuvant and neoadjuvant therapy. Ann of amaximum diameter of 2.5 cm, a low mitotic count of less than Surg Oncol. 2004; 11: 465 – 475. one mitotic figure in 10 × 40 high powered fields, and no evidence 10. Judson I. Gastrointestinal stromal tumors (GIST): Biology and treat- of necrosis. Importantly, the perforation of the diverticulum was ment. Ann Oncol. 2002; 13: 4287 – 4289. also not associated with the tumor nodule. 11. Park J, Wolff B, Tollefson M, Walsh E, Larson D. Meckel diverticulum. The Mayo Clinic experience with 1476 patients (1950 – 2002). Ann Surg. 2005; 241: 529 – 533. Conclusion 12. Joensuu H. Gastrointestinal stromal tumor (GIST). Ann Oncol. 2006; 10: 280 – 286. 13. Chang M, Choe G, Kim W, Kim Y. Small intestine stromal tumors: GISTs arising from Meckel’s diverticulum are an extremely rare A clinicopathological study of 31 tumors. Pathol Int. 1998; 48: 341 5 but recognized complication. Surgery is considered thestandard – 347. treatment for non-metastatic GISTs with enblocresection and clear 14. Dematteo RP, Gold JS, Saran L, Gönen M, Liau KH,Maki RG, et al. margins. Tumormitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Can- cer. 2008; 112(3): 608 – 615. 15. Khoury MG, Aulicino MR. Gastrointestinal stromal tumor (GIST) References presenting in a Meckel’s diverticulum. Abdom Imaging. 2007; 32: 78 – 80. 1. Dumper J, Mackenzie S, Mitchell P, Sutherland F, Quan ML, Mew D. Complications of Meckel’s diverticula in adults. Can J Surg. 2006; 49:

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 327 M. Mokhtari, S. Zeraatian Nejad Davani

Case Report Primary Adrenal Hydatid Cyst Presenting with Arterial Hypertension

Maral Mokhtari MD•1, Sam ZeraatianNejadDavani MD2

Abstract Hydatid disease is an endemic illness in some countries. The main sites of involvement are the liver and lungs, but rarely,it can be seen in other organs as well. Herein, we report a case of primary adrenal hydatid cyst accompanied by arterial hypertension.

Keywords:Adrenal gland, hydatid cyst, hypertension

Cite this article as: Mokhtari M, ZeraatianNejad Davani S. Primary Adrenal Hydatid Cyst Presenting with Arterial Hypertension. Arch Iran Med. 2012; 15(5): 328 – 330.

Introduction pain with radiation to her back. She had a 2-year history of arterial hypertension (systolic 150 – 170 and diastolic 95 – 105) and ydatid disease is a parasitic disease most commonly caused was on anti-hypertensive medications. Physical examination was by the larval stage of the tapeworm Echinococcus granulo- unremarkable except for a blood pressure of 150/95. Laboratory H sus.1 Humans may become intermediate hosts through con- examinations that included hematological and biochemical stud- tact with a definitive host or by ingestion of contaminated water or ies were within normal limits. As a part of the diagnostic workup, vegetables.2 abdomeno pelvic computed tomography scan (CT scan) and plain In humans, eggs hatch and embryos migrate through the intesti- chest X-ray were performed. Chest X-ray was unremarkable; how- nal mucosa before entering the portal circulation, causing hepatic ever the abdominal CT scan showed a solitary lesion measured 5 hydatid disease. If embryos bypass the liver, they can reach the cm with coarse calcification in the right adrenal gland (Figure1). pulmonary circulation via the inferior vena cava, forming cysts in The other organs were unremarkable. Due to the possibility of the lungs.2–5 The most frequent sites of hydatid cyst involvement pheochromocytoma,the urine catecholamine level was measured are the liver (45% – 75%) and lungs (10% – 50%).4 Embryos may which was normal. The patient underwent open laparotomy and a reach other organs or tissues in the body via the systemic circula- right adrenalectomy was performed. tion. These unusual sites include the brain, muscles, kidneys, heart, Gross examination revealed a thick-walled, calcified cystic mass adrenals, and numerous other sites, all of which may cause preop- filled with an amorphous, fragile, creamy-white material measured erative diagnostic difficulties.1 5.5×5 cm(Figures 2 A,B). Microscopic study showed a calcified The hydatid cyst wall has 3 layers of which the outermost layer cyst that had a fibrous wall with no epithelial lining. The cyst was is the pericyst, the middle layer is the laminated membrane, and filled with a pink amorphous material that contained rare hooklet the innermost layer is called the endocyst or germinal epithelium.1 of echinococcus granulosus (Figures 3 A, B, C). Localization of the hydatid cyst in the adrenal glands is very rare The histologic diagnosis was primary adrenal hydatid cyst. (less than 1% of all cases).4,5 Most reported cases have been dis- The post-operative period was uneventful and the patient was covered incidentally, but some adrenal hydatid disease has been discharged with normal blood pressure. Thus anti-hypertensive reported to coexist with arterial hypertension.4–9 There are a few medications were discontinued.During the following 3 months, reports of adrenal hydatid cyst presenting with symptoms sugges- the patient remained normotensive. tive of pheochromocytoma(episodes of headache, sweating, palpi- tations, and hypertension).5 Discussion Herein we report a case of primary adrenal hydatidosis,accompanied by arterial hypertension. Hydatid disease is a parasitic disease, endemic in Iran and some countries. Cysts located in organs other than the liver and lungs are Case report usually manifestation of generalized disease.4 Adrenal gland involvement may be due to secondary spread re- A 66-year-old female referred to the Surgical Department at sulting from spontaneous or intra-operative rupture of a primary Fasa University of Medical Scienceswith complaints of right flank cyst, but the primary hydatid cyst of the adrenal gland is a rare event.2 Cysts of the adrenal glands are usually unilateral (90%) and Authors’ Affiliations:1Department of Pathology, Shiraz University of Medical show no special predilection for either side.4 2 Sciences, Shiraz, Iran, Department of Surgery, Fasa University of Medical Sci- Adrenal hydatid disease is slow-growing, therefor it isusually an ences, Fasa, Iran. •Corresponding author and reprints:Maral Mokhtari MD, Pathology incidental discovery. When symptoms are present they are related Department,Shiraz University of Medical Sciences, Shiraz, Iran. to visceral compression. The most prominent features are flank Fax: +987112301784, E-mail: [email protected]. pain, gastrointestinal symptoms (bloating, nausea, vomiting, con- Accepted for publication: 12 October 2011

328 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Primary adrenal hydatid cyst and arterial hypertension

Figure 1. Abdominal CT scan shows a calcified mass in the right adrenal gland.

(A) (B) Figures 2 A,B. Large cystic adrenal mass filled with chalky white material. stipation, and anorexia) and a palpable mass.2,7Rarely, hydatid cyst the number of cysts, and possible complications.2 coexists with arterial hypertension and is referred to as Goldblatt’s In radiologic modalities calcification is seen in about 20% of hy- phenomenon which may be caused by external compression of the datid cysts and its presence in an adrenal mass is suggestive of renal artery by the cyst.3Some hypertensive patients have normal hydatid cyst.2 blood pressure after surgical removal of the hydatid cyst, as in The complications of adrenal hydatid disease include rupture, fis- our patient, however presence of adrenal hydatid cyst as the sole tula formation, hemorrhage, and anaphylactic shock.2,7 etiology of the hypertension is controversial .Some authors have Differential diagnosis of an adrenal cyst include endothelial cyst, reported that the hypertension may continue even after complete pseudocyst, cystic neoplasms such as lymphangioma, post-trau- resection of the cyst.9 matic cyst, cystic pheochromocytoma, abscess, and other congeni- Nouria et al.5 have reported a case of adrenal hydatid cyst with tal or acquired cysts.2,4 cardinal symptoms of pheochromocytoma and elevated Vanillyl- mandelic acid (VMA) level. They suggested that the elevation of Conclusion catecholamine may be due to compression of the adrenal medulla by the cyst leading to catecholamine release. Primary hydatid cyst of the adrenal gland is a rare disease that In our case the urine VMA was within normal limits so the pres- may mimic many adrenal lesions, therefore it should be consid- sure effect on the adrenal medulla was a remote possibility. Com- ered in the differential diagnosis of all adrenal cysts, particularly pression of the renal artery may be the responsible cause of hyper- in endemic areas. This can be rarely accompanied by arterial hy- tension because of normalization of blood pressure after surgery. pertension as well as adrenal pheochromocytoma.Although imag- Serological studies may help to diagnose hydatid cyst but they ing studies assist with diagnosis, however the exact nature of the lack sensitivity and specificity. Imaging studies such as ultrasound, adrenal hydatid cyst requires histologic examination. CT scan and MRI can assist with diagnosis, site of involvement,

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 329 M. Mokhtari, S. Zeraatian Nejad Davani

(A) (B) Figures 3A,B. Fibrosed, calcified cyst wall with remnants of the adrenal cortex. H & E 100x, 400x.

Figure3C. Hooklet of echinococcus granulosus.H & E, oil immersion.

References hydatid cyst presenting as a phaeochromocytoma. BJU International. 2000; 86(6): 754. 6. Escudero M, Sabater L, Calavete J, Camps B, Labios M, Liedo S. Arte- 1. Yuskel M, Demirplat G, Sever A, Bakris S, Bulbuloglu E, Elmas rial hypertension due to primary adrenal hydatid cyst. Surgery. 2002; N.Hydatiddisease involving some rare locations in the body: Apictorial 132(5): 894 – 895. essay. Korean J Radiol. 2007; 8: 531 – 540. 7. Ozarmagan S, Erbil Y, Barbaros U, Salmaslioglu A, Bozbora A. Pri- 2. Sallami S, Ben Rhouma S, Horanchi A. Primary adrenal hydatid cyst: mary hydatid disease in the adrenal gland: A case report. Braz J Infect A case report. Ibnosina J Med BS. 2010; 2(1): 38 – 41. Dis2006; 10 (5): 362 – 363. 3. Abdulmajed M, Resorlu B, Kara C, Turkolmez K. Isolated primary hy- 8. Gurbuz R, Guven S, Klinc M, AbasiyanikF, Gokce G, Peskin M. Pri- datidcyst of adrenal gland: A case report. Turkish Journal of Urology. mary hydatid cyst in adrenal gland: A case report. Int Urol Nephrol. 2010; 36(2): 211 – 215. 2005; 37: 21 – 23. 4. Dionigi G, Carrafiello G, Recaldini C, Sessa F, Boni L, Rovera F, et al. 9. Safioleas MC, Moulakakis KG, Kostaksis A. Coexistence of primary Laparoscopic resection of a primary hydatidcyst of the adrenal gland: adrenal hydatid cyst and arterial hypertension: Reports of a case and A case report. J Med Case Reports. 2007; 1: 61 . review of the literature. Acta Chir Belg. 2006; 106: 719 – 721. 5. Nouria Y, Benyounes A, Kbaier I, Attyaoui F, Horanchi A. Adrenal

330 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Primary Intrathoracic Synovial Sarcoma

Case Report Primary Intrathoracic Biphasic Synovial Sarcoma

Yilmaz Tezcan MD•1, Mehmet Koc MD1, Husnu Kocak MD2, Yusuf Kaya MD2

Abstract Synovial sarcomas are most frequently observed in the extremities. Although synovial sarcomas are the third most common histological type of soft-tissue sarcomas of the extremities, primary mediastinal synovial sarcoma is extremely rare. Monophasic synovial sarcoma is the most commonly observed subtype. whereas the biphasic subtype is less common. We present our case which was diagnosed as biphasic synovial sarcoma located in the anterior mediastinum, which is considered to be a rare entity. The patient underwent surgical resection together with multimodal adjuvant radiotherapy and chemotherapy.

Keywords: Chemotherapy, prognosis, radiotherapy, synovial sarcoma

Cite this article as: Tezcan Y, Koc M, Kocak H, Kaya Y. Primary Intrathoracic Biphasic Synovial Sarcoma. Arch Iran Med. 2012; 15(5): 331 – 332.

Case Report Adjuvant radiotherapy was planned for the patient due to close surgical margins, young age, and tumor size (13 cm). A total of 66 Our case was a 38-year-old married female who presented with Gy adjuvant radiotherapy was applied to the primary tumor and complaints of cough, dyspnea, pain, and fatigue for 2 – 3 months. consisted of an initial 50 Gy (Phase I) dose with a boost of 16 Gy PA chest radiography revealed a mass in the anterior and left side (Phase II), followed by adjuvant chemotherapy with 4 cycles of if- mediastinum (Figure 1). A subsequent CT scan of the thorax osfamide and adriablastin. The treatments were well tolerated and showed a soft tissue mass, 13 – 14 cm in diameter, in the anterior the patient was observed each 3 months for follow up visits. A tho- and left side mediastinum (Figure 2). The same mass was verified rax CT performed 6 months after treatment end did not reveal any by an MRI of the thorax (Figure 3). Following routine examina- pathological findings (Figure 4). After approximately 36 months (3 tions, the patient underwent a left thoracotomy with complete exci- years), the patient was lost due to disease progression. sion of the mediastinal mass. The surgical procedure was as follows: the patient was placed Discussion on her right side with one arm raised. An incision was made on the skin of the rib cage. Muscle layers were cut and a rib removed Primary mediastinal synovial sarcomas are extremely rare in to gain access to the cavity. Retractors were used to hold the ribs the thorax and lungs. Primary pulmonary sarcomas account for < apart, exposing the tumor. The tumor and capsule were removed 0.5% of lung cancers.1 However, an increase has been observed in intact after which the layers of the skin, muscle, and other tissu- these tumors in recent years.2 Leiomyosarcomas, fibrosarcomas, es were closed with stitches and staples. Next, the chest wall was and hemangiopericytomas are the most common types of primary closed. The left thoracotomy procedure was completed without pulmonary sarcomas.3 Primary pulmonary and mediastinal syno- complication. vial sarcomas are more aggressive than soft tissue synovial sarco- The pathology specimen consisted of a tumor that resembled mas. While biphasic synovial sarcomas arise in the pleural cavity,4 encapsulated grey-white soft tissue, which macroscopically mea- most are localized within the pulmonary parenchyma5 and rarely sured 13×12×8 cm. There were groups of cells that had oval nu- extend into the bronchial structures.6 Mediastinal lymphadenopa- clei, fusiform cytoplasm, and malignant tumor that consisted of thy is rare.7 solid masses of epithelioid cells with wide eosinophilic cytoplasms Synovial sarcomas are histologically classified into four types: and oval, pleomorphic nucleus . Focal necrosis was present in the biphasic, monophasic fibrous, monophasic epithelial, and poorly tumor and mitotic activity was found to be 2/10 BBA. Tumor cells differentiated. Monophasic synovial sarcoma is the most common- stained positive in solid epithelioid areas with cytokeratin; focal ly observed subtype, and studies show that epithelial components staining was observed with S100, CD99, and cytokeratin 7. Based of biphasic tumors are surrounded by pneumocytes. Direct chest on histomorphological and immunohistochemical findings, the radiography is used primarily for diagnosis where the lesion pres- case was diagnosed as biphasic synovial sarcoma. According to ents a typically uniform view with well-circumscribed rounded or postoperative TNM staging, this case was staged as T2bN0M0. lobulated borders.7–8 Some patients have mediastinal shift. Bilat- eral pleural effusion is common. CT scan is more sensitive than Authors’ Affiliations: 1Selcuk University, Meram Faculty of Medicine, Depart- chest radiography for detecting calcified tumor matrix and corti- ment of Radiation Oncology, Konya, Turkey, 2Mersin State Hospital, Department cal destruction.9 These tumors are less vascular and MRI imaging of Thoracic Surgery, Mersin, Turkey. •Corresponding author and reprints: Yilmaz Tezcan MD, Selcuk University, presents three findings (clear, dark, and grey) that reflect tumor, Meram Faculty of Medicine, Department of Radiation Oncology , 42090-Konya, hemorrhage, and necrosis.10 Clinically, patients may show varied Turkey. Tel: 0332-2236942 , Fax: 0332-2236182, symptoms such as cough, dyspnea, chest pain, and fatigue depend- E-mail: [email protected]. Accepted for publication: 16 November 2011 ing on the size and extent of the mass.

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 331 Y. Tezcan, M. Koc, H. Kocak, et al.

Figure 1. PA chest radiography prior to treatment. Figure 2. CT scan of the thorax prior to treatment.

Figure 3. Thorax MRI prior to treatment. Figure 4. Thorax CT scan performed 6 months after the treatments

CT-guided needle biopsy is adequate for diagnosis. Prognosis is study of 12 cases. Lung Cancer. 2002; 38: 283 – 289. related to the phase of the disease, and is generally poor. The five- 4. Gaertner E, Zeren EH, Fleming MV, Colbay TV, Travis WD. Bipha- 3 sic synovial sarcomas arising in the pleural cavity. A clinicopathologic year survival rate is between 36 – 76%. study of five cases.Am J Surg Pathol. 1996; 20: 36 – 45. Tumor size (≥ 9 cm), male patients, over the age of 20 years, the 5. Zeren H, Moran CA, Suster S, Fishback NF, Koss MN. Primary pul- presence of extensive tumor necrosis, high grade, large number of monary sarcomas with features of monophasic synovial sarcoma: A mitosis (> 9 – 10), neurovascular invasion, and in recent years, the clinicopathological, immunohistochemical, and ultrastructural study of 25 cases. Hum Pathol. 1995; 26: 474 – 480. presence of the SYT-SSX1 variant can be listed as poor prognostic 6. Essary LR, Vargas SO, Fletcher CD. Primary pleuropulmonary sy- factors.11 Complete resection is mentioned as the most significant novial sarcoma: Reappraisal of a recently described anatomic subset. prognostic factor in a meta-analysis. This meta-analysis has shown Cancer. 2002; 94: 459 – 469. that the application of adjuvant radiotherapy and adjuvant chemo- 7. Duran Mendicuti A, Costello P, Vargas SO. Primary synovial sarcoma of the chest: Radiographic and clinicopathologic correlation. J Thorac therapy following complete surgical resection prolongs the time of Imaging. 2003; 18: 87 – 93. local recurrence and survival without recurrence, and accordingly 8. Zaring RA, Roepke JE. Pathologic quiz case. Pulmonary mass in a causes an increase in total survival rate.12,13 patient presenting with a hemothorax. Diagnosis: Primary pulmonary biphasic synovial sarcoma. Arch Pathol Lab Med. 1999; 123: 1287 – Synovial sarcomas are tumors which have moderate chemosensi- 1289. tivity, with about 50% response rates to regimens containing ifos- 9. Tateishi U, Gladish GW, Kusumoto M, Hasegawa T, Yokoyama R, famide and doxorubicin.14 Radiotherapy is recommended in cases Moriyama N. Chest wall tumors: Radiologic findings and pathologic with positive margins.15 correlation: Part 2. Malignant tumors. Radiographics. 2003; 23: 1491 – 1508. In summary, we have presented a rare case of biphasic synovial 10. Frazier AA, Franks TJ, Pugatch RD, Galvin JR. From the archives of sarcoma located in the anterior mediastinum. In these rarely ob- the AFIP: Pleuropulmonary synovial sarcoma. Radiographics. 2006; served cases, survival can be increased through complete resection 26: 923 – 940. and aggressive multimodal treatments. 11. Trassard M, Le Doussal V, Hacène K, Terrier P, Ranchère D, Guillou L, et al. Prognostic factors in localized primary synovial sarcoma: A multicenter study of 128 adult patients. J Clin Oncol. 2001; 19: 525 – 534. References 12. Dennison S, Weppler E, Giacoppe G. Primary pulmonary synovial sarcoma: A case report and review of current diagnostic and therapeutic 1. Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer. 1995; 75: standards. Oncologist. 2004; 9: 339 – 342. 191 – 202. 13. Mankin HJ, Hornicek FJ. Diagnosis, classification, and management of 2. Roberts CA, Seemayer TA, Neff JR, Alonso A, Nelson M, Bridge JA. soft tissue sarcomas. Cancer Control. 2005; 12: 5 – 21. Translocation (X; 18) in primary synovial sarcoma of the lung. Cancer 14. Albritton KH, Randall RL. Prospects for targeted therapy of synovial Genet Cytogenet. 1996; 88: 49 – 52. sarcoma. J Pediatr Hematol Oncol. 2005; 27: 219 – 222. 3. Etienne-Mastroianni B, Falchero L, Chalabreysse L, Loire R, Ranchere 15. Al-Rajhi N, Husain S, Coupland R, McNamee C, Jha N. Primary peri- D, Souquet PJ, et al. Primary sarcomas of the lung: A clinicopathologic cardial synovial sarcoma: A case report and literature review. J Surg Oncol. 1999; 70: 194 – 198.

332 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Photoclinic

Photoclinic

Figure 1. Hepatic portal venous gas (arrowheads).

Figure 2. Air in the soft tissue around the sigmoid colon and rectum (arrows) consistent with pneumatosis intestinalis.

Cite this article as: Jarmakani MF, Mohebbi MR. Photoclinic. Arch Iran Med. 2012; 15(5): 333 – 334.

A 63-year-old female was admitted with complaints of pain in mission, diabetes mellitus, chronic obstructive pulmonary disease, the lower abdominal quadrants. Her past medical history was sig- rheumatoid arthritis, coronary artery disease, and hypercholester- nificant for gangrenoussmall bowel resected 2 months prior to ad- olemia. Laboratory results included a wbc count of 28150/mm3 with a significant left shift, Hgb of 9.6, BUN of 23 and Cr of 1.6. Morwan F. Jarmakani MD1, Mohammad R. Mohebbi MD•2 Abdominal CT scan showed evidence of air in the portal system 1 2 Authors’ affiliations: Department of Rediology, Mercy Medical center, Sioux- and liver (Figure 1, arrowheads). land Medical Education Foundation-University of Iowa. •Corresponding author and reprints: Mohammad R. Mohebbi MD, Siouxland Medical Education Foundation-University of Iowa, 2501 Pierce Street, Sioux City, Iowa, 51104, USA. Tel: +1-712-294-5000, Fax: +1712-294-5092, What is your diagnosis? E-mail: [email protected]. Accepted for publication: 16 November 2011 See the next page

Archives of Iranian Medicine, Volume 15, Number 5, May 2012 333 M.F. Jarmakani, M. R. Mohebbi

Photoclinic Diagnosis: Hepatic Portal Venous Gas in a Case of Ischemic Necrotic Colon

Abdominal CT scan showed evidence of air in the soft tissue with the centripetal flow of bile, thus appearing more centrally in around the sigmoid colon and rectum (Figure 2, arrows) consistent the liver.1 In our case, we believe that the gas in the portal vein with pneumatosis intestinalis. The patient underwent resection of was due to the ischemia and necrosis of the sigmoid colon with re- the sigmoid colon which confirmed an ischemic, necrotic bowel. sultant mucosal damage and pneumatosis intestinalis. A repeat CT Air in the liver can be either in the portal venous system or the scan of the abdomen 2 weeks after resection of the necrotic colon hepatobiliary tree. The appearance of gas in the portal venous sys- did not show evidence of air in the portal system. tem in adults is usually a sign of lethal conditions such as intestinal infarction. It has been described in association with a variety of References pathologic conditions that include intestinal ischemia and necrosis (75%), ulcerative colitis (8%), and intra-abdominal abscess (6%).1,2 1. Peloponissios N, Halkic N, Pugnale M, Jornod P, Nordback P, Meyer Patients with hepatic portal venous gas have an overall survival A, et al. Hepatic portal gas in adults: Review of the literature and pre- 2 sentation of a consecutive series of 11 cases. Arch Surg. 2003; 138: rate of less than 25%. Portal venous gas has also been observed 1367 – 1370. following endoscopic retrograde cholangiopancreatography and 2. Liebman PR, Patten MT, Manny J, Benfield JR, Hechtman HB. Hepat- endoscopic sphincterotomy with a subsequent uneventful course.3 ic portal venous gas in adults: Etiology, pathophysiology, and clinical Gas in the portal venous system is carried by the centrifugal flow significance.Ann Surg. 1978; 187: 281 – 287. 3. Simmons TC. Hepatic portal venous gas due to endoscopic sphincter- of blood in the periphery of the liver, appearing to extend to within otomy. Am J Gastroenterol. 1988; 83: 326. 2 cm of the hepatic capsule. Inversely, gas in the biliary tract moves

334 Archives of Iranian Medicine, Volume 15, Number 5, May 2012 Excerpts from Persian Medical Literature

Excerpts from Persian Medical Literature Investigation of Periodontal Conditions in Patients with Rheumatoid Arthritis Periodontal disease with alveolar bone resorption and tooth loss is common in rheumatoid arthritis (RA). RA subjects show inadequate plaque control due to physical disabilities as well as a compromised immune response, both of which might result in a greater predisposi- tion to periodontal disease in these subjects compared to the normal population. This study aims to evaluate the prevalence of periodontal disease among RA patients. Periodontal status (plaque, index, papillary bleeding index, and missing teeth) was examined in 70 individuals that included 35 patients with active RA and 35 healthy individuals as the control group. The results were analyzed using SPSS software and student’st-test. Patients with RAcomprised 31 females (88.6%) and 4 males (11.4%) with a mean age of 45 years. The healthy control group included 26 females (74.3%) and 9 males (25.7%) with a mean age of 37 years. Patients with RA showed significant increases in plaque index (P=0.0001), papillary bleeding index (P=0.002),and number of missing teeth (P=0.03) compared to the control group. Three patients also had secondary Jorgen’ssyndrome. Patients with RA had more periodontal disorders compared to the control group. The effects of this chronic inflammatory disease and immune host deficiency could be attributed to the presence of a physical disability which precludes the maintenance of oral health and the gingival effects of anti-rheumatic medications. Authors:Taheri M, Saghafi M,Najafi MH,Radvar M, Marjani S, Javanbakht A, Baghani Z. Source: J Mash Dent Sch.2011; 35(4): 283 – 288.

Effects of Stress Management Training on Glycemic Control in Women with Type 2 Diabetes Diabetes is a complicated disease which often leads to a number of psychological disorders such as stress, anxiety, and depression. Complete treatment of this disease requires psychological assessment and cognitive behavioral therapy. The purpose of this research is to study the effects of stress management training on glycemic control, stress, depression, and anxiety in women with type 2diabetes. The study population consisted of 46 type 2 diabetic women, aged 32–65 years, matched for age and additional criteria considered in this research. Subjects were randomly divided into two groups, experimental (n=23) and control (n=23). We assessed depression, anxiety, and stress by the DASS scale. HbA1c levels for all patients were measured prior to intervention. The experimental group underwent 12 sessions of stress management based on the cognitive-behavior method, which was conductedfor 2 hours each week, after which patients were again assessed for DASS and HbA1c, and after 6 months as the follow up period in both groups. There was a significant difference between experimental and control groups in HbA1c levels. The rate of HbA1c in the experimental group significantly decreased compared to controls P( <0.001).There was a significant difference between the groups in DASS scores and HbA1c levels afterthe final intervention session and the 6 month follow up P( <0.001). It is recommended that cognitive behavior therapy be considered as an addition to treatment programs for type 2 diabetic patients. Authors: Hamid N. Source:Iranian Journal of Endocrinology and Metabolism. 2011; 13(4):346 – 353.

Seroepidemiology Study of Hepatitis E Virus Infection in Tehran Province: A Population-Based Study Hepatitis E virus (HEV) is the second most prevalent agent of acute hepatitis in adults after hepatitis B. The transmission routeforthis infection is fecal-oral. There are limited studies on epidemiology of this virus in the Iranian general population. In this study, we have evaluated the prevalence of hepatitis E infection amongthe general population of some of the towns located in Tehran Province, in addition to the eastern and northern sections ofthe city of Tehran, Iran. In this cross-sectional study conducted during 2006 and 2007, 501 subjects were selected by random cluster sampling from Tehran Province. Demographic data (questionnaire) and blood samples were collected;anti-HEV antibodies were measured by ELISA. Chi- square, logistic regression, and t-tests were used for statistical analysis. Of the total 493 subjects with a mean age of 40.98 ± 17.10, there were180 males and 313 females. Of these, 48 (9.7%) were positive for anti-HEV antibody. There were no significant differences in HEV seropositivity compared to sex or age. The prevalence in Tehran Province was high, which indicated the endemic state of this infection in the studied population. The results were similar to those from the eastern section of Golestan Province, yet contradict results from Isfahan Province. Authors:Mohebbi SRI, Rostaminejad M, Ebrahim Tahaei SM, Pourhoseingholi MA, Habibi M, Azimzadeh P, et al. Source:The Journal of Urmia Nursing and Midwifery Faculty. 2012; 9(6): 457 – 463.

Prophylactic Effect of Dexamethasone on Postoperative Nausea and Vomiting in Patients Undergoing StapedectomySurgery Nausea and vomiting are considered among the most common complications that follow middle ear surgery, andare the basis for the incidence of additional adverse consequences. This study aims to evaluate the effect of 16 mg prophylactic intravenous dexamethasone on postoperative nausea and vomiting after stapedectomy. In a randomized, double-blind controlled study we divided 70 patients who were candidates for stapedectomy into 2 equal groups, using the same sedation administered by one surgeon. While the case group received 16 mg dexamethasone 30 minutes before surgery, the control group received 4ml intravenous saline as a placebo. Patients were controlled 1–24 hours after surgery in terms of nausea and vomiting, and dependent variables such as vertigo and tinnitus. In this study, 70 patients (38 females, 32 males) were enrolled. The rate of postoperative nausea and vomiting in the case group was 31.4% (11 patients) and the control group was 60% (21 patients), which was statistically significant P( = 0.03). Prophylactic use of 16 mg intravenous dexamethasone half an hour before surgery can significantly reduce the incidence of nausea and vomiting following stapedectomy. Authors: Khorsandi Ashtiani MT, Mokhtari Z, Hajimohammadi F, Ghadirian L. Source:Journal of Medical Council of Islamic Republic of Iran. 2011;3: 284 – 291.

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