Hypertension and mortality in the Golestan Cohort Study: A prospective study of 50 000 adults in Iran.

High blood pressure has been the second most important determinant of disease burden in Iran since the 1990s. Despite well-recognized evidence on the association of high blood pressure and mortality in other countries, this relationship has not been fully investigated in the demographic setting of Iran. The current study is the first large-scale longitudinal study of this association in Iran. Briefly, 50 045 subjects between 40 and 75 years of age have been recruited and followed. Blood pressure measurements were carried out at baseline. Causes of death were reported and verified by verbal autopsy throughout the follow-up period. The outcomes of interest were all-cause deaths and deaths due to ischemic heart disease (IHD) or stroke. Cox proportional hazards regression models were used to estimate hazard ratios (HRs). A total of 46 674 subjects free from cardiovascular disease at baseline were analyzed. Absolute mortality rates increased along with increasing systolic or diastolic blood pressure above 120 and 80 mm Hg, respectively. Adjusted HRs (95% confidence intervals) for each 20 mm Hg increase in systolic blood pressure in all age groups were 1.18 (1.13-1.23) for all-cause mortality, 1.21 (1.13-1.31) for deaths due to IHD and 1.50 (1.39-1.63) for deaths due to stroke. Unadjusted and adjusted HRs were higher in younger subjects and decreased with increasing age of the participants. High blood pressure is a serious threat to the health of Iranians. The entire health-care system of Iran should be involved in a comprehensive action plan for controlling blood pressure.

Pilot study of cytological testing for oesophageal squamous cell dysplasia in a high-risk area in Northern Iran.

BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is a fatal disease with 5-year survival rates of <5% in Northern Iran. Oesophageal squamous dysplasia (ESD) is the precursor histologic lesion of ESCC. This pilot study was conducted to assess the feasibility, safety, and acceptability of non-endoscopic cytological examination of the oesophagus and to provide initial data on the accuracy of cytological atypia for identifying patients with ESD in this very-high-risk area. METHODS: Randomly selected asymptomatic participants of the Golestan Cohort Study were recruited. A cytological specimen was taken using a capsule sponge device and evaluated for atypical cells. Sections of the cytological specimen were also stained for p53 protein. Patient acceptability was assessed using a visual analogue scale. The cytological diagnosis was compared with a chromoendoscopic examination using Lugol's solution. RESULTS: Three hundred and forty-four subjects (43% male, mean (s.d.) age 55.6 (7.9) years) were referred to the study clinic. Three hundred and twelve met eligibility criteria and consented, of which 301 subjects (96.5%) completed both cytological and endoscopic examinations. There were no complications. Most of the participants (279; 92.7%) were satisfied with the examination. The sensitivity and specificity of the cytological examination for identifying subjects with high-grade ESD were 100 and 97%, respectively. We found an accuracy of 100% (95% CI=99-100%) for a combination of cytological examination and p53 staining to detect high-grade ESD. CONCLUSIONS: The capsule sponge methodology seems to be a feasible, safe, and acceptable method for diagnosing precancerous lesions of the oesophagus in this population, with promising initial accuracy data for the detection of high-grade ESD.

Gastric atrophy and oesophageal squamous cell carcinoma: possible interaction with dental health and oral hygiene habit.

BACKGROUND: Gastric fundal atrophy has been hypothesised to increase the risk of oesophageal squamous cell carcinoma (OSCC), but studies have shown inconsistent results. METHODS: We measured serum pepsinogen I (PGI) and pepsinogen II (PGII) among 293 incident cases and 524 matched neighbourhood controls in a high-risk area of Northern Iran. Conditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: After controlling for age, sex, residence area and other potential confounders, gastric atrophy (defined by a validated criterion, PGI <55 µg dl(-1)) was associated with a two-fold increased risk (OR=2.01, 95% CI: 1.18, 3.45) of OSCC in the absence of nonatrophic pangastritis (defined as PGII <11.8 µg dl(-1)). Stratification by PGII decreased the misclassification errors due to cancer-induced gastritis. Presence of both poor dental health, indicated by higher than median sum of decayed, missing, and filled teeth (DMFT score), and gastric atrophy further increased the risk of OSCC (OR=4.15, 95% CI: 2.04, 8.42) with relative excess risk due to interaction (RERI) of 1.47 (95% CI: -1.15, 4.1). Coexistence of poor oral hygiene habit with gastric atrophy elevated OSCC risk eight times (OR=8.65, 95% CI: 3.65, 20.46) and the additive interaction index was marginally statistically significant (RERI=4.34, 95% CI: -1.07, 9.76). CONCLUSION: Gastric atrophy is a risk factor for OSCC, and poor dental health and oral hygiene habit may act synergistically in increasing the risk.

Gastroenterology and hepatology training in the islamic republic of iran.

BACKGROUND Training in internal medicine has significantly evolved alongside the development of science, technology and new facilities during the past fifty years. After the specialty of internal medicine, there are multiple subspecialty training programs which have started since 1985 in the Islamic Republic of Iran. In this manuscript we want to define the characteristics of the gastroenterology subspecialty training program in our country. METHODS The characteristics of approved gastroenterology training centers were gathered through a questionnaire. The questionnaire was consisted; the establishment date, the number and academic rank of trainers, the number of trainees, hospital beds, the number and types of diagnostic and therapeutic procedures in a year, the characteristics of training programs and their curriculum composition. The collected data was discussed and revised in a focused group of gastroenterologists from training centers and the board members of Iranian Association of Gastroenterology and Hepatology (IAGH). RESULTS There are 11 training centers with 94 trainers and 65 trainees, with a ratio of trainers to trainees of 1.36. Fifty four percent of trainers are assistant professor. Yearly, 36 new fellows are admitted. Four centers have adequate facilities for training in advanced gastroenterology, and in three centers there are facilities for liver transplantation. The duration of training in internal medicine is four years, whereas in gastroenterology it is two years. The admission for this subspecialty is not university based and with other subspecialty programs, there is a national entrance examination. CONCLUSION There are adequate well known training centers with a suitable ratio of trainer to trainee in the Islamic Republic of Iran. The duration of the GI fellowship is short and implementation of post subspecialty programs for completing the required capabilities of fellows is necessary. The capacity of fellowship admission should be revised according to needs of the country in the fields of health maintenance, research and medical education programs.

A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors.

AIM: Our objective was to investigate the effects and tolerability of fixed-dose combination therapy on blood pressure and LDL in adults without elevated blood pressure or lipid levels. METHODS: This was a double-blind randomised placebo-controlled trial in residents of Kalaleh, Golestan, Iran. Following an 8-week placebo run-in period, 475 participants, aged 50 to 79 years, without cardiovascular disease, hypertension or hyperlipidaemia were randomised to fixed-dose combination therapy with aspirin 81 mg, enalapril 2.5 mg, atorvastatin 20 mg and hydrochlorothiazide 12.5 mg (polypill) or placebo for a period of 12 months. The primary outcomes were changes in LDL-cholesterol, systolic and diastolic blood pressure and adverse reactions. Analysis was by intention-to-treat basis. RESULTS: At baseline, there were differences in systolic blood pressure (6 mmHg). Taking account of baseline differences, at 12 months, polypill was associated with statistically significant reductions in blood pressure (4.5/1.6 mmHg) and LDL-cholesterol (0.46 mmol/l). The study drug was well tolerated, but resulted in the modest reductions in blood pressure and lipid levels. CONCLUSION: The effects of the polypill on blood pressure and lipid levels were less than anticipated, raising questions about the reliability of the reported compliance. There is a case for a fully powered trial of a polypill for the prevention of cardiovascular disease.

The role and frequency of glutathione s-transferase P1 polymorphism in Iranian patients affected with reflux esophagitis.

Reflux esophagitis is a common complication of the gastroesophageal reflux disease. Glutathione s-transferases (GSTs) have important role in the protection of cells from the products of oxidative stress. GSTP1*B allele has a correlation with susceptibility to several diseases. In this case-control study, the role and frequency of GSTP1 polymorphism was evaluated in Iranian patients with erosive reflux esophagitis. Seventy patients with erosive reflux esophagitis and 75 normal individuals were enrolled in this study. The grade of esophagitis was determined via endoscopy. DNA was extracted from venous blood of each subject using the salting out method. GSTP1 genetic polymorphisms were detected using the polymerase chain reaction restriction fragment length polymorphism method. There was a significant difference in GSTP1 genotype frequency between patients and normal groups (P= 0.006). Also, in the patient group, the grade B of esophagitis was significantly associated with variant GSTP1 genotype (P= 0.028). The rate of throat pain symptom was higher in the no-variant group (P < 0.036). The GSTP1*B allele frequency in Iranian normal groups is similar to Orientals. Reflux esophagitis are more commonly found in variant (*B/*B and *A/*B) GSTP1 genotypes. In addition, GSTP1 polymorphism is correlated with a higher grade of esophagitis.

Prevalence of Nonalcoholic Steatohepatitis in Iran: A Population based Study.

BACKGROUND Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common form of chronic liver disease worldwide and is no longer considered a benign disease. Its prevalence has not been determined in a large-scale population-based study in Iran. METHODS A total of 6583 individuals aged 18 to 65 were randomly selected from three geographically distinct provinces in Iran. Blood samples were obtained from each subject and a questionnaire was completed exploring data including self-admitted regular alcohol use. Serums were tested for anti-HCV antibody (anti-HCV), hepatitis B surface antigen and anti-hepatitis B core antibody. Positive samples for anti-HCV antibody were re-tested and those positive in a repeat ELISA were confirmed by a recombinant immunoblot assay (RIBA) test. Serums were also tested for ALT levels. Subjects with elevated ALT defined as serum ALT ≥40 IU/L with no history of alcohol consumption and negative HBV and HCV infection were considered as "presumed NASH". RESULTS In this study 5589 subjects were analyzed. Two hundred and forty two individuals (4.3%) were diagnosed with elevated ALT levels. Among individuals with elevated ALT, 15 (6.2%) were diagnosed with either hepatitis B or hepatitis C. The overall weighted prevalence of presumed NASH was 2.9%. According to multivariate analysis, male sex, urban lifestyle, and being overweight or obese were significantly associated with "presumed NASH". CONCLUSION Obesity and metabolic syndrome, the most predictive factors of fatty liver disease, are increasing in Iran, therefore the prevalence of NAFLD/NASH and related complications are expected to increase in the future. This population based study gives a crude estimate of the prevalence of NASH around the country. Studies with more accurate surrogates of NASH need to be done. The disparity among different provinces merits special consideration.

Opium, tobacco, and alcohol use in relation to oesophageal squamous cell carcinoma in a high-risk area of Iran.

The very high incidence of oesophageal squamous cell carcinoma (ESCC) in Golestan Province in northeastern Iran was suggested by studies in the 1970s as partly due to opium use, which is not uncommon in this area, but based on limited numbers. From December 2003 to June 2007, we administered a validated structured questionnaire to 300 ESCC cases and 571 controls, matched on neighbourhood of residence, age (+/-2 years), and sex. We used conditional logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. Compared with those who used neither tobacco nor opium, risk of ESCC was increased in those who used tobacco only (OR, 95% CI: 1.70, 1.05-2.73), in those who used opium only (2.12, 1.21-3.74), and in those who used both tobacco and opium (2.35, 1.50-3.67). All forms of tobacco use (cigarettes, hookah, and nass) were associated with higher ESCC risk. Similarly, use of both crude opium and other forms of opium were associated with higher risk. Alcohol consumption was seen in only 2% of the cases and 2% of the controls, and was not associated with ESCC risk.

Germline BRCA2 mutations and the risk of esophageal squamous cell carcinoma.

The incidence of esophageal squamous cell carcinoma (ESCC) is very high among the Turkmen population of Iran. Family studies suggest a genetic component to the disease. Turkmen are ethnically homogenous and are well suited for genetic studies. A previous study from China suggested that BRCA2 might play a role in the etiology of ESCC. We screened for mutations in the coding region of the BRCA2 gene in the germline DNA of 197 Turkmen patients with ESCC. A nonsense variant, K3326X, was identified in 9 of 197 cases (4.6%) vs 2 of 254 controls (0.8%) (OR=6.0, 95% CI=1.3-28; P=0.01). This mutation leads to the loss of the C-terminal domain of the BRCA2 protein, a part of the region of interaction with the FANCD2 protein. We observed nine other BRCA2 variants in single cases only, including two deletions, and seven missense mutations. Six of these were judged to be pathogenic. In total, a suspicious deleterious BRCA2 variant was identified in 15 of 197 ESCC cases (7.6%).

Validity and reliability of a new food frequency questionnaire compared to 24 h recalls and biochemical measurements: pilot phase of Golestan cohort study of esophageal cancer.

BACKGROUND: A pilot study was carried out to evaluate validity and reproducibility of a food frequency questionnaire (FFQ), which was designed to be used in a prospective cohort study in a population at high risk for esophageal cancer in northern Iran. METHODS: The FFQ was administered four times to 131 subjects, aged 35-65 years, of both sexes. Twelve 24-h dietary recalls for two consecutive days were administered monthly during 1 year and used as a reference method. The excretion of nitrogen was measured on four 24-h urine samples, and plasma levels of beta-carotene, retinol, vitamin C and alpha-tocopherol was measured from two time points. Relative validity of FFQ and 24-h diet recall was assessed by comparing nutrient intake derived from both methods with the urinary nitrogen and plasma levels of beta-carotene, retinol, vitamin C and alpha-tocopherol. RESULTS: Correlation coefficients comparing energy and nutrients intake based on the mean of the four FFQ and the mean of twelve 24-h diet recalls were 0.75 for total energy, 0.75 for carbohydrates, 0.76 for proteins and 0.65 for fat. Correlation coefficients between the FFQ-based intake and serum levels of beta-carotene, retinol, vitamin C and vitamin E/alpha-tocopherol were 0.37, 0.32, 0.35 and 0.06, respectively. Correlation coefficients between urinary nitrogen and FFQ-based protein intake ranged from 0.23 to 0.35. Intraclass correlation coefficients used to measure reproducibility of FFQ ranged from 0.66 to 0.89. CONCLUSION: We found that the FFQ provides valid and reliable measurements of habitual intake for energy and most of the nutrients studied.

Golestan cohort study of oesophageal cancer: feasibility and first results.

To investigate the incidence of oesophageal cancer (EC) in the Golestan province of North-East Iran, we invited 1349 rural and urban inhabitants of Golestan province aged 35-80 to undergo extensive lifestyle interviews and to provide biological samples. The interview was repeated on a subset of 130 participants to assess reliability of questionnaire and medical information. Temperature at which tea was consumed was measured on two occasions by 110 subjects. Samples of rice, wheat and sorghum were tested for fumonisin contamination. An active follow-up was carried out after 6 and 12 months. A total of 1057 subjects (610 women and 447 men) participated in this feasibility study (78.4% participation rate). Cigarette smoking, opium and alcohol use were reported by 163 (13.8%), 93 (8.8%) and 39 (3.7%) subjects, respectively. Tobacco smoking was correlated with urinary cotinine (kappa = 0.74). Most questionnaire data had kappa > 0.7 in repeat measurements; tea temperature measurement was reliable (kappa = 0.71). No fumonisins were detected in the samples analysed. During the follow-up six subjects were lost (0.6%), two subjects developed EC (one dead, one alive); in all, 13 subjects died (with cause of death known for 11, 84.6%). Conducting a cohort study in Golestan is feasible with reliable information obtained for suspected risk factors; participants can be followed up for EC incidence and mortality.

Epidemiologic features of upper gastrointestinal tract cancers in Northeastern Iran.

Previous studies have shown that oesophageal and gastric cancers are the most common causes of cancer death in the Golestan Province, Iran. In 2001, we established Atrak Clinic, a referral clinic for gastrointestinal (GI) diseases in Gonbad, the major city of eastern Golestan, which has permitted, for the first time in this region, endoscopic localisation and histologic examination of upper GI cancers. Among the initial 682 patients seen at Atrak Clinic, 370 were confirmed histologically to have cancer, including 223 (60%) oesophageal squamous cell cancers (ESCC), 22 (6%) oesophageal adenocarcinomas (EAC), 58 (16%) gastric cardia adenocarcinomas (GCA), and 58 (16%) gastric noncardia adenocarcinomas. The proportional occurrence of these four main site-cell type subdivisions of upper GI cancers in Golestan is similar to that seen in Linxian, China, another area of high ESCC incidence, and is markedly different from the current proportions in many Western countries. Questioning of patients about exposure to some known and suspected risk factors for squamous cell oesophageal cancer confirmed a negligible history of consumption of alcohol, little use of cigarettes or nass (tobacco, lime and ash), and a low intake of opium, suggesting that the high rates of ESCC seen in northeastern Iran must have other important risk factors that remain speculative or unknown. Further studies are needed to define more precisely the patterns of upper GI cancer incidence, to test other previously suspected risk factors, and to find new significant risk factors in this high-risk area.

Prevalence of gastric precancerous lesions in Ardabil, a high incidence province for gastric adenocarcinoma in the northwest of Iran.

BACKGROUND/AIMS: Ardabil Province, in northwestern Iran, has the highest rate of gastric (predominantly cardia) adenocarcinoma in Iran. This study aimed to investigate the feasibility of endoscopic screening and to look for associated Helicobacter pylori infection and gastric precancerous lesions. METHODS: One thousand one hundred and five adult volunteers, residents of Ardabil and Meshkinshahr, districts, 40 years old and above were selected and invited by a simple random household canvass in rural and urban locations. Informed consents were obtained and upper gastrointestinal video endoscopy was performed to biopsy all visible lesions and standard sites in the antrum, corpus, and cardia. RESULTS: One thousand and eleven of the invited individuals agreed to participate, including 494 men and 517 women, with a mean (SD) age of 53.32 (10.39) years. Endoscopy was well tolerated by all subjects; 96.7% of antral and 80.7% of cardia mucosal biopsies were satisfactory. The urease test or histology for H pylori was positive in at least 89.2% of subjects. Histological evidence of mucosal atrophy was seen in 39.3% of antral and 21.9% of cardia samples. Chronic gastritis with or without activity, reactive atypia of glandular epithelium, intestinal metaplasia, dysplasia, and cancer were found in 95.1%, 38.0%, 8.7%, 0.2%, and 0.3% of antral and 85.3%, 22.9%, 3.8%, 0.3%, and 0.1% of cardiac biopsies, respectively. CONCLUSION: Endoscopic screening for upper gastrointestinal diseases was feasible and well tolerated in Ardabil, Iran. Most subjects showed H pylori infection. Atrophic gastritis, reactive atypia, and intestinal metaplasia were common in antrum, corpus, and cardia subsites.