Zaffar Amin Shah

Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study.

CONTEXT To improve the treatment outcomes in women with polycystic ovary syndrome (PCOS), various drugs like glitazones, oral contraceptive pills, or antiandrogens have been combined with metformin. OBJECTIVE The aim of the study was to compare the efficacy of the combination of low-dose spironolactone and metformin with either drug alone in the management of women with PCOS. DESIGN AND SETTING The present study was an open-label, randomized study conducted at a tertiary care referral center. PATIENTS AND INTERVENTION Of 204 women who met the 2006 Androgen Excess-PCOS criteria for PCOS, 198 were randomized into 3 equal groups to receive metformin (1000 mg/d), low-dose spironolactone (50 mg/d), or a combination of both drugs for a period of 6 months. A total of 169 subjects (n = 56 metformin, 51 spironolactone, 62 combination) completed the study. MAIN OUTCOME MEASURES Menstrual cycle pattern, Ferriman-Gallwey score, body mass index (BMI), waist-hip ratio, blood pressure, LH, FSH, total T, glucose and insulin sensitivity indices were measured at baseline (0 mo) and 3 and 6 months after the intervention. Recording of adverse events and drug compliance was assessed at each of the visits. RESULTS The 3 groups had comparable mean age and BMI at baseline. By 6 months, menstrual cycles/y increased, whereas Ferriman-Gallwey score, serum total T, and area under the curve-glucose and -insulin decreased significantly (P < .05) in the combination group as compared to either drug alone. There was no significant change in body weight, BMI, waist-hip ratio, and blood pressure in any of the 3 groups. The combination group had better compliance than either drug alone, and the adverse event rate was not higher. CONCLUSION The combination of low-dose spironolactone with metformin seems superior to either drug alone in terms of clinical benefits and compliance in women with PCOS.

High prevalence of vitamin D deficiency among newly diagnosed youth-onset diabetes mellitus in north India

OBJECTIVES Vitamin D deficiency is common at all ages, and low levels of vitamin D have been associated with high incidence of type 1 diabetes. Similar results are not consistent for type 2 diabetes. The aim of the present study was to estimate vitamin D status in newly detected youth-onset diabetes in north India. SUBJECTS AND METHODS This was a prospective case control study at a tertiary care hospital in north India. Seventy two newly detected youth-onset diabetes subjects (age < 25 years), and 41 age- and gender-matched healthy controls were studied. In addition to basic information and management regarding their diabetes, metabolic parameters and serum 25(OH)D were measured in both the groups. RESULTS Vitamin D deficiency was seen in 91.1% of the subjects with diabetes, and 58.5% of the healthy controls. Mean ±SD 25(OH)D was significantly low, 7.88 ± 1.20 ng/mL in subjects with diabetes against 16.64 ± 7.83 ng/mL in controls. Sixty percent of cases had severe Vitamin D deficiency compared with 8.3% in controls. Levels of vitamin D did not correlate with clinical parameters, such as gender, body mass index; or with biochemical parameters, such as serum calcium, phosphorus, alkaline phosphatase, fasting plasma glucose, and HbA1C. CONCLUSION Vitamin D deficiency is common in people with youth-onset diabetes.

Molecular Gate Keepers Succumb to Gene Aberrations in Colorectal Cancer in Kashmiri Population, Revealing a High Incidence Area

Background/Aim: Colorectal cancer (CRC) is one of the leading malignancies worldwide and has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. The aim of this study was to identify p53 and K-ras gene mutations in CRC patients in a Kashmiri population, and to assess whether these mutations are linked with clinicopathological parameters. Materials and Methods: Paired tumor and normal tissue samples from a consecutive series of 53 patients undergoing resective surgery for CRC were prospectively studied for p53 and K-ras gene mutations by PCR/single strand conformation polymorphism (SSCP). Results: Less than half (45%, 19/42) of the patients presented mutations in the p53 gene. Twenty eight mutations were found in the p53 gene, which comprised of 23 substitutions (17 transitions + 6 transversions), and five insertions. The 23 substitutions constituted 18 missense mutations, two nonsense mutations, and three silent mutations. Of the 28 mutations (7.14%) observed in this study, 2 were not previously reported for CRC samples and were identified as novel p53 mutations. A few patients (22.64%, 12/53) presented with mutations in K-ras, constituting 13 missense mutations, out of which 11 were G→A transitions, one was a G→C transversion, and one a G→T transversion. More than half (61.5%) of the mutations occurred in codon 12 whereas a few (38.5%) occurred in codon 13. One tumor contained missense mutations in both codons. Comparison of the mutation profiles of our patients with those of other ethnic populations and regions reflected both differences and similarities, indicating co-exposure to a unique set of risk factors. Conclusion: Mutations of the p53 and K-ras genes are some of the most common genetic changes in the development of human CRC. The high frequency of p53 gene mutations implicates p53 as a predominant factor for CRC in the high-risk ethnic Kashmiri population.

SMAD4 - Molecular gladiator of the TGF-β signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene

BackgroundThe development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the SMAD4 gene mutations with KRAS mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of SMAD4 gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and KRAS mutant genotype.MethodsWe examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of SMAD4 and exon 1 of KRAS by PCR-SSCP and/or PCR-Direct sequencing.ResultsThe overall mutation rate of mutation cluster region (MCR) region of SMAD4 gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the SMAD4 gene mutants were found to have mutations in KRAS gene as well. The association between the KRAS mutant genotype with SMAD4 mutants was found to be significant (P =< 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the SMAD4 gene (P =< 0.05).ConclusionOur study suggests that SMAD4 gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the KRAS mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.

Analysis of molecular aberrations of Wnt pathway gladiators in colorectal cancer in the Kashmiri population

The development and progression of colorectal cancer (CRC) is a multi-step process, and the Wnt pathways with its two molecular gladiators adenomatous polyposis coli (APC) and β-catenin plays an important role in transforming a normal tissue into a malignant one. In this study, we aimed to investigate the role of aberrations in the APC and β-catenin genes in the pathogenesis of CRC in the Kashmir valley, and to correlate it with various clinicopathological variables. We examined the paired tumour and normal-tissue specimens of 86 CRC patients for the occurrence of aberrations in the mutation cluster region (MCR) of the APC gene and exon 3 of the β-catenin gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and/or PCR-direct sequencing. Analysis of promoter hypermethylation of the APC gene was also carried out using methylation-specific PCR (MS-PCR). The overall mutation rate of the MCR of the APC gene among 86 CRC cases was 12.8 per cent (11 of 86). Promoter hypermethylation of APC was observed in 54.65 per cent (47 of 86) of cases. Furthermore, we found a significant association between tumour location, tumour grade and node status and the methylation status of the APC gene (p ≤ 0.05). Although the number of mutations in the APC and β-catenin genes in our CRC cases was very low, the study confirms the role of epigenetic gene silencing of the pivotal molecular gladiator, APC, of the Wnt pathway in the development of CRC in the Kashmiri population.

Effect of Vitamin D supplementation on glycemic parameters and progression of prediabetes to diabetes: A 1-year, open-label randomized study

Background: Whether Vitamin D supplementation in prediabetes subjects prevents the development of diabetes is a matter of debate, and the results are inconsistent. This open-label, randomized study in subjects with prediabetes evaluated the effect of 12 months of Vitamin D supplementation on glycemic parameters and progression of prediabetes to diabetes in an ethnically homogeneous Kashmiri population. Materials and Methods: A total of 147 subjects were diagnosed as prediabetes out of which 137 subjects were randomized to receive in addition to standard lifestyle measures, either Vitamin D 60,000 IU weekly for 4 weeks and then 60,000 IU monthly (n = 69) or no Vitamin D (n = 68). Fasting plasma glucose (FPG), 2-h plasma glucose and A1C levels were estimated at 0, 6 and 12 months. Changes in FPG, 2-h plasma glucose, A1C level and the proportion of subjects developing diabetes were assessed among 129 subjects. Results: At 12 months, A1C levels were significantly lesser (5.7% ± 0.4%) in the Vitamin D supplemented group when compared with non-Vitamin D supplemented (6.0% ± 0.3%). Similarly, FPG (97 ± 7) and 2-h plasma glucose (132 ± 16) were significantly less in Vitamin D supplemented group as compared with non-Vitamin D supplemented group (FPG = 116 ± 6 and 2-h plasma glucose = 157 ± 25) at 12 months. Nine out of 65 in non-Vitamin D supplemented and seven out of 64 in the Vitamin D supplemented group developed diabetes. Conclusions: Vitamin D supplementation in prediabetes subjects significantly lowered FPG, 2-h plasma glucose and A1C levels.

Pattern of urinary albumin excretion in normotensive young and adolescent Indian women with polycystic ovary syndrome

Objective: Polycystic ovarian syndrome (PCOS) is a clinically heterogeneous endocrine disorder affecting up to 4–8% of women of reproductive age. The aim of this study was to evaluate the presence of microalbuminuria in women with PCOS and study its correlation with the various metabolic, clinical, and hormonal parameters. Materials and Methods: A cross-sectional study involving 69 PCOS women was carried out in a tertiary care center hospital. The diagnosis of PCOS was made according to the Rotterdam criteria. Blood samples were collected in the follicular phase of the menstrual cycle and analyzed for fasting luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), 17-hydroxyprogesterone (17-OHP), total testosterone (T), glucose, insulin, and lipid profile. Urinary albumin was measured in the first void spot urine sample. Results: The mean age of the subjects was 22.0 ± 4.1 years and 21.8 ± 4.7 years in normoalbuminuric and microalbuminuric groups, respectively. Urinary albumin excretion (UAE) varied from 5 mg/l to 100 mg/ml, with a median of 5 mg/l. Microalbuminuria was observed in 17/69 (24.6%) of subjects. The mean UAE was 3.65 ± 4.44 mg/l in the normoalbuminuria group versus 45.29 ± 22.74 mg/l in the microalbuminuria group. Upon univariate analysis, hip circumference, diastolic blood pressure, and fasting blood glucose showed significant correlations with urinary albumin concentration (r = 0.264, 0.264, and 0.551, respectively; P = 0.028, 0.029, and 0.000, respectively). No association between UAE and the usual cardiovascular risk factors could be found upon regression analysis. Conclusion: About 24.6% of women with PCOS showed presence of microalbuminuria in the first void spot urine sample. Screening for the presence of microalbuminuria can help in early identification of a subset of PCOS women with a high risk for future CVD, who can be subjected to preventive strategies at the earliest. However, further studies are needed before recommending routine use of UAE in PCOS cases for the detection of CVD risk.

Pattern of 25 hydroxy vitamin D status in North Indian people with newly detected type 2 diabetes: A prospective case control study.

Background: Vitamin D deficiency (VDD) has been linked to impaired glucose tolerance and type 2 diabetes (T2D) in humans. The aim of the present study was to find the vitamin D status in newly detected T2D patients compared with healthy controls. Materials and Methods: One hundred and two, newly detected T2D patients and similar number of age, body mass index (BMI), and gender matched healthy controls without diabetes were studied. In addition to basic information, metabolic parameters and serum 25 hydroxy vitamin D (25HD) were measured in both the groups. Results: Overall 25HD, was lower (mean ± SD, 18.81 ± 15.18 ng/ml) in patients with T2D as compared to healthy controls (28.46 ± 18.89 ng/ml) (P = 0.00). Taking a cut of 30 ng/ml, 81% of T2D patients had either VDD or insufficiency compared to 67% of healthy control subjects. Severe VDD (25HD of < 5 ng/ml) was seen in 16.2% of patients with diabetes and 2.5% of control subjects. Levels of 25HD had a negative correlation with HbA1c, fasting plasma glucose. Conclusions: VDD is common in people with new onset T2D.

Prevalence of metabolic syndrome in the family members of women with polycystic ovary syndrome from North India

Background: Polycystic ovary syndrome (PCOS) is the most complex and common endocrine disorder of women in reproductive years. In addition to irregular menstrual cycles, chronic anovulation and hyperandrogenism, it has many metabolic manifestations such as obesity, hyperlipidemia, hyperinsulinemia, insulin resistance, dysglycemia, increased risk of cardiovascular disease or possibly endometrial cancer. Familial clustering of PCOS in consistence with the genetic susceptibility has been described. Materials and Methods: The present study assessed the clinical, biochemical and hormonal parameters including prevalence of metabolic syndrome by two different criteria in the first- degree relatives of patients with PCOS. Results: The average age of 37 index patients was 23 ± 3.6 years, with the mean age of menarche as 13.3 ± 1.2 years. The mean age and age of menarche in mothers (n = 22) was 48.8 ± 5.1 and 13 ± 1.3 years, respectively, whereas as it was 23.5 ± 4.7 and 13.3 ± 1.2 years in sisters (n = 22), respectively. Metabolic syndrome (MS) defined by International Diabetes Federation (IDF) criteria was present in 10 index patients, 1 brother, 4 sisters, 17 mothers and 15 fathers while as by Adult Treatment Panel III (ATP III) it was in 8 index patients, 5 sisters, 16 mothers and 11 fathers. Conclusion: The presence of MS or related metabolic derangements is high in the family members of women with PCOS.

Pattern of adrenal morphology and function in pulmonary tuberculosis: response to treatment with antitubercular therapy.

Although previous studies have shown enlargement of adrenal glands in patients with tuberculosis, only few have studied its natural history. Similarly, there have been variable reports of adrenal function in these patients. Some but not all the studies revealed a high prevalence of adrenal insufficiency. The aim of this study was to prospectively study the adrenal cortical function and morphology before and after treatment of pulmonary tuberculosis.