Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies

<p>Background: Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.</p> <p>Methods and Findings: We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.</p> <p>Conclusions: Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.</p&gt

Chemical Contamination of Green Turtle (Chelonia mydas) Eggs in Peninsular Malaysia: Implications for Conservation and Public Health

BACKGROUND: Persistent organic pollutants (POPs)-such as organochlorine pesticides (OCPS), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs)-and heavy metals have been reported in sea turtles at various stages of their life cycle. These chemicals can disrupt development and function of wildlife. Furthermore, in areas such as Peninsular Malaysia, where the human consumption of sea turtle eggs is prevalent, egg contamination may also have public health implications. OBJECTIVE: In the present study we investigated conservation and human health risks associated with the chemical contamination of green turtle (Chelonia mydas) eggs in Peninsular Malaysia. METHODS: Fifty-five C mydas eggs were collected from markets in Peninsular Malaysia and analyzed for POPs and heavy metals. We conducted screening risk assessments (SRAs) and calculated the percent of acceptable daily intake (ADI) for POPs and metals to assess conservation and human health risks associated with egg contamination. RESULTS: C mydas eggs were available in 9 of the 33 markets visited. These eggs came from seven nesting areas from as far away as Borneo Malaysia. SRAs indicated a significant risk to embryonic development associated with the observed arsenic concentrations. Furthermore, the concentrations of coplanar PCBs represented 3-300 times the ADI values set by the World Health Organization. CONCLUSIONS: The concentrations of POPs and heavy metals reported in C mydas eggs from markets in Peninsular Malaysia pose considerable risks to sea turtle conservation and human health

Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Women's Preferences Regarding Infant or Maternal Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission of HIV during Breastfeeding and Their Views on Option B+ in Dar es Salaam, Tanzania.

The WHO 2010 guidelines for prevention of mother-to-child transmission (PMTCT) of HIV recommended prophylactic antiretroviral treatment (ART) either for infants (Option A) or mothers (Option B) during breastfeeding for pregnant women with a CD4 count of >350 cell/µL in low-income countries. In 2012, WHO proposed that all HIV-infected pregnant women should receive triple ART for life (B+) irrespective of CD4 count. Tanzania has recently switched from Option A to B+, with a few centers practicing B. However, more information on the real-life feasibility of these options is needed. This qualitative study explored women's preferences for Option A vs B and their views on Option B+ in Dar es Salaam, Tanzania. We conducted four focus group discussions with a total of 27 pregnant women with unknown HIV status, attending reproductive and child health clinics, and 31 in-depth interviews among HIV-infected pregnant and post-delivery women, 17 of whom were also asked about B+. Most participants were in favor of Option B compared to A. The main reasons for choosing Option B were: HIV-associated stigma, fear of drug side-effects on infants and difficult logistics for postnatal drug adherence. Some of the women asked about B+ favored it as they agreed that they would eventually need ART for their own survival. Some were against B+ anticipating loss of motivation after protecting the child, fearing drug side-effects and not feeling ready to embark on lifelong medication. Some were undecided. Option B was preferred. Since Tanzania has recently adopted Option B+, women with CD4 counts of >350 cell/µL should be counseled about the possibility to "opt-out" from ART after cessation of breastfeeding. Drug safety and benefits, economic concerns and available resources for laboratory monitoring and evaluation should be addressed during B+ implementation to enhance long-term feasibility and effectiveness

Artemether-lumefantrine versus artemisinin-naphthoquine in Papua New Guinean children with uncomplicated malaria: A six months post-treatment follow-up study

Background: In a recent trial of artemisinin-naphthoquine (artemisinin-NQ) and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up. To determine whether, consistent with the long elimination half-life of NQ, this difference in efficacy would be more durable, clinical episodes of malaria were assessed in a subset of trial patients followed for six months post-treatment. Methods: For children completing trial procedures and who were assessable at six months, all within-trial and subsequent clinical malaria episodes were ascertained, the latter by clinic attendances and/or review of hand-held health records. Presentations with non-malarial illness were also recorded. Differences between allocated treatments for pre-specified endpoints were determined using Kaplan-Meier survival analysis. Results: Of 247 children who were followed to Day 42, 176 (71.3%) were included in the present sub-study, 87 allocated to AM-LM and 89 to artemisinin-NQ. Twenty children in the AM-LM group (32.8%) had a first episode of clinical malaria within six months compared with 10 (16.4%) in the artemisinin-NQ group (P=0.033, log rank test). The median (interquartile range) time to first episode of clinical malaria was 64 (50-146) vs 116 (77-130) days, respectively (P=0.20). There were no between-group differences in the incidence of first presentation with non-malarial illness (P=0.31). Conclusions: The greater effectiveness of artemisinin-NQ over conventional AM-LM extends to at least six months post-treatment for clinical malaria but not non-malarial illness. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000913077

Information Technology to Support Improved Care For Chronic Illness

BackgroundIn populations with chronic illness, outcomes improve with the use of care models that integrate clinical information, evidence-based treatments, and proactive management of care. Health information technology is believed to be critical for efficient implementation of these chronic care models. Health care organizations have implemented information technologies, such as electronic medical records, to varying degrees. However, considerable uncertainty remains regarding the relative impact of specific informatics technologies on chronic illness care.ObjectiveTo summarize knowledge and increase expert consensus regarding informatics components that support improvement in chronic illness care.DesignA systematic review of the literature was performed. "Use case" models were then developed, based on the literature review, and guidance from clinicians and national quality improvement projects. A national expert panel process was conducted to increase consensus regarding information system components that can be used to improve chronic illness care.ResultsThe expert panel agreed that informatics should be patient-centered, focused on improving outcomes, and provide support for illness self-management. They concurred that outcomes should be routinely assessed, provided to clinicians during the clinical encounter, and used for population-based care management. It was recommended that interactive, sequential, disorder-specific treatment pathways be implemented to quickly provide clinicians with patient clinical status, treatment history, and decision support.ConclusionsSpecific informatics strategies have the potential to improve care for chronic illness. Software to implement these strategies should be developed, and rigorously evaluated within the context of organizational efforts to improve care

The climate sensitivity of Norway spruce [Picea abies (L.) Karst.] in the southeastern European Alps

Tree ring chronologies were developed from trees growing at two sites in Slovenia which differed in their ecological and climatological characteristics. Ring width, maximum latewood density, annual height increment and latewood cellulose carbon isotope composition were developed at both sites and time-series verified against instrumental climate data over the period (AD 1960–AD 2002). Ring width sensitivity to summer temperature is site-dependent, with contrasting responses at alpine and lowland sites. Maximum density responds to September temperatures, suggesting lignification after cell division has ended for the season. Stable carbon isotopes have great potential, responding to summer temperature at oth alpine and lowland stands. Height increment appears relatively insensitive to climate, and is likely to be dominated by local stand dynamics

Going Deeper: Metagenome of a Hadopelagic Microbial Community

The paucity of sequence data from pelagic deep-ocean microbial assemblages has severely restricted molecular exploration of the largest biome on Earth. In this study, an analysis is presented of a large-scale 454-pyrosequencing metagenomic dataset from a hadopelagic environment from 6,000 m depth within the Puerto Rico Trench (PRT). A total of 145 Mbp of assembled sequence data was generated and compared to two pelagic deep ocean metagenomes and two representative surface seawater datasets from the Sargasso Sea. In a number of instances, all three deep metagenomes displayed similar trends, but were most magnified in the PRT, including enrichment in functions for two-component signal transduction mechanisms and transcriptional regulation. Overrepresented transporters in the PRT metagenome included outer membrane porins, diverse cation transporters, and di- and tri-carboxylate transporters that matched well with the prevailing catabolic processes such as butanoate, glyoxylate and dicarboxylate metabolism. A surprisingly high abundance of sulfatases for the degradation of sulfated polysaccharides were also present in the PRT. The most dramatic adaptational feature of the PRT microbes appears to be heavy metal resistance, as reflected in the large numbers of transporters present for their removal. As a complement to the metagenome approach, single-cell genomic techniques were utilized to generate partial whole-genome sequence data from four uncultivated cells from members of the dominant phyla within the PRT, Alphaproteobacteria, Gammaproteobacteria, Bacteroidetes and Planctomycetes. The single-cell sequence data provided genomic context for many of the highly abundant functional attributes identified from the PRT metagenome, as well as recruiting heavily the PRT metagenomic sequence data compared to 172 available reference marine genomes. Through these multifaceted sequence approaches, new insights have been provided into the unique functional attributes present in microbes residing in a deeper layer of the ocean far removed from the more productive sun-drenched zones above

The Role of Medical Interpretation on Breast and Cervical Cancer Screening Among Asian American and Pacific Islander Women

We examined whether the impact of medical interpretation services was associated with the receipt of a mammogram, clinical breast exam, and Pap smear. We conducted a large cross-sectional study involving four Asian American and Pacific Islander (AAPI) communities with high proportions of individuals with limited English proficiency (LEP). Participants were recruited from community clinics, churches and temples, supermarkets, and other community gathering sites in Northern and Southern California. Among those that responded, 98% completed the survey rendering a total of 1,708 AAPI women. In a series of multivariate logistic regression models, it was found that women who typically used a medical interpreter had a greater odds of having received a mammogram (odds ratio [OR] = 1.85; 95% confidence interval [CI] = 1.21, 2.83), clinical breast exam (OR = 3.03; 95% CI = 1.82, 5.03), and a Pap smear (OR = 2.34; 95% CI = 1.38, 3.97) than those who did not usually use an interpreter. The study provides support for increasing language access in healthcare settings. In particular, medical interpreters may help increase the utilization of breast and cervical cancer screening among LEP AAPI women