Compliance and persistence with osteoporosis medications: A critical review of the literature

It is widely acknowledged that compliance and persistence with oral osteoporosis medications, particularly with bisphosphonates, is poor. Several excellent reviews have been written on compliance and persistence with osteoporosis medications and have discussed improvements seen with extended dosing intervals. This review begins with studies on extended dosing intervals to examine the limitations of administrative claims data. It also looks at compliance and persistence across multiple medical conditions, examining the importance of prescription fulfillment, intentional choice, causation and possible interventions

Association between different levels of dysglycemia and metabolic syndrome in pregnancy

<p>Abstract</p> <p>Background</p> <p>In this study, we sought to evaluate the prevalence of metabolic syndrome (MS) in a cohort of pregnant women with a wide range of glucose tolerance, prepregnancy risk factors for MS during pregnancy, and the effects of MS in the outcomes in the mother and in the newborn.</p> <p>Methods</p> <p>One hundred and thirty six women with positive screening for gestational diabetes mellitus (GDM) were classified by two diagnostic methods: glycemic profile and 100 g OGTT as normoglycemic, mild gestational hyperglycemic, GDM, and overt GDM. Markers of MS were measured between 2428^thduring the screening.</p> <p>Results</p> <p>The prevalence of MS was: 0%; 20.0%; 23.5% and 36.4% in normoglycemic, mild hyperglycemic, GDM, and overt GDM groups, respectively. Previous history of GDM with or without insulin use, BMI ≥ 25, hypertension, family history of diabetes in first degree relatives, non-Caucasian ethnicity, history of prematurity and polihydramnios were statistically significant prepregnancy predictors for MS in the index pregnancy, that by its turn increased the adverse outcomes in the mother and in the newborn.</p> <p>Conclusion</p> <p>The prevalence of MS increases with the worsening of glucose tolerance; impaired glycemic profile identifies pregnancies with important metabolic abnormalities even in the presence of a normal OGTT, in patients that are not classified as having GDM.</p

Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analysed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumours. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts (PDX). Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a down-regulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate EMT plays a key role in OCS tumourigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes

Exposure to general anesthesia and risk of alzheimer's disease: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is common among older adults and leads to significant disability. Volatile anesthetic gases administered during general anesthesia (GA) have been hypothesized to be a risk factor for the development of AD. The objective of this study is to systematically review the association between exposure to GA and risk of AD.</p> <p>Methods</p> <p>We searched electronic databases including MEDLINE, Embase, and Google scholar for observational studies examining the association between exposure to GA and risk of AD. We examined study quality using a modified version of the Newcastle-Ottawa risk of bias assessment for observational studies. We used standard meta-analytic techniques to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Subgroup and sensitivity analyses were undertaken to evaluate the robustness of the findings.</p> <p>Results</p> <p>A total of 15 case-control studies were included in the review. No cohort studies were identified that met inclusion criteria. There was variation in the methodological quality of included studies. There was no significant association between any exposure to GA and risk of AD (pooled OR: 1.05; 95% CI: 0.93 - 1.19, Z = 0.80, <it>p </it>= 0.43). There was also no significant association between GA and risk of AD in several subgroup and sensitivity analyses.</p> <p>Conclusions</p> <p>A history of exposure to GA is not associated with an increased risk of AD although there are few high-quality studies in this area. Prospective cohort studies with long-term follow-up or randomized controlled trials are required to further understand the association between GA and AD.</p

The Bacterial Intimins and Invasins: A Large and Novel Family of Secreted Proteins

Gram-negative bacteria have developed a limited repertoire of solutions for secreting proteins from the cytoplasmic compartment to the exterior of the cell. Amongst the spectrum of secreted proteins are the intimins and invasins (the Int/Inv family; TC# 1.B.54) which are characterized by an N-terminal β-barrel domain and a C-terminal surface localized passenger domain. Despite the important role played by members of this family in diseases mediated by several species of the Enterobacteriaceae, there has been little appreciation for the distribution and diversity of these proteins amongst Gram-negative bacteria. Furthermore, there is little understanding of the molecular events governing secretion of these proteins to the extracellular milieu.In silico approaches were used to analyze the domain organization and diversity of members of this secretion family. Proteins belonging to this family are predominantly associated with organisms from the γ-proteobacteria. Whilst proteins from the Chlamydia, γ-, β- and ε-proteobacteria possess β-barrel domains and passenger domains of various sizes, Int/Inv proteins from the α-proteobacteria, cyanobacteria and chlorobi possess only the predicted β-barrel domains. Phylogenetic analyses revealed that with few exceptions these proteins cluster according to organismal type, indicating that divergence occurred contemporaneously with speciation, and that horizontal transfer was limited. Clustering patterns of the β-barrel domains correlate well with those of the full-length proteins although the passenger domains do so with much less consistency. The modular subdomain design of the passenger domains suggests that subdomain duplication and deletion have occurred with high frequency over evolutionary time. However, all repeated subdomains are found in tandem, suggesting that subdomain shuffling occurred rarely if at all. Topological predictions for the β-barrel domains are presented.Based on our in silico analyses we present a model for the biogenesis of these proteins. This study is the first of its kind to describe this unusual family of bacterial adhesins

Hypertension in Sub-Saharan Africa: Cross-Sectional Surveys in Four Rural and Urban Communities

Background: Cardiovascular disease (CVD) is the leading cause of adult mortality in low-income countries but data on the prevalence of cardiovascular risk factors such as hypertension are scarce, especially in sub-Saharan Africa (SSA). This study aims to assess the prevalence of hypertension and determinants of blood pressure in four SSA populations in rural Nigeria and Kenya, and urban Namibia and Tanzania. Methods and Findings: We performed four cross-sectional household surveys in Kwara State, Nigeria; Nandi district, Kenya; Dar es Salaam, Tanzania and Greater Windhoek, Namibia, between 2009-2011. Representative population-based samples were drawn in Nigeria and Namibia. The Kenya and Tanzania study populations consisted of specific target groups. Within a final sample size of 5,500 households, 9,857 non-pregnant adults were eligible for analysis on hypertension. Of those, 7,568 respondents ≥18 years were included. The primary outcome measure was the prevalence of hypertension in each of the populations under study. The age-standardized prevalence of hypertension was 19.3% (95%CI:17.3-21.3) in rural Nigeria, 21.4% (19.8-23.0) in rural Kenya, 23.7% (21.3-26.2) in urban Tanzania, and 38.0% (35.9-40.1) in urban Namibia. In individuals with hypertension, the proportion of grade 2 (≥160/100 mmHg) or grade 3 hypertension (≥180/110 mmHg) ranged from 29.2% (Namibia) to 43.3% (Nigeria). Control of hypertension ranged from 2.6% in Kenya to 17.8% in Namibia. Obesity prevalence (BMI ≥30) ranged from 6.1% (Nigeria) to 17.4% (Tanzania) and together with age and gender, BMI independently predicted blood pressure level in all study populations. Diabetes prevalence ranged from 2.1% (Namibia) to 3.7% (Tanzania). Conclusion: Hypertension was the most frequently observed risk factor for CVD in both urban and rural communities in SSA and will contribute to the growing burden of CVD in SSA. Low levels of control of hypertension are alarming. Strengthening of health care systems in SSA to contain the emerging epidemic of CVD is urgently needed

MrkH, a Novel c-di-GMP-Dependent Transcriptional Activator, Controls Klebsiella pneumoniae Biofilm Formation by Regulating Type 3 Fimbriae Expression

Klebsiella pneumoniae causes significant morbidity and mortality worldwide, particularly amongst hospitalized individuals. The principle mechanism for pathogenesis in hospital environments involves the formation of biofilms, primarily on implanted medical devices. In this study, we constructed a transposon mutant library in a clinical isolate, K. pneumoniae AJ218, to identify the genes and pathways implicated in biofilm formation. Three mutants severely defective in biofilm formation contained insertions within the mrkABCDF genes encoding the main structural subunit and assembly machinery for type 3 fimbriae. Two other mutants carried insertions within the yfiN and mrkJ genes, which encode GGDEF domain- and EAL domain-containing c-di-GMP turnover enzymes, respectively. The remaining two isolates contained insertions that inactivated the mrkH and mrkI genes, which encode for novel proteins with a c-di-GMP-binding PilZ domain and a LuxR-type transcriptional regulator, respectively. Biochemical and functional assays indicated that the effects of these factors on biofilm formation accompany concomitant changes in type 3 fimbriae expression. We mapped the transcriptional start site of mrkA, demonstrated that MrkH directly activates transcription of the mrkA promoter and showed that MrkH binds strongly to the mrkA regulatory region only in the presence of c-di-GMP. Furthermore, a point mutation in the putative c-di-GMP-binding domain of MrkH completely abolished its function as a transcriptional activator. In vivo analysis of the yfiN and mrkJ genes strongly indicated their c-di-GMP-specific function as diguanylate cyclase and phosphodiesterase, respectively. In addition, in vitro assays showed that purified MrkJ protein has strong c-di-GMP phosphodiesterase activity. These results demonstrate for the first time that c-di-GMP can function as an effector to stimulate the activity of a transcriptional activator, and explain how type 3 fimbriae expression is coordinated with other gene expression programs in K. pneumoniae to promote biofilm formation to implanted medical devices