ERBB4 gene polymorphisms and the risk of prostate cancer in a sample of Iranian Population.

Genetic polymorphisms in ERBB4 are thought to be associated with cancer susceptibility. In the present study, we aimed to assess the impact of ERBB4 rs12052398 T>C, rs13393577 A>G, rs13424871 A>T, rs16847082 A>G and rs6147150 (12-bp I/D) polymorphisms on risk of prostate cancer (PCa) in a sample of Iranian population. In a case-control study, we enrolled 169 patients with pathologically confirmed PCa and 182 subjects with benign prostatic hyperplasia (BPH). No significant association was found among ERBB4 polymorphisms and risk of PCa. Subjects carrying TT/AA/AA/AG/ID, TC/AA/AA/AA/II, TT/AA/AT/AA/II and TT/AA/AT/AG/ID genotypes are associated with a decreased risk of PCa. Our findings suggest that haplotypes CAAAI and TAAAD (rs12052398, rs13393577, rs13424871, rs16847082 and rs6147150I) of the ERBB4 polymorphisms are associated with a significantly lower risk of PCa. Further studies with a larger sample sizes and diverse ethnicities are necessary to verify our findings.

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.

Reliability of pre-transplant live donor renal biopsies in predicting the graft outcome.

BACKGROUND: Biopsy from deceased donors is of great value in predicting the efficacy and mid-term and long-term outcome of kidney transplantation. OBJECTIVE: To determine the prevalence of pathological changes in live donors' kidneys and their association with the graft outcome. METHODS: This cohort study was performed among a group of renal transplant recipients. Biopsy was taken from donor's kidney. The functionality of the grafted kidney was then evaluated by measuring serum creatinine, based on which, the patients were categorized into "successful" and "unsuccessful" groups. The results were compared based on biopsy results. RESULT: We studied 58 kidneys from live donors. The mean±SD urine volume on the first day after transplantation was 10,052±3286 mL. Absence of allograft dysfunction was seen in 55 (95%) patients during a month, 51 (88%) patients in 6 months, and 53 (91%) within a year. Glomerulosclerosis was seen in 20 (35%) patients, fibrosis in 9 (16%), tubular atrophy in 5 (9%), and intimal fibrosis in 3 (5%). The mean±SD serum creatinine in patients within 1-month survival was 1.15±0.19, within 3-month survival was 1.17±0.20, within 6-month survival was 1.21±0.20, within 9-month survival was 1.43±1.28, and within 1-year survival was 1.14±0.22. CONCLUSION: Kidney biopsy from live donors can show us a general status of kidney. Serum creatinine is the test of choice for evaluating the grafted kidney function.

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.

Esophagitis may not be a Major Precursor Lesion for Esophageal Squamous Cell Carcinoma in a High Incidence Area in North-Eastern Iran.

BACKGROUND Esophageal squamous cell carcinoma (ESCC) is usually detected in advanced stages resulting in a very poor prognosis. Early diagnosis needs identification of clinically relevant precancerous lesions which could become the target of screening and early treatment. Our aim was to check whether esophagitis could serve as a relevant histological precursor of ESCC in Northern Iran. METHODS During 2001-2005, all adult patients who were referred to Atrak clinic for upper gastrointestinal endoscopy and biopsy were enrolled. Atrak clinic is a major center for upper gastrointestinal cancer research in eastern Golestan. All subjects had been complaining of upper GI symptoms and were under further investigation to rule out cancer. Biopsies from the endoscopically normal mid-esophagus and also just above the esophago-gastric junction were obtained in all subjects whose esophagus appeared normal during endoscopy and from endoscopically normal appearing mucosa at the proximal vicinity of any detected mass. Microscopic examinations for the verification of the presence or absence of esophagitis was performed by independant histological examination of the samples by two pathologists. All the discrepant diagnoses were resolved in joint diagnostic sessions. RESULTS During the study period 836 patients were enrolled including 419 non cancer patients (endoscopy clinic controls), 387 cancer patients, and 30 subjects with clinical diagnosis of malignancy referred for histological reconfirmation of diagnosis by repeated biopsy. Mild or marked mid-esophagitis was diagnosed in 39 (9.3%), 47 (12.5%) and 12 (40%) of endoscopy clinic controls, cancer patients and those who were suspicious for upper gastrointestinal malignancies. CONCLUSION Our observation does not show evidence for esophagitis to be a predisposing factor for ESCC in Gonbad region In North Eastern Iran.

Effect of chitosan-polyvinyl alcohol blend nanofibrous web on the healing of excision and incision full thickness wounds.

Chitosan-polyvinyl alcohol (PVA) blend nanofibrous webs were fabricated in different blend ratios through electrospinning procedures. From scanning electron microscopy (SEM) results, 25/75 blend ratio of chitosan-PVA was selected for biological studies. In vivo studies were carried out on the dorsum of rats of two types: longitudinal incisional wounds (n=8 rats) and round excisional wounds (n=8). Pathological study was done on the wounds to investigate the healing process. The histological study in wound healing indicated that the administration of chitosan nanofibrous web improved the wound healing, qualitatively and quantitatively.

Excess costs associated with common healthcare-associated infections in an Iranian cardiac surgical unit.

Healthcare-associated infection (HCAI) following open heart surgery is not only a major cause of mortality and morbidity, but also carries higher costs. There are limited data on the additional costs due to HCAI in non-western countries. To estimate the direct cost of the four most common HCAIs in an Iranian sample, we studied 1191 patients admitted for elective open heart surgery. HCAIs were defined using the National Nosocomial Infections Surveillance criteria (Centers for Disease Control and Prevention, Atlanta, GA, USA). The financial costs of length of stay per day in hospital, paraclinical services, medications, instruments, and operating room were provided by the hospital's finance department. The contribution of HCAI to excess direct medical costs in patients with HCAI was assessed by multivariable linear regression. In the study population, the mean age was 57.3±11.9 years, 857 (72.0%) were men, and 64 (5.4%) developed HCAI. In total there were 73 infections of which the most common was surgical site infection (49.3%), followed by urinary tract infection (20.5%), bloodstream infection (16.5%), and pneumonia (13.7%). After adjustment for other confounders HCAI remained associated with excess direct medical costs (ß=1707.06, SE=90.84; P < 0.001). The medical costs in patients with HCAI were almost twice those in patients without HCAI. More than half of the excess cost was attributable to prolonged hospitalisation.

Histopathological Study of Chronic Hepatitis B: A Comparative Study of Ishak and METAVIR Scoring Systems.

BACKGROUND: Ishak and METAVIR scoring systems are among the most commonly used histopathological systems to evaluate chronic hepatitis. OBJECTIVE: To assess the level of agreement between these two scoring systems in patients with chronic hepatitis B. METHODS: Liver biopsy samples taken from 92 patients with chronic hepatitis B were considered as the training set; 57 more biopsy specimens were used as the validation set. In the training set, grade of necroinflammation and stage of fibrosis for each liver biopsy specimen were determined by two expert liver pathologists using both Ishak and METAVIR systems. Inter-observer variability between the two pathologists was evaluated. Biopsy specimens of the validation set were seen and scored by a third expert pathologist. In the training set, criteria were developed to categorize Ishak grading and staging systems separately to best fit with the METAVIR scoring system. The criteria found in the training set, was then tested in the validation set. The level of agreement between the two scoring systems was assessed by weighted kappa statistics. RESULTS: For the training set, agreement between the two pathologists was excellent. Using our proposed criteria in the training set, there was excellent level of agreement in grading (κ = 0.89) and staging (κ = 0.99) between Ishak and METAVIR systems. In the validation set, the criteria led to substantial correlation (κ = 0.61) in grading, and excellent correlation (κ = 0.94) in staging between the two systems. CONCLUSION: Using our proposed criteria, excellent or at least substantial concordance between Ishak and METAVIR scoring systems can be achieved for the degree of both necro-inflammatory changes and fibrosis.

Pancreatic islet beta cell protective effect of oral vanadyl sulphate in streptozotocin-induced diabetic rats, an ultrastructure study.

We sought to determine the ultrastructure of pancreatic islet beta cells of streptozotocin-induced diabetic rats treated with oral vanadyl sulphate. Diabetes was induced in male Wistar rats by intravenous injection of 40 mg kg(-1) streptozotocin. The same volume of normal saline was injected in sham animals. Animals were divided into treated and control groups. Vanadyl sulphate was added to the drinking water of the treated animals at a concentration of 1 mg mL(-1) up to three months. Two months after vanadyl sulphate withdrawal animals were killed. Ultrastructure of islet beta cells were studied by transmission electron microscope. In diabetic treated rats plasma glucose and fluid intake returned to normal levels within three months while control animals remained diabetic. Well granulated cytoplasm, well developed endoplasmic reticulum, increase in the number of immature granules in the cytoplasm with no clear signs of cell injury were found in the islet beta cells of diabetic treated rats. Lymphocyte filteration, nuclear picnosis, cytoplasmic vacuolization were found frequently in the islet beta cells of untreated diabetic rats. In conclusion as was evident in thin sections of panceatic islet beta cells of treated diabetic rats in this study, vanadyl sulphate through preserving islet beta cells structure and ultrastructure contributes in reversing diabetic signs and symptoms in streptozotocin induced diabetic rats.

Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice.

Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of beta cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a mu-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40 mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10 mg/kg/day subcutaneously) for 24 days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1beta, tumor necrosis factor-alpha and interferon-gamma] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of beta cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of beta cells and insulitis in the MLDS model of type 1 diabetes.

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%).

Combination of gastric atrophy, reflux symptoms and histological subtype indicates two distinct aetiologies of gastric cardia cancer.

INTRODUCTION: Atrophic gastritis is a risk factor for non-cardia gastric cancer, and gastro-oesophageal reflux disease (GORD) for oesophageal adenocarcinoma. The role of atrophic gastritis and GORD in the aetiology of adenocarcinoma of the cardia remains unclear. We have investigated the association between adenocarcinoma of the different regions of the upper gastrointestinal tract and atrophic gastritis and GORD symptoms. METHODS: 138 patients with upper GI adenocarcinoma and age- and sex-matched controls were studied. Serum pepsinogen I/II was used as a marker of atrophic gastritis and categorised to five quintiles. History of GORD symptoms, smoking and H pylori infection were incorporated in logistic regression analysis. Lauren classification of gastric cancer was used to subtype gastric and oesophageal adenocarcinoma. RESULTS: Non-cardia cancer was associated with atrophic gastritis but not with GORD symptoms; 55% of these cancers were intestinal subtype. Oesophageal adenocarcinoma was associated with GORD symptoms, but not with atrophic gastritis; 84% were intestinal subtype. Cardia cancer was positively associated with both severe gastric atrophy [OR, 95% CI: 3.92 (1.77 to 8.67)] and with frequent GORD symptoms [OR, 95% CI: 10.08 (2.29 to 44.36)] although the latter was only apparent in the non-atrophic subgroup and in the intestinal subtype. The association of cardia cancer with atrophy was stronger for the diffuse versus intestinal subtype and this was the converse of the association observed with non-cardia cancer. CONCLUSION: These findings indicate two distinct aetiologies of cardia cancer, one arising from severe atrophic gastritis and being of intestinal or diffuse subtype similar to non-cardia cancer, and one related to GORD and intestinal in subtype, similar to oesophageal adenocarcinoma. Gastric atrophy, GORD symptoms and histological subtype may distinguish between gastric versus oesophageal origin of cardia cancer.

Patterns of K-ras mutation in colorectal carcinomas from Iran and Italy (a Gruppo Oncologico dell'Italia Meridionale study): influence of microsatellite instability status and country of origin.

BACKGROUND: K-ras mutations are a key step in colorectal cancer progression. Such mutations have been widely studied in case series from Western countries but there are few data on the rate and spectrum of mutations in tumors from countries where the epidemiological features of the disease are different. PATIENTS AND METHODS: Tumor samples from 182 Iranian colorectal cancer patients (170 sporadic cases and 12 HNPCC cases) were screened for K-ras mutations at codons 12, 13 and 61 by sequencing analysis. The cases were also characterized for microsatellite instability at mononucleotide repeats by PCR and fragment analysis, and classified according to microsatellite instability status. The frequency and the spectrum of K-ras mutations were compared with those observed in a series of colorectal cancer patients from Italy. RESULTS: K-ras mutations were observed in 68/182 (37.4%) cases. Mutation frequencies were similar in HNPCC-associated, sporadic MSI-H and sporadic microsatellite-stable (MSS) tumors. However, the G13D substitution was more frequent in HNPCC (3/4, 75%) and sporadic MSI-H (7/11, 63.6%) tumors compared to sporadic MSS tumors (11/53, 20.4%) (P <0.01). Comparison of mutations in the two series from Iran and Italy showed a significantly higher frequency of G13D among Italian patients. CONCLUSIONS: While the frequency of K-ras mutations could be similar, the mutational spectrum could be differentially influenced by genetic and environmental factors.

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.