Association of CAPN10 SNPs and Haplotypes with Polycystic Ovary Syndrome among South Indian Women

Polycystic Ovary Syndrome (PCOS) is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63) with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p = 0.007) with highly significant odds ratio when compared to TC (OR = 2.51, p = 0.003, 95% CI = 1.37–4.61) as well as TT (OR = 1.94, p = 0.016, 95% CI = 1.13–3.34). While the haplotype carrying the SNP-44 and SNP-19 variants (21121) exhibited a 2 fold increase in the risk for PCOS (OR = 2.37, p = 0.03), the haplotype containing SNP-56 and SNP-19 variants (11221) seems to have a protective role against PCOS (OR = 0.20, p = 0.004). Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS

The YARHG Domain: An Extracellular Domain in Search of a Function

We have identified a new bacterial protein domain that we hypothesise binds to peptidoglycan. This domain is called the YARHG domain after the most highly conserved sequence-segment. The domain is found in the extracellular space and is likely to be composed of four alpha-helices. The domain is found associated with protein kinase domains, suggesting it is associated with signalling in some bacteria. The domain is also found associated with three different families of peptidases. The large number of different domains that are found associated with YARHG suggests that it is a useful functional module that nature has recombined multiple times

The prognostic influence of bcl-2 in malignant glioma

The bcl-2 gene is one of a complex group of genes which control programmed cell death. Bcl-2 acts to extend cell survival by blocking apoptosis, and thereby may influence tumour prognosis. This study of 187 high grade gliomas reviews clinicopathological prognostic features and the relationship to bcl-2 expression. Bcl-2 immunostaining was assessed in 159 specimens from these patients, by scoring systems of 0 to 3 for intensity of scoring and proportion of cells staining. Age, histology, pre- and post-operative performance status were found to be strongly predictive of survival (log rank test P<0.0001). The type of surgery performed did not influence survival in this group of patients. The expression of bcl-2 had a significant relationship with survival (univariate Cox model P=0.0302, hazard ratio 0.8, 95% confidence interval 0.65–0.98), with increased staining associated with improved survival. Multivariate analysis showed performance status, histology and proportion of cells staining for bcl-2 to be independently predictive of survival. Bcl-2 staining was not related to histological grade of tumours

Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan

Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common, affecting up to one in five women of reproductive age. It has significant and diverse clinical implications including reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles) and psychological features (increased anxiety, depression and worsened quality of life). Polycystic ovary syndrome is a heterogeneous condition and, as such, clinical and research agendas are broad and involve many disciplines. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and bodyweight. Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS. Furthermore, it has clinical implications across the lifespan and is relevant to related family members with an increased risk for metabolic conditions reported in first-degree relatives. Therapy should focus on both the short and long-term reproductive, metabolic and psychological features. Given the aetiological role of insulin resistance and the impact of obesity on both hyperinsulinaemia and hyperandrogenism, multidisciplinary lifestyle improvement aimed at normalising insulin resistance, improving androgen status and aiding weight management is recognised as a crucial initial treatment strategy. Modest weight loss of 5% to 10% of initial body weight has been demonstrated to improve many of the features of PCOS. Management should focus on support, education, addressing psychological factors and strongly emphasising healthy lifestyle with targeted medical therapy as required. Monitoring and management of long-term metabolic complications is also an important part of routine clinical care. Comprehensive evidence-based guidelines are needed to aid early diagnosis, appropriate investigation, regular screening and treatment of this common condition. Whilst reproductive features of PCOS are well recognised and are covered here, this review focuses primarily on the less appreciated cardiometabolic and psychological features of PCOS

State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy

The CAPN10 Gene Is Associated with Insulin Resistance Phenotypes in the Spanish Population

Cardiovascular disease is the leading cause of morbidity and mortality in the industrialized world. Familial aggregation of cardiovascular risk factors is a frequent finding, but genetic factors affecting its presentation are still poorly understood. The calpain 10 gene (CAPN10) has been associated with type 2 diabetes (T2DM), a complex metabolic disorder with increased risk of cardiovascular disease. Moreover, the CAPN10 gene has been associated with the presence of metabolic syndrome (MS) in T2DM and in polycystic ovary syndrome (PCOS). In this work, we have analysed whether the polymorphisms UCSNP44, -43, -19 and -63 are related to several cardiovascular risk factors in the context of MS. Molecular analysis of CAPN10 gene was performed in 899 individuals randomly chosen from a cross-sectional population-based epidemiological survey. We have found that CAPN10 gene in our population is mainly associated with two indicators of the presence of insulin resistance: glucose levels two hours after a 75-g oral glucose tolerance test (OGTT) and HOMA values, although cholesterol levels and blood pressure values are also influenced by CAPN10 variants. In addition, the 1221/1121 haplogenotype is under-represented in individuals that fulfil the International Diabetes Federation (IDF) diagnostic criteria for MS. Our results suggest that CAPN10 gene is associated with insulin resistance phenotypes in the Spanish population

The Germ Cell Nuclear Proteins hnRNP G-T and RBMY Activate a Testis-Specific Exon

The human testis has almost as high a frequency of alternative splicing events as brain. While not as extensively studied as brain, a few candidate testis-specific splicing regulator proteins have been identified, including the nuclear RNA binding proteins RBMY and hnRNP G-T, which are germ cell-specific versions of the somatically expressed hnRNP G protein and are highly conserved in mammals. The splicing activator protein Tra2β is also highly expressed in the testis and physically interacts with these hnRNP G family proteins. In this study, we identified a novel testis-specific cassette exon TLE4-T within intron 6 of the human transducing-like enhancer of split 4 (TLE4) gene which makes a more transcriptionally repressive TLE4 protein isoform. TLE4-T splicing is normally repressed in somatic cells because of a weak 5′ splice site and surrounding splicing-repressive intronic regions. TLE4-T RNA pulls down Tra2β and hnRNP G proteins which activate its inclusion. The germ cell-specific RBMY and hnRNP G-T proteins were more efficient in stimulating TLE4-T incorporation than somatically expressed hnRNP G protein. Tra2b bound moderately to TLE4-T RNA, but more strongly to upstream sites to potently activate an alternative 3′ splice site normally weakly selected in the testis. Co-expression of Tra2β with either hnRNP G-T or RBMY re-established the normal testis physiological splicing pattern of this exon. Although they can directly bind pre-mRNA sequences around the TLE4-T exon, RBMY and hnRNP G-T function as efficient germ cell-specific splicing co-activators of TLE4-T. Our study indicates a delicate balance between the activity of positive and negative splicing regulators combinatorially controls physiological splicing inclusion of exon TLE4-T and leads to modulation of signalling pathways in the testis. In addition, we identified a high-affinity binding site for hnRNP G-T protein, showing it is also a sequence-specific RNA binding protein

Using shared goal setting to improve access and equity : a mixed methods study of the Good Goals intervention in children's occupational therapy

Peer reviewedPublisher PD

Heat and moisture exchangers (HMEs) and heated humidifiers (HHs) in adult critically ill patients: a systematic review, meta-analysis and meta-regression of randomized controlled trials

The aims of this systematic review and meta-analysis of randomized controlled trials are to evaluate the effects of active heated humidifiers (HHs) and moisture exchangers (HMEs) in preventing artificial airway occlusion and pneumonia, and on mortality in adult critically ill patients. In addition, we planned to perform a meta-regression analysis to evaluate the relationship between the incidence of artificial airway occlusion, pneumonia and mortality and clinical features of adult critically ill patients