ANTXR1 (TEM8) overexpression in gastric adenocarcinoma makes the protein a potential target of immunotherapy.

BACKGROUND: Despite the promise of immunotherapy for gastric adenocarcinoma, choices for the selection of effective antigenic targets are very limited. Previously published data and our own in-house computational analysis have suggested that ANTXR1 is a potential target, simultaneously expressed in malignant tumor cells and the endothelial cells of the tumors. However, the expression pattern of ANTXR1 protein in clinical samples of gastric adenocarcinoma has not been fully evaluated. METHODS: Using immunohistochemistry (IHC), we recorded the percentage of ANTXR1 positive cells separately in tumor cells and endothelial cells in the primary tumor, non-tumor gastric tissue adjacent to the primary tumor, and tumor in metastatic sites of 140 gastric adenocarcinoma patients. We also evaluated the association of ANTXR1 expression with the Lauren histological classification of the primary tumors, the patient's history of neoadjuvant chemotherapy and/or radiotherapy, and the patient's overall survival. RESULTS: ANTXR1 was expressed in a mean of 73.89 ± 30.12% of tumor cells and 13.55 ± 20.53% of endothelial cells in the primary tumors. Intestinal adenocarcinomas had lower ANTXR1 expression in the tumor cells and higher ANTXR1 expression in the endothelial cells of the tumor regions, and a history of neoadjuvant therapy was associated with increased ANTXR1 expression in the endothelial cells of the tumor regions. Finally, above median expression of ANTXR1 in the tumor cells of the tumor regions was associated with significantly lower overall patient survival. CONCLUSIONS: Our findings suggest that ANTXR1 is a promising candidate for preclinical and clinical evaluation for gastric adenocarcinoma immunotherapy.

Mortality from respiratory diseases associated with opium use: a population-based cohort study.

BACKGROUND: Recent studies have suggested that opium use may increase mortality from cancer and cardiovascular diseases. However, no comprehensive study of opium use and mortality from respiratory diseases has been published. We aimed to study the association between opium use and mortality from respiratory disease using prospectively collected data. METHODS: We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50 045 adults were enrolled from 2004 to 2008, and followed annually until June 2015, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest. RESULTS: During the follow-up period, 331 deaths from respiratory disease were reported (85 due to respiratory malignancies and 246 due to non-malignant aetiologies). Opium use was associated with an increased risk of death from any respiratory disease (adjusted HR 95% CI 3.13 (2.42 to 4.04)). The association was dose-dependent with a HR of 3.84 (2.61 to 5.67) for the highest quintile of cumulative opium use versus never use (Ptrend<0.001). The HRs (95% CI) for the associations between opium use and malignant and non-malignant causes of respiratory mortality were 1.96 (1.18 to 3.25) and 3.71 (2.76 to 4.96), respectively. CONCLUSIONS: Long-term opium use is associated with increased mortality from both malignant and non-malignant respiratory diseases.

Phenotyping and follow up of forty-seven Iranian patients with common variable immunodeficiency.

BACKGROUND: Common variable immune deficiency (CVID) is a heterogeneous syndrome with a wide variety of signs and symptoms. This study describes the phenotyping and survival of the CVID patients in the allergy and clinical immunology department of Rasol-E-Akram Hospital of Iran University of Medical Sciences in Tehran. METHOD: We retrospectively reviewed hospital files of CVID patients in our department until January 2014. All patients were diagnosed with standard diagnostic criteria of CVID, treated and visited monthly, during the follow-up period. We divided the patients into four phenotypes; infection only, cytopenia, polyclonal lymphocytic infiltration and unexplained enteropathy. The immunologic, demographic and clinical findings in different phenotypes were analysed. RESULTS: The study included 47 CVID patients with mean age at onset of symptoms and diagnosis of 11.2 and 20.2 years, respectively. Phenotyping of our patients was: only infection (62%), cytopenia (26%) and PLI (19%) and 94% of cases had only one phenotype. We did not find a significant relation between the clinical phenotypes and immunologic or demographic data. Rate of parental consanguinity in our cases was 47%. Parental consanguinity was related to lower age at onset, lower age at diagnosis and higher baseline IgG levels. Patients with malignancy and autoimmunity had significantly higher age at onset. Our patients were followed-up for 6.9 years and the mortality rate during this time was 6%. CONCLUSIONS: Parental consanguinity and age at onset of CVID symptoms may have important roles in CVID manifestations.

Contact with ruminants is associated with esophageal squamous cell carcinoma risk.

The etiology of esophageal squamous cell carcinoma (ESCC) in the high risk area of northern Iran is only partially known. We aimed to investigate prolonged animal contact as a risk factor for ESCC in this population. From 2003 to 2007, we administered a validated questionnaire to 300 ESCC cases and 571 randomly selected controls matched for neighborhood of residence, age (±2 years) and sex. Questions on lifelong exposure to equines, ruminants, canines, and poultry, including duration and level of contact, were asked in a face-to-face interviews. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. A total of 94.7% of cases and 68.7% of controls reported lifelong history of contact with ruminants. After controlling for potential confounders, contact with ruminants was associated with an eightfold increase (95% CI: 3.92-14.86) in risk of ESCC, and increments in duration of contact raised the risk estimates in a dose-dependent manner. Contact with equines and poultry did not significantly change associated OR for ESCC risk and contact with ruminants. OR (95% CI) for contact with canines was 1.99 (1.35-2.93) which after exclusion of contact with ruminants was not significant (OR for contact only with canine: 3.18, 95% CI: 0.73-13.17). These results add to the evidence that contact with ruminants may increase the risk of ESCC.

Opium use: an emerging risk factor for cancer?

An estimated 16·5 million people worldwide illicitly use opiates, of whom 4 million use raw opium. We did a systematic review to investigate the association between opium use and cancer incidence and mortality. Opium use was associated with an increased risk of cancers of the oesophagus, stomach, larynx, lung, and urinary bladder. Although the present evidence suggests that these associations are possibly causal, further epidemiological studies (particularly prospective studies that collect detailed data about lifetime opium use and control for a broad range of potential confounders) are needed.

EBV-Associated Gastric Cancer; An In Situ Hybridization Assay on Tissue Microarray: A Multi-Region Study from Four Major Provinces of Iran.

BACKGROUND: Gastric cancer is the fourth leading cause of cancer-related deaths in the world. The identification of gastric cancer subtypes related to recognizable microbial agents may play a pivotal role in the targeted prevention and treatment of this cancer. The current study is conducted to define the frequency of Epstein-Barr virus (EBV) infection in gastric cancers of four major provinces, with different incidence rates of gastric cancers, in Iran. METHODS: Paraffin blocks of 682 cases of various types of gastric cancer from Tehran, South and North areas of Iran were collected. Twelve tissue microarray (TMA) blocks were constructed from these blocks. Localization of EBV in tumors was assessed by in situ hybridization (ISH) for EBV-encoded RNA (EBER). Chi-squared test was used to evaluate the statistical significance between EBV-associated gastric cancer (EBVaGC) and clinicopathologic tumor characteristics. RESULTS: Fourteen out of 682 cases (2.1%) of gastric adenocarcinoma were EBER-positive. EBER was positive in 8 out of 22 (36.4%) of medullary carcinomas and 6 out of 660 (0.9%) of non-medullary type, which was a statistically significant difference (P<0.001). The EBVaGCs were more frequent in younger age (P=0.009) and also showed a trend toward the lower stage of the tumor (P=0.075). CONCLUSION: EBV-associated gastric adenocarcinoma has a low prevalence in Iran. This finding can be due to epidemiologic differences in risk factors and exposures, and the low number of gastric medullary carcinomas in the population. It may also be related to gastric tumor heterogeneity not detected with the TMA technique.

A population-based prospective study on obesity-related non-communicable diseases in northern Iran: rationale, study design, and baseline analysis.

Background: Iran is facing an epidemiological transition with the increasing burden of non-communicable diseases, such as obesity-related disorders and cardiovascular diseases (CVDs). We conducted a population-based prospective study to assess the prevalence and incidence rates of CVDs and obesity-related metabolic disorders and to evaluate the predictive ability of various CVD risk assessment tools in an Iranian population. Method: We enrolled 5,799 participants in Amol, a city in northern Iran, in 2009-2010 and carried out the first repeated measurement (RM) after seven years (2016-2017). For all participants, demographic, anthropometric, laboratory, hepatobiliary imaging, and electrocardiography data have been collected in the enrollment and the RM. After enrollment, all participants have been and will be followed up annually for 20 years, both actively and passively. Results: We adopted a multidisciplinary approach to overcome barriers to participation and achieved a 7-year follow-up success rate of 93.0% with an active follow-up of 5,394 participants aged 18-90 years. In the RM, about 64.0% of men and 81.2% of women were obese or overweight. In 2017, about 16.2% and 5.2% of men had moderate or severe non-alcoholic fatty liver disease, while women had a significantly higher prevalence of metabolic syndrome (35.9%), and type 2 diabetes mellitus (20.9%) than men. Of 160 deceased participants, 69 cases (43.1%) died due to CVDs over seven years. Conclusion: The most prevalent obesity-related chronic disease in the study was metabolic syndrome. Across the enrollment and RM phases, women exhibited a higher prevalence of obesity-related metabolic disorders. Focusing on obesity-related metabolic disorders in a population not represented previously and a multidisciplinary approach for enrolling and following up were the strengths of this study. The study outcomes offer an evidence base for future research and inform policies regarding non-communicable diseases in northern Iran.

Opium: an emerging risk factor for gastric adenocarcinoma.

Opium use has been associated with higher risk of cancers of the esophagus, bladder, larynx, and lung; however, no previous study has examined its association with gastric cancer. There is also little information on the associations between hookah (water pipe) smoking or the chewing of tobacco products and the risk of gastric cancer. In a case-control study in Golestan Province of Iran, we enrolled 309 cases of gastric adenocarcinoma (118 noncardia, 161 cardia and 30 mixed-location adenocarcinomas) and 613 matched controls. Detailed information on long-term use of opium, tobacco products and other covariates were collected using structured and validated lifestyle and food frequency questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models. Opium use was associated with an increased risk of gastric adenocarcinoma, with an adjusted OR (95% CI) of 3.1 (1.9-5.1), and this increased risk was apparent for both anatomic subsites (cardia and noncardia). There was a dose-response effect, and individuals with the highest cumulative opium use had the strongest association (OR: 4.5; 95% CI: 2.3-8.5). We did not find a statistically significant association between the use of any of the tobacco products and risk of gastric adenocarcinoma, overall or by anatomic subsite. We showed, for the first time, an association between opium use and gastric adenocarcinoma. Given that opium use is a traditional practice in many parts of the world, these results are of public health significance.

Decoding the expression pattern of MUC3A in gastric adenocarcinoma: unveiling the key to successful immunotherapy.

AIMS: Despite the promise of immunotherapy for gastric adenocarcinoma, resistance is common, necessitating the validation of new targets. Based on our previous bioinformatics analysis, the MUC3A antigen emerged as a promising candidate for immunotherapy against gastric adenocarcinoma. However, a comprehensive understanding of its expression at protein level remains elusive, despite its crucial role in determining clinical response. We also sought to establish a connection between the expression pattern and relevant clinical variables of the disease, whenever feasible. METHODS: Immunohistochemistry was used to determine the percentage of MUC3A-positive tumor cells in primary (PT) and metastatic tumor (MT) sites of 190 gastric adenocarcinoma patients. We also evaluated the association between MUC3A expression and variables such as Lauren classification, history of neoadjuvant chemotherapy and/or radiotherapy, and overall patient survival. RESULTS: Median MUC3A expression was 50% in PT and 70% in MT sites, exhibiting a positive correlation. MT intestinal type showed significantly higher MUC3A expression compared to other types. Neoadjuvant therapy history did not affect MUC3A expression. Higher MUC3A expression correlated with improved survival. CONCLUSIONS: Based on our previous bioinformatics data and the consistently high expression of MUC3A on gastric tumor cells, we propose advancing experimental aspects of anti-MUC3A immunotherapy for gastric adenocarcinoma.

A Single nucleotide polymorphism in the ALDH2 gene modifies the risk of esophageal squamous cell carcinoma in BRCA2 p.K3326* carriers.

Esophageal squamous cell carcinoma (ESCC) has a very high incidence rate in northeastern Iran. Our team previously reported the BReast CAncer gene 2 (BRCA2) p.K3326* mutation as a moderately penetrant ESCC susceptibility variant in northern Iran (odds ratio (OR) = 3.64, 95% confidence interval (CI) = 1.74-7.59, P = 0.0003). Recently, it has been reported that aldehydes can induce BRCA2 haploinsufficiency in cells with a heterozygous pathogenic BRCA2 mutation and predispose them to carcinogenic effects. Based on this observation, we speculate that dysfunctional variants in Aldehyde Dehydrogenase 2 Family Member (ALDH2) may result in aldehyde-induced BRCA2 haploinsufficiency and increase cancer risk in BRCA2 mutation carriers. In support of this hypothesis, our team recently reported the breast cancer risk modifying effect of an ALDH2 common polymorphism, rs10744777, among Polish carriers of the BRCA2 p.K3326* mutation. In the current case-control study, we aimed to investigate the ESCC risk modifying effect of this ALDH2 polymorphism among BRCA2 p.K3326* mutation carriers. We assessed the interaction between the ALDH2 rs10744777 polymorphism and BRCA2 p.K3326* mutation in ESCC risk by genotyping this ALDH2 variant in the germline DNA of 746 ESCC cases and 1,373 controls from northern Iran who were previously genotyped for the BRCA2 p.K3326* mutation. Among a total of 464 individuals with TT genotype of the ALDH2 rs10744777 polymorphism, which is associated with lower ALDH2 expression, we found 9 of 164 cases versus 3 of 300 controls who carried the BRCA2 p.K3326* variant (OR = 5.66, 95% CI = 1.22-26.2, P = 0.018). This finding supports our hypothesis that the ALDH2-rs10744777 TT genotype may be a significant risk modifier of ESCC in individuals with a BRCA2 p.K3326* mutation.

Interpatient variability in mesothelin expression necessitates its evaluation before gastric cancer immunotherapy.

Aims: Mesothelin (MSLN) was applied for the immunotherapy of ovarian cancer and mesothelioma with a minimum expression of 60% to obtain a clinical response. Here, the authors evaluated MSLN expression as a potential target of gastric adenocarcinoma immunotherapy. Materials & methods: The expression of MSLN was evaluated by immunohistochemistry and was reported in primary tumor (PT) and metastatic tumor (MT) sites. Results: The results showed that only 17.1% and 13.5% of the patients had 60% or more MSLN expression in PT and MT sites, respectively. The expression of MSLN in PTs and MTs was not influenced by Lauren classification, neoadjuvant therapy or tumor stage. Conclusions: Interpatient variability in MSLN expression necessitates its evaluation before MSLN-based gastric cancer immunotherapy.

Mutations in Fanconi anemia genes and the risk of esophageal cancer.

The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2-44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97-6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran.

Effect of rose oil on Gastroesophageal Reflux Disease in comparison with omeprazole: A double-blind controlled trial.

BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GERD) as one of the most common ailments of gastrointestinal system diminishes quality of life and impairs physical functioning and work productivity. Proton-pump inhibitors (PPIs), such as omeprazole play a more dominant role in amelioration of GERD symptoms; nonetheless, there is a growing concern about their side effects. According to traditional Persian medicine (TPM), the use of rose oil is recommended to alleviate GERD symptoms. MATERIALS AND METHODS: Therefore, a randomized double-blind controlled trial was performed on 70 subjects who were randomly enrolled in two groups and received either rose oil softgel or omeprazole capsule combined with the placebo. Data were collected within 3 sessions of visit using the Mayo-gastroesophageal reflux questionnaire (GERQ). RESULTS: Although, our findings showed that reflux symptoms were decreased in both groups after receiving medicine and the decrement was significant in treatment group, before and after the intervention, this decrease was not significant between two groups. CONCLUSION: Given that the rose oil used in this study was produced according to the Iranian method and effective ingredients of Rosa damascena were preserved in sesame oil in production process, it seems that effectiveness of this product can be due to its tonic and enlivening properties. Consumption of rose oil soft capsule alleviates cardinal GERD symptoms similar to omeprazole. It seems that rose oil can have the same effects as PPIs in treatment of GERD but with no side effects due to its different mechanisms of action.

Long-term opiate use and risk of cardiovascular mortality: results from the Golestan Cohort Study.

AIMS: Tens of millions of people worldwide use opiates but little is known about their potential role in causing cardiovascular diseases. We aimed to study the association of long-term opiate use with cardiovascular mortality and whether this association is independent of the known risk factors. METHODS AND RESULTS: In the population-based Golestan Cohort Study-50 045 Iranian participants, 40-75 years, 58% women-we used Cox regression to estimate hazard ratios and 95% confidence intervals (HRs, 95% CIs) for the association of opiate use (at least once a week for a period of 6 months) with cardiovascular mortality, adjusting for potential confounders-i.e. age, sex, education, wealth, residential place, marital status, ethnicity, and tobacco and alcohol use. To show independent association, the models were further adjusted for hypertension, diabetes, waist and hip circumferences, physical activity, fruit/vegetable intake, aspirin and statin use, and history of cardiovascular diseases and cancers. In total, 8487 participants (72.2% men) were opiate users for a median (IQR) of 10 (4-20) years. During 548 940 person-years-median of 11.3 years, >99% success follow-up-3079 cardiovascular deaths occurred, with substantially higher rates in opiate users than non-users (1005 vs. 478 deaths/100 000 person-years). Opiate use was associated with increased cardiovascular mortality, with adjusted HR (95% CI) of 1.63 (1.49-1.79). Overall 10.9% of cardiovascular deaths were attributable to opiate use. The association was independent of the traditional cardiovascular risk factors. CONCLUSION: Long-term opiate use was associated with an increased cardiovascular mortality independent of the traditional risk factors. Further research, particularly on mechanisms of action, is recommended.

Genome-Wide DNA Methylation Profiling of Esophageal Squamous Cell Carcinoma from Global High-Incidence Regions Identifies Crucial Genes and Potential Cancer Markers.

Epigenetic mechanisms such as aberrant DNA methylation (DNAme) are known to drive esophageal squamous cell carcinoma (ESCC), yet they remain poorly understood. Here, we studied tumor-specific DNAme in ESCC cases from nine high-incidence countries of Africa, Asia, and South America. Infinium MethylationEPIC array was performed on 108 tumors and 51 normal tissues adjacent to the tumors (NAT) in the discovery phase, and targeted pyrosequencing was performed on 132 tumors and 36 NAT in the replication phase. Top genes for replication were prioritized by weighting methylation results using RNA-sequencing data from The Cancer Genome Atlas and GTEx and validated by qPCR. Methylome analysis comparing tumor and NAT identified 6,796 differentially methylated positions (DMP) and 866 differential methylated regions (DMR), with a 30% methylation (Δß) difference. The majority of identified DMPs and DMRs were hypermethylated in tumors, particularly in promoters and gene-body regions of genes involved in transcription activation. The top three prioritized genes for replication, PAX9, SIM2, and THSD4, had similar methylation differences in the discovery and replication sets. These genes were exclusively expressed in normal esophageal tissues in GTEx and downregulated in tumors. The specificity and sensitivity of these DNAme events in discriminating tumors from NAT were assessed. Our study identified novel, robust, and crucial tumor-specific DNAme events in ESCC tumors across several high-incidence populations of the world. Methylome changes identified in this study may serve as potential targets for biomarker discovery and warrant further functional characterization. SIGNIFICANCE: This largest genome-wide DNA methylation study on ESCC from high-incidence populations of the world identifies functionally relevant and robust DNAme events that could serve as potential tumor-specific markers. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2612/F1.large.jpg.

Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.

BACKGROUND: Evidence is emerging for a role of opiates in various cancers. In this study, we aimed to investigate the association between regular opium use and cancer incidence. METHODS: This study was done in a population-based cohort of 50 045 individuals aged 40-75 years from northeast Iran. Data on participant demographics, diet, lifestyle, opium use, and different exposures were collected upon enrolment using validated questionnaires. We used proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% CIs for the association between opium use and different cancer types. FINDINGS: During a median 10 years of follow-up, 1833 participants were diagnosed with cancer. Use of opium was associated with an increased risk of developing all cancers combined (HR 1·40, 95% CI 1·24-1·58), gastrointestinal cancers (1·31, 1·11-1·55), and respiratory cancers (2·28, 1·58-3·30) in a dose-dependent manner (ptrend<0·001). For site-specific cancers, use of opium was associated with an increased risk of developing oesophageal (1·38, 1·06-1·80), gastric (1·36, 1·03-1·79), lung (2·21, 1·44-3·39), bladder (2·86, 1·47-5·55), and laryngeal (2·53, 1·21-5·29) cancers in a dose-dependent manner (ptrend<0·05). Only high-dose opium use was associated with pancreatic cancer (2·66, 1·23-5·74). Ingestion of opium (but not smoking opium) was associated with brain (2·15, 1·00-4·63) and liver (2·46, 1·23-4·95) cancers in a dose-dependent manner (prend<0·01). We observed consistent associations among ever and never tobacco users, men and women, and individuals with lower and higher socioeconomic status. INTERPRETATION: Opium users have a significantly higher risk of developing cancers in different organs of the respiratory, digestive, and urinary systems and the CNS. The results of this analysis show that regular use of opiates might increase the risk of a range of cancer types. FUNDING: World Cancer Research Fund International, Cancer Research UK, Tehran University of Medical Sciences, US National Cancer Institute, International Agency for Research on Cancer.

Opiate and Tobacco Use and Exposure to Carcinogens and Toxicants in the Golestan Cohort Study.

BACKGROUND: There is little information on human exposure to carcinogens and other toxicants related to opiate use, alone or in combination with tobacco. METHODS: Among male participants of the Golestan Cohort Study in Northeast Iran, we studied 28 never users of either opiates or tobacco, 33 exclusive cigarette smokers, 23 exclusive users of smoked opiates, and 30 opiate users who also smoked cigarettes (dual users; 21 smoked opiates and 9 ingested them). We quantified urinary concentrations of 39 exposure biomarkers, including tobacco alkaloids, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC), and used decomposition to parse out the share of the biomarker concentrations explained by opiate use and nicotine dose. RESULTS: Dual users had the highest concentrations of all biomarkers, but exclusive cigarette smokers and exclusive opiate users had substantially higher concentrations of PAH and VOC biomarkers than never users of either product. Decomposition analysis showed that opiate use contributed a larger part of the PAH concentrations than nicotine dose, and the sum of 2- and 3-hydroxyphenanthrene (∑2,3-phe) resulted almost completely from opiate use. Concentrations of most VOC biomarkers were explained by both nicotine dose and opiate use. Two acrylamide metabolites, a 1,3-butadiene metabolite and a dimethylformamide metabolite, were more strongly explained by opiate use. Acrylamide metabolites and ∑2,3-phe were significantly higher in opiate smokers than opiate eaters; other biomarkers did not vary by the route of opiate intake. CONCLUSIONS: Both cigarette smokers and opiate users (by smoking or ingestion) were exposed to many toxicants and carcinogens. IMPACT: This high exposure, particularly among dual opiate and cigarette users, can have a substantial global public health impact.

Gluten sensitivity enteropathy in patients with recurrent aphthous stomatitis.

BACKGROUND: Gluten sensitive enteropathy (GSE) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in susceptible individuals. Recurrent aphthous stomatitis (RAS) may be the sole manifestation of GSE. The aim of this study was to determine the prevalence of gluten sensitivity enteropathy (GSE) in a large group of patients with RAS and assess the efficacy of gluten free diet (GFD) on the improvement of aphthous lesions in those who were diagnosed with GSE. METHODS: Two hundred and forty seven patients with RAS were included. The patients had at least three aphthous attacks per year. Patients were screened by IgA anti-endomysial antibody (EMA), IgA anti tissue transglutaminase (TTG) and serum IgA level. Those with a positive serology underwent endoscopic biopsies of the duodenal mucosa and patients with negative serology were excluded. The diagnosis of GSE was based on a positive serological test and abnormal duodenal histology. For patients with GSE, gluten free diet was recommended. RESULTS: Six out of 247 RAS patients had positive TTG test alone, and one had positive EMA and TTG. All 7 patients with positive serologic tests underwent duodenal biopsies. Histological findings were compatible with GSE in all of them (Marsh I in four patients, Marsh II in two patients and Marsh IIIB in one another.). The mean age of GSE patients was 27.42 +/- 10.56 (range, 13 to 40) years old. They were suffering from RAS for an average duration of 4.5 years. All of the 7 GSE patients had not responded to the routine anti-aphthae medications, including topical corticosteroids, tetracycline and colchicine. Four patients who adhered to a strict gluten-free diet showed noticeable improvement in their aphthous lesions over a period of 6 months. CONCLUSION: A significant minority (e.g. 2.83%) of RAS patients have GSE. This could be compared with the 0.9% prevalence of GSE in the general population of Iran. This study suggests that evaluation for celiac disease is appropriate in patients with RAS. Additionally, the unresponsiveness to conventional anti-aphthae treatment could be an additional risk indicator.

Prevalence of celiac disease among patients with Behcet's disease in Iran.

BACKGROUND: Behcet's disease and Celiac disease, both common in Iran, share many immunopathogenic and clinical features. Based on the possible association between these two diseases, this study is designed to determine the frequency of non-diagnosed celiac disease in patients with Behcet's disease. METHODS: The sera of 288 consecutive patients with Behcet's disease were screened with anti-endomysial antibody and anti-tissue transglutaminase antibody for celiac disease. Those with a positive test underwent upper gastrointestinal endoscopy and duodenal biopsies to confirm the diagnosis of celiac disease. The patients with celiac disease were put on a gluten free diet to evaluate its efficacy on the improvement of their lesions. RESULTS: Fourteen patients had positive anti-tissue transglutaminase antibody test (two with positive anti-endomysial antibody as well). Duodenal biopsies showed findings compatible with Marsh 3 in one and Marsh 1 in three other patients. All the diagnosed patients with celiac disease responded to the gluten free diet. CONCLUSION: Our findings didn't support any association between celiac disease and Behcet's disease in Iranian patients compared to the general population of Iran.

Hydroxyurea therapy in 49 patients with major beta-thalassemia.

Major thalassemia is one of the most common hemoglobinopathies in many Asian countries including Iran. Pharmacologic agents such as hydroxyurea have been known to enhance the production of fetal hemoglobin, and also an increase in total hemoglobin level has been repeatedly reported during hydroxyurea treatment in patients with sickle cell disease and in several patients with intermediate beta-thalassemia. We evaluated the long-term efficacy and safety of hydroxyurea in major beta-thalassemic patients. Forty-nine beta-thalassemic patients enrolled in the study. The mean follow-up time was 60 months. The mean dose of hydroxyurea was 10 mg/kg per day (8-15 mg/kg). Before starting hydroxyurea, all patients underwent routine biochemical laboratory tests. Patients with low platelet count (<100,000/mm3), neutropenia (polymorphonuclear neutrophil<1,200/mm3), pregnancy, and on interferon treatment were excluded.Twenty-eight out of 49 enrolled patients were females with the mean age of 18.38 years (10-40 years). The mean packed red cell transfusions during one year before starting of hydroxyurea was 22.75 units which decreased to 6.02 units after treatment (P<0.01). The mean ferritin level during the first period was 2751.44 ng/mL, but decreased to 1594.20 ng/mL after one year of hydroxyurea therapy (P<0.001).We observed a substantial and persistent increase in hemoglobin level and a significant decrease in blood transfusion. Hydroxyurea treatment was well-tolerated and it did not cause any hematopoietic suppression except in one patient who developed transient thrombocytopenia which resolved after short period of hydroxyurea cessation. We did not encounter any malignancies including leukemia in the five-year follow-up.