Cardiovascular disease risk in young Indian women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with significant risk factors for cardiovascular disease (CVD) like insulin resistance, hyperinsulinism, hypertension and dyslipidemia. We studied CVD risk in young women (18-35 years age) with PCOS using carotid intima media thickness (CIMT) and brachial artery flow mediated dilation (FMD) which are markers of subclinical atherosclerosis. Fifty women with PCOS (age: 24.3 ± 4 years; body mass index [BMI]: 24.6 ± 4 kg/m(2)) were compared with 50 age and BMI matched healthy controls (age: 24.6 ± 5 years; BMI: 23.9 ± 4 kg/m(2)). CIMT was significantly higher (0.55 ± 0.09 mm versus 0.40 ± 0.1 mm, p value <0.0001) and FMD was significantly lower (9.39 ± 4.36% versus 13.89 ± 4.77%, p value <0.0001) in cases as compared to controls. These differences in CIMT and FMD remained significant when subgroup were analyzed, obese PCOS versus obese controls and non obese PCOS versus non-obese controls. In stepwise linear regression PCOS was associated with CIMT and FMD independent of age, BMI and blood pressure. Young women with PCOS irrespective of their BMI have evidence for increased CVD risk as shown by increased CIMT and a lower FMD.

Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele.

Type 1 diabetes (T1D; or insulin-dependent diabetes mellitus, IDDM) is an autoimmune disease with both genetic and environmental components. In addition to the human leukocyte antigen (HLA) complex, the single major genetic contributor of susceptibility, an unknown number of other unidentified genes are required to mediate disease. Although many loci conferring susceptibility to T1D have been mapped, their identification has proven problematic due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci implicated in diabetes-prone NOD (non-obese diabetic) mice, together with application of biologically relevant stratification methods. We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B. Significant bias in transmission of IL12B alleles was observed in affected sibpairs and was confirmed in an independent cohort of simplex families. A single base change in the 3' UTR showed strong linkage disequilibrium with the T1D susceptibility locus. The IL12B 3' UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases.

Quality of life and gender role behavior in disorders of sexual differentiation in India.

OBJECTIVE: Culture-specific tools to assess longterm psychosocial outcomes for patients with disorders of sexual differentiation are scant. We conducted a study to develop tools for evaluating gender role behavior and health related quality of life for Indian adolescent patients with intersex disorders. We also studied factors important to parents while deciding sex of rearing for their baby. METHODS: A 29-item gender role behavior questionnaire and an 18-item health related quality-of-life questionnaire were administered to 82 healthy controls, 13 patients with intersex disorders and 18 patients with type 1 diabetes mellitus. Internal consistency was checked by Cronbach's alpha and test-retest reliability using intra-class correlation coefficient. Responses of 28 parents to a questionnaire on factors affecting the decision of sex of rearing were recorded on a 5-point Likert scale in order of importance. RESULTS: Cronbach's alpha was 0.92 and 0.75, and intra-class correlation coefficient 0.76 and 0.75, for the gender role behavior and quality-of-life questionnaires respectively, indicating a high degree of internal consistency and stability. The mean composite scores for healthy girls on the gender role behavior questionnaire (82.5 +/- 8.7) differed significantly from that for healthy boys (53.2 +/- 7.1, p <0.001). Factors important to parents while making decisions for sex of rearing were appearance of the genitalia, medical advice, ability to bear children and economic independence. CONCLUSIONS: We have created valid tools to study gender role behavior and quality of life in adolescent patients with intersex disorders in India. We have also identified in a quantitative way the factors of greatest importance to parents while deciding sex of rearing. These results have direct utility in the management of patients with intersex disorders in India and other similar cultures.

Tumor necrosis factor-alpha allele 2 shows an association with insulin-dependent diabetes mellitus in Latvians.

Insulin-dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune disease. Genes contributing the most for development of IDDM are located on chromosome 6p21.3 in the region called the major histocompatibility complex (MHC). HLA-DQ8/DR4 and DQ2/DR3 have shown positive association with IDDM, while DQ6 has negative association with IDDM in most Caucasian populations. The location of the tumor necrosis factor alpha (TNF-alpha) gene in the MHC suggests the role of TNF in the etiology of IDDM as an autoimmune disease. The TNF region contains several polymorphisms that are associated with different levels of TNF-alpha production and susceptibility to autoimmune and infectious diseases. Ninety-two Latvian IDDM patients corresponding to WHO diagnostic criteria and 107 unrelated age- and sex-matched healthy controls were analyzed for the frequency of TNF-alpha alleles to test the hypothesis that TNF-alpha is associated with IDDM. We found that TNF-alpha microsatellite allele 2 is associated with IDDM, 29/92 (32%), versus 14/107 (13%) in healthy controls. The test of the strongest association of the MICA A5 allele and TNF-alpha allele 2 with IDDM showed that both are independently associated with the disease.

Islet-cell antibodies in malnutrition-related diabetes mellitus from north India.

The etiology of malnutrition-related diabetes mellitus (MRDM)--protein-deficient pancreatic diabetes (PDPD) and fibro-calculous pancreatic diabetes (FCPD)-is unclear. We studied the role of autoimmunity against pancreatic islet cells in the etiology of these two subtypes of MRDM by measuring islet-cell antibodies (ICA) in 23 patients with PDPD, 25 with FCPD and 62 with Type 1 diabetes. Three patients (13%) with PDPD had detectable ICA. Including a patient with a high titre of ICA (> 80 JDF units). The frequency of ICA in patients with PDPD was significantly lower than subjects with Type 1 diabetes (22/62, 35%; P < 0.05). Among patients studied at onset. ICA prevalence was lower in the PDPD patients (1/7, 14%) compared to subjects with Type 1 diabetes (8/20, 40%). No patient of FCPD had detectable ICA (P < 0.001 vs. Type 1 diabetes subjects). We conclude that autoimmunity may play a role in the etiology of some patients with the PDPD subtype of MRDM. However, FCPD is unlikely to have an autoimmune etiology.

Etiology and outcome of childhood and adolescent diabetes mellitus in North India.

The etiology of childhood onset diabetes mellitus (DM) varies between regions and races, and its long-term outcome is affected by social and economic factors. There are scant data on the etiology of childhood DM and outcome of multidisciplinary team management from developing countries. We retrospectively analyzed case records of 160 predominantly middle socio-economic group patients with onset of DM < or =18 years of age for etiology and features at presentation. In addition, we prospectively studied acute and chronic complications and metabolic control in a subset of 67 patients. Type 1 DM comprised 81%, type 2 DM 8%, and fibrocalculous pancreatic DM 9% of patients. Mean HbA1c was 8.0+/-1.5%. Retinopathy was present in 22% and nephropathy in 18% of those with DM duration > or =5 years (mean age 21.2+/-6.8 years, mean duration 10.2+/-4.6 years). The frequency of ketoacidosis and severe hypoglycemia was 5.0 and 3.3 episodes per 100 patient years. Mortality was 7% over 823 person years of follow up. We conclude that fairly good metabolic control is achievable in a middle socio-economic population in India, with the assistance of a diabetes education program. The frequency of microvascular complications is comparable to that in the literature. However, mortality remains unacceptably high.

Growth charts suitable for evaluation of Indian children.

OBJECTIVE: To assess the suitability of recently published reference anthropometric data for evaluation of the growth of children in our region. SETTING: Referral Pediatric Endocrinology Clinic in tertiary level care hospital. SUBJECTS: 280 normal school children and 155 children referred for growth retardation to the clinic in 1993 and 1994. METHODS: Heights of school children were plotted on growth charts created from recently published reference growth data of children from high socioeconomic group families. The case records of 155 children referred for growth evaluation were retrospectively analyzed for (i) etiology of short stature, (ii) height percentile based on previously used Indian Council of Medical Research (ICMR) references, and (iii) height percentile and standard deviation scores based on the new references. RESULTS: 93% of school children fell above and 7% below the 5th centile of the new height references. Of the 129 clinic children diagnosed to have growth retardation, 128 fell below the 5th centile of the new references. However, 38 of these (29.5%) fell above the 5th centile of ICMR references. These included patients with pathological causes of short stature. Twenty four of 26 children labelled as having no growth problem fell above the 5th centile of new reference data. CONCLUSIONS: The 5th height centile of new reference data from high socioeconomic group children is an appropriate cut off below which to evaluate children for short stature in our region. It will allow earlier identification and treatment than the hitherto used ICMR percentiles, and yet is not expected to result in over investigation of normal children.

Deteriorating diabetic control through adolescence-do the origins lie in childhood?

AIMS: To determine whether intra-individual measures of diabetes control deteriorated through adolescence and whether HbA1c in late childhood was predictive of HbA1c after adolescence. METHODS: Retrospective analysis of sequential 3-6 monthly data including HbA1c, height, weight, and total daily insulin dosage in 118 patients with Type 1 diabetes aged between 8.00 and 17.99 years between 1983 and 1999. RESULTS: In females mean body mass index (BMI) increased sharply during adolescence but there was no significant increase in males. The mean total daily dose of insulin/weight (TDDI/W) increased sharply for females through puberty. Males exhibited a constant rate of increase in mean TDDI/W from pre- to post-puberty. There was a constant increase in mean HbA1c for females, with an estimated increase from pre- to post-puberty of 0.92%. In males there was only a slight increase from pre- to peri-puberty and no change subsequently. Comparing pre-puberty (8-9.99 years) and post-puberty (15-17.99 years) in the total group, 47% of patients remained in the same mean HbA1c grouping, 37% had worsened control and 16% had improved control. Analysis of change in the absolute value of mean HbA1c showed that the majority of patients had mean HbA1c values that remained within +/- 1% (54%) or +/- 2% (82%) from pre- to post-puberty. A significant proportion showed significantly worsening control with only a minority showing improved metabolic control from pre- to post-puberty. CONCLUSIONS: The likelihood of a significant improvement in HbA1c from late childhood to adolescence is remote, with the majority of patients having either constant or deteriorating metabolic control.

Extrahepatic portal vein obstruction in children: anthropometry, growth hormone, and insulin-like growth factor I.

BACKGROUND: Extrahepatic portal vein obstruction has been shown to cause growth retardation in children, though literature is scant. No information is available regarding the cause of growth retardation in these patients. METHODS: To document the presence of growth retardation in this disease, we studied growth and nutrition in 33 consecutive prepubertal patients. Anthropometry, fasting growth hormone, and insulin-like growth factor I levels were compared in 22 well-nourished patients from this group with 35 age-matched well-nourished controls. RESULTS: Mean +/- SD height standard deviation score of well-nourished patients (-1.88 +/- 1.33) was significantly below that of the controls (-1.06 +/- 0.64, p < 0.01). Patients also had significantly lower midarm muscle circumference z scores (-2.65 +/- 1.09) than controls (-1.17 +/- 1.09, p < 0.0001), though triceps skinfold thickness z scores were comparable in the two groups (-1.06 +/- 0.68 vs -1.24 +/- 0.79, p = NS). Insulin-like growth factor I z scores were significantly lower in patients (-1.48 +/- 0.88) than in controls (-0.49 +/- 1.09, p < 0.001), whereas basal growth hormone was significantly higher in patients (4.60 +/- 3.70 mIU/L) compared with controls (2.66 +/- 0.82, p < 0.01). CONCLUSION: Extrahepatic portal vein obstruction in children leads to growth retardation. Anthropometric and preliminary hormonal evaluation suggest resistance to the action of growth hormone as a possible mechanism.

Role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indians.

AIMS: To determine the role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indian patients by measuring islet autoantibodies. METHODS: In a cross-sectional study, 145 young patients with diabetes (onset < 30 years) were subdivided into the following categories: Type 1 diabetes (n = 83), malnutrition-modulated diabetes mellitus (MMDM, n = 31) and fibro-calculous pancreatic diabetes (FCPD, n = 31). MMDM subjects presented with emaciation and severe insulin-requiring but ketosis-resistant diabetes, while FCPD was associated with idiopathic chronic calcific pancreatitis. Antibodies to glutamic acid decarboxylase (GADA) and IA-2 (IA-2 A) were detected by immunoprecipitation of 35S-labelled recombinant antigens and cytoplasmic islet cell antibody (ICA) by indirect immunofluorescence. RESULTS: GADA were present in a significant proportion (23%) of patients with MMDM. In contrast, IA-2 A was increased only among patients with Type 1 diabetes (22%), but not MMDM (3%, P < 0.05). Among patients with a duration of diabetes < 2 years, GADA and/or IA-2 A were found in 61% of Type 1 diabetic and 37% of MMDM patients (P < 0.01). MMDM patients who were positive for GADA had a shorter duration of diabetes, but did not differ in their age at onset of diabetes, body mass index, fasting plasma C-peptide, or frequency of thyroid microsomal and parietal cell antibodies. FCPD subjects had the lowest prevalence of autoantibodies: IA-2 and ICA were absent, while GADA were present in 7% (P < 0.05 vs. Type 1 diabetes). CONCLUSIONS: GADA, though not IA-2 A, were present in a substantial proportion of patients with the MMDM variant of diabetes, suggesting that islet autoimmunity may play a role in its pathogenesis. In contrast, none of the islet antibodies was increased in subjects with FCPD, making it likely that it is a secondary type of diabetes.

Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis.

OBJECTIVE: To examine the role of NRAMP1 in susceptibility to juvenile rheumatoid arthritis (JRA). METHODS: DNA from 119 JRA patients (72 pauciarticular, 47 polyarticular) and 111 healthy controls from Latvia was genotyped for a functional repeat polymorphism in the promoter of NRAMP1 and a linked (<150 kb) microsatellite D2S1471. The findings were compared with those from HLA-DQ alleles typed previously. Chi-square analyses were performed using the Mantel-Haenszel test and stratification according to pure Latvian or pure Russian descent. Haplotype analysis was performed using the Associate program to implement the expectation-maximization algorithm based on the gene-counting technique. RESULTS: Allele 3 at NRAMP1 conferred increased risk (odds ratios [ORs] 2.26, 2.31, and 2.19; P = 0.0006, 0.003, and 0.019) of disease in the JRA, pauciarticular, and polyarticular patient groups, respectively. Allele 2 conferred protection (OR 0.44, 0.43, and 0.46). Alleles at D2S1471 that conferred susceptibility (6 and 12) or protection (11) did so only when on a haplotype with alleles 3 or 2, respectively, at NRAMP1. Allele 3 at NRAMP1 was additive with HLA-DQ7 for susceptibility (OR 3.71, 3.71, and 4.02), and allele 2 at NRAMP1 was additive with HLA-DQ5 for protection (OR 0.19, 0.08, and 0.12). CONCLUSION: The NRAMP1 allele conferring susceptibility to JRA drives high levels of NRAMP1 expression, while the allele associated with protection drives low levels. These 2 alleles are inversely associated with susceptibility to infectious disease, consistent with their maintenance in populations through balancing selection.

Atopy in children in relation to BCG vaccination and genetic polymorphisms at SLC11A1 (formerly NRAMP1) and D2S1471.

The influence of the SLC11A1 (formerly NRAMP1) gene on the association between BCG vaccination and atopy in children was studied in 179 children, BCG vaccinated in infancy, and 307 children without BCG vaccination, all 3 to 8 years of age and with atopic heredity. DNAs were genotyped for a functional repeat polymorphism (designated GTn) in the promoter of SLC11A1 and a linked microsatellite D2S1471. Associations between genotype, atopic symptoms and allergen-specific IgE-antibodies in relation to the BCG status of the children were assessed. Atopy in relation to SLC11A1 GTn-alleles was similarly distributed between the two groups. In BCG vaccinated children, genotype associations were observed for D2S1471 and atopy, with carriage of allele 5 conferring increased risk of atopy (odds ratio (OR) 2.6; 95% confidence interval (CI) 1.3-5.5; P = 0.01), and particularly IgE responses to airborne allergens (OR = 4.3; 95% CI 1.7-10.7; P = 0.002). No linkage disequilibrium was found between the SLC11A1 GTn repeat and the microsatellite D2S1471, and therefore no haplotype associations were observed for atopy in BCG- or non-BCG vaccinated children. Stratification by BCG vaccination unmasked a potential genetic risk factor for atopy in the region of the SLC11A1 locus, and point to the importance of genotype by environment interactions in determining disease susceptibility.