Challenges in management of Warfarin anti-coagulation in advanced HIV/AIDS patients with venous thrombotic events - A case series from a research clinic in rural Kericho, Kenya

Background: Venous thrombotic events (VTE) occur at high rates in HIV/AIDS patients and are likely under-diagnosed in rural sub-Saharan Africa.Objective: To describe clinical presentations and challenges in the management of VTE in patients with advanced HIV/AIDS.Design: Case series from patients enrolled in a prospective observational cohort study.Settings: A clinical research centre in rural Kericho, Kenya.Subjects: Two hundred patients with median age 38 (30-47) years, BMI 16.9 (12.4-20.3) kg/m2, haemoglobin 9.3 (6.8-13.4) g/dL, CD4+ T-cell count 27 (4-77) cells/mm3 and plasma HIV RNA 5.23 (3.70-5.88) log10copies/mL.Interventions: VTE cases were diagnosed by clinical presentation and Doppler/ radiographic confirmation.  Anti-coagulation therapy was managed by a multidisciplinary team; patients were initiated on enoxaparin or heparin followed by warfarin.Results: Over two years, 11 patients (5.5%) experienced VTE. All but one (10/11, 90.9%) case occurred within six months of starting ART. Nine patients had peripheral VTE (five popliteal, four femoral) and two had cerebral sinus thromboses. VTE was diagnosed 52 (1-469) days after ART initiation, and 81.8% of cases were outpatients at presentation. All patients received at least one concomitant medication that could significantly interact with warfarin (efavirenz, nevirapine, lopinavir/ritonavir, rifampicin, trimethoprim-sulfamethoxazole, and fluconazole). A median of 39 (10-180) days and eight (4-22) additional clinic visits were required to achieve/maintain a therapeutic INR of 2-3. Two minor bleeding complications occurred. No recurrent VTE cases were observed.Conclusion: Consideration of VTE and preparedness for management in patients with advanced HIV/AIDS starting ART is critical in sub-Saharan Africa. Overcoming challenges in anti-coagulation is possible in rural settings using a multidisciplinary team approach

Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker

Background: The molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor alpha beta-positive CD8(+) memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples. Results: We identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation. Conclusions: DNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed

Contextual and individual assessment of dental pain period prevalence in adolescents: a multilevel approach

<p>Abstract</p> <p>Background</p> <p>Despite evidence that health and disease occur in social contexts, the vast majority of studies addressing dental pain exclusively assessed information gathered at individual level.</p> <p>Objectives</p> <p>To assess the association between dental pain and contextual and individual characteristics in Brazilian adolescents. In addition, we aimed to test whether contextual Human Development Index is independently associated with dental pain after adjusting for individual level variables of socio-demographics and dental characteristics.</p> <p>Methods</p> <p>The study used data from an oral health survey carried out in São Paulo, Brazil, which included dental pain, dental exams, individual socioeconomic and demographic conditions, and Human Development Index at area level of 4,249 12-year-old and 1,566 15-year-old schoolchildren. The Poisson multilevel analysis was performed.</p> <p>Results</p> <p>Dental pain was found among 25.6% (95%CI = 24.5-26.7) of the adolescents and was 33% less prevalent among those living in more developed areas of the city than among those living in less developed areas. Girls, blacks, those whose parents earn low income and have low schooling, those studying at public schools, and those with dental treatment needs presented higher dental-pain prevalence than their counterparts. Area HDI remained associated with dental pain after adjusting for individual level variables of socio demographic and dental characteristics.</p> <p>Conclusions</p> <p>Girls, students whose parents have low schooling, those with low <it>per capita </it>income, those classified as having black skin color and those with dental treatment needs had higher dental pain prevalence than their counterparts. Students from areas with low Human Development Index had higher prevalence of dental pain than those from the more developed areas regardless of individual characteristics.</p

TLR Tolerance Reduces IFN-Alpha Production Despite Plasmacytoid Dendritic Cell Expansion and Anti-Nuclear Antibodies in NZB Bicongenic Mice

Genetic loci on New Zealand Black (NZB) chromosomes 1 and 13 play a significant role in the development of lupus-like autoimmune disease. We have previously shown that C57BL/6 (B6) congenic mice with homozygous NZB chromosome 1 (B6.NZBc1) or 13 (B6.NZBc13) intervals develop anti-nuclear antibodies and mild glomerulonephritis (GN), together with increased T and B cell activation. Here, we produced B6.NZBc1c13 bicongenic mice with both intervals, and demonstrate several novel phenotypes including: marked plasmacytoid and myeloid dendritic cell expansion, and elevated IgA production. Despite these changes, only minor increases in anti-nuclear antibody production were seen, and the severity of GN was reduced as compared to B6.NZBc1 mice. Although bicongenic mice had increased levels of baff and tnf-α mRNA in their spleens, the levels of IFN-α-induced gene expression were reduced. Splenocytes from bicongenic mice also demonstrated reduced secretion of IFN-α following TLR stimulation in vitro. This reduction was not due to inhibition by TNF-α and IL-10, or regulation by other cellular populations. Because pDC in bicongenic mice are chronically exposed to nuclear antigen-containing immune complexes in vivo, we examined whether repeated stimulation of mouse pDC with TLR ligands leads to impaired IFN-α production, a phenomenon termed TLR tolerance. Bone marrow pDC from both B6 and bicongenic mice demonstrated markedly inhibited secretion of IFN-α following repeated stimulation with a TLR9 ligand. Our findings suggest that the expansion of pDC and production of anti-nuclear antibodies need not be associated with increased IFN-α production and severe kidney disease, revealing additional complexity in the regulation of autoimmunity in systemic lupus erythematosus

A methodology for detecting the orthology signal in a PPI network at a functional complex level

Contains fulltext : 93730.pdf (preprint version ) (Open Access)13 p

Dor dentaria e fatores associados em adolescentes brasileiros: a Pesquia Nacional de Saude do Escolar (PeNSE), Brasil, 2009

Abstract published in English and Portuguese English title: Dental pain and associated factors in Brazilian adolescents: the National school-based health survey (PeNSE), Brazil, 2009The aim of this study was to assess the prevalence of dental pain and associated socio-demographic and behavioral factors in Brazilian adolescents, using data from the National School-Based Health Survey (PeNSE), Brazil, 2009. The survey was conducted by the Brazilian Institute of Geography and Statistics (IBGE) and Ministry of Health in students 11 to 17 years of age or older in the 27 State capitals, using a self-administered questionnaire. Analyses included Poisson regression following a hierarchical approach. Prevalence of dental pain in the sample (n = 54,985) in the previous six months was 17.8% (95%CI: 17.5-18.1). Higher prevalence was associated with female gender, age 14 years and over, racial self-identification as black, brown, or indigenous, enrollment in public schools, lower maternal schooling, not living with the mother, history of smoking or drinking, less frequent toothbrushing, and heavy consumption of sweets and soft drinks. Dental pain was thus associated with socio-demographic factors and health-related behaviors. = O objetivo deste estudo foi estimar a prevalência da dor de dente em adolescentes brasileiros e analisar fatores sociodemográficos e comportamentais associados, utilizando os dados da Pesquisa Nacional de Saúde do Escolar (PeNSE) de 2009. A pesquisa foi realizada pelo Instituto Brasileiro de Geografia e Estatística e pelo Ministério da Saúde em escolares com idades entre 11 e 17 anos ou mais, das 27 capitais brasileiras, por meio de questionário autoaplicável. Utilizou-se a análise de regressão de Poisson, segundo um modelo hierárquico de determinação. A prevalência de dor na amostra (n = 54.985) nos últimos seis meses foi de 17,8% (IC95%: 17,5-18,1). Prevalências mais elevadas foram encontradas em mulheres, naqueles com 14 anos ou mais, das raças preta, parda e indígena, de escolas públicas, cujas mães tinham baixa escolaridade, que não moravam com a mãe, que haviam experimentado cigarro e álcool alguma vez na vida, que relataram menor frequência de escovação e maior consumo de guloseimas e refrigerantes. A prevalência de dor foi considerável e associada a aspectos sociodemográficos e de comportamentos relacionados à saúde.Maria do Carmo Matias Freire, Cláudio Rodrigues Leles, Luciana Monteiro Vasconcelos Sardinha, Moacir Paludetto Junior, Deborah Carvalho Malta, Marco A. Pere

The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic datasets to gain insights in the epigenetic control of cell states relevant for human health and disease

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

BioRXiv version. Please see https://rubenarslan.github.io/generation_scotland_pedigree_gcta/ to access this website in a browsable form