Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial.

Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS: Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS: The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 μg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS: The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.info:eu-repo/semantics/publishedVersio

Antibodies against HDL Components in Ischaemic Stroke and Coronary Artery Disease

Quantitative and qualitative defects of high-density lipoprotein (HDL) are important in atherogenesis. In this study, we investigated whether antibodies against HDL components had additional value to conventional cardiovascular risk factors for the diagnosis of ischaemic stroke (IS) and coronary artery disease (CAD). Cross-sectional study was conducted on 53 patients with IS, 51 with CAD and 55 healthy controls, and in vitro studies to validate findings of the clinical study. We determined serum immunoglobulin G (IgG) antibodies against HDL (aHDL), apolipoproteins (aApoA-I, aApoA-II and aApoC-I) and paraoxonase-1 (aPON1) as well as PON1 activity (PON1a), total antioxidant capacity and biomarkers of endothelial activation (serum nitric oxide metabolites, 3-nitrotyrosine, VCAM-1 and ICAM-1); in vitro assays tested the capacity of IgG aHDL purified from high titer patients to inhibit PON1a and to reverse protective effect of HDL on endothelial cells. IgG aHDL, aApoA-I and aPON1 were higher in IS and CAD than controls (p < 0.001), predicted negatively PON1a and positively VCAM-1 and ICAM-1. By adding IgG aHDL and aApoA-I to a traditional cardiovascular risk factors model for IS and by adding IgG aHDL in a similar model for CAD, we obtained better discrimination of IS and CAD from healthy controls. IgG aHDL purified from IS and CAD inhibited PON1a by 38% (p < 0.01) and abrogated the protective effect of HDL on VCAM-1 expression by 126% compared with non-specific human IgG (p < 0.001). IgG against HDL components interfere with the antioxidant and anti-inflammatory properties of HDL and may represent novel biomarkers for vascular disease that need to be investigated in prospective studies.info:eu-repo/semantics/publishedVersio

Major acute splenic sequestration crisis in an adult patient with sickle-cell disease

A crise de retenção esplénica é uma complicação, frequentemente, fatal da drepanocitose. É rara em adultos, pela elevada incidência de autoesplenectomia durante a infância. Heterozigóticos com traços de drepanocitose e de beta-talassémia têm fenótipos menos graves, podendo manter um baço funcional até à idade adulta. Descrevemos um caso de crise de retenção esplénica num homem de 19 anos, com concentração mínima de hemoglobina de 2,9g/dL, que resolveu após esplenectomia emergente. Os poucos casos descritos na literatura acarretam uma mortalidade elevada. Um diagnóstico rápido e actuação imediata são necessários para garantir a sobrevivência. É apresentada uma revisão da fisiopatologia e da abordagem terapêutica desta entidade

Magnésio – associação com inflamação e doença renal no lúpus eritematoso sistémico

Introduction: Recent studies suggest that magnesium deficiency may play a role in inflammation. In diabetes and cardio-vascular diseases, conditions with a component of chronic inflammation, C–reactive protein levels are higher and associated with low serum magnesium. The objective of this study is to evaluate serum magnesium levels in patients with systemic lupus erythematosus and its potential association with inflammation and renal manifestations. Methods: All patients with systemic lupus erythematosus followed in a Systemic Immune Diseases Unit, from January 2012 until January 2014, were included in this cross sectional analysis. Patients with infection, neoplasia, liver failure and chronic kidney disease (stage > 3) were excluded. Clinical information and laboratory results (serum magnesium, C-reactive protein, erythrocyte sedimentation rate, serum creatinine and spot urine test) were collected. A multivariate analysis was performed to explore possible predictive factors for hypomagnesaemia. Results: One hundred and two patients were included (94.1% female, 21-86 years). 33.4% had hypertension, 8.8% had diabetes and 20.6% had hypomagnesaemia (< 1.8mg/dL). There were no significant differences between the inflammatory parameters of patients with hypomagnesaemia or normomagnesaemia. Serum magnesium was significantly lower with increasing comorbidities (p = 0.01). Leukocyturia was significantly higher in the hypomagnesaemia group (p = 0.03) and haematuria had a negative correlation with serum magnesium (-0.23, p < 0.05). Multivariate analysis showed that patients with hypertension and diabetes had higher risk of hypomagnesaemia: OR 42.29 (95% CI, 1.43-1249.31). Leukocyturia was also individually and independently associated with hypomagnesaemia: OR 8.37 (95% CI, 1.40-49.97). Conclusion: The presence of hypomagnesaemia in our patients with systemic lupus erythematosus was high. There was no association between the levels of serum magnesium and the inflammatory parameters. Increasing comorbidities and leukocyturia were independent predictors of lower serum magnesium. Finally, the association of leukocyturia and haematuria with lower serum magnesium may suggest a relationship with a higher disease activity.Introdução: Estudos recentes sugerem uma relação entre inflamação e défice de magnésio. Em doenças com inflamação crónica, como a diabetes e doenças cárdio-vasculares, os níveis séricos de proteína C-reativa são mais altos e associados a menores níveis séricos de magnésio. O objetivo desde trabalho é avaliar o magnésio sérico em doentes com lúpus eritematoso sistémico e a sua associação com inflamação e manifestações renais. Métodos: Foram incluídos neste estudo transversal, doentes com lúpus eritematoso sistémico, seguidos numa unidade de doenças imunomediadas sistémicas, entre Janeiro 2012 e Janeiro 2014. Foram excluídos os doentes com infeção, neoplasia, insuficiência hepática e doença renal crónica (estadio > 3). Foi colhida informação clínica e laboratorial (magnésio sérico, proteína C-reativa, velocidade de sedimentação, creatinina sérica e exame sumário de urina). Foi usada uma análise multivariada para explorar possíveis fatores preditivos de hipomagnesémia. Resultados: Foram incluídos 102 doentes (94.1% do sexo feminino, 21-86 anos), 33.4% com hipertensão, 8.8% com diabetes e 20.6% com hipomagnesémia (< 1.8mg/ dL). Não houve diferenças significativas nos parâmetros inflamatórios entre os doentes com hipomagnesémia e normomagnesémia. Os valores de magnésio foram mais baixos nos doentes com mais comorbilidades associadas (p = 0.01). A leucocitúria foi significativamente maior no grupo com hipomagnesémia (p = 0.03) e a hematúria correlacionou-se negativamente com o magnésio sérico (r = -0.23, p < 0.05). Na análise multivariada, doentes com hipertensão e diabetes apresentaram maior risco de hipomagnesemia: OR 42.29 (95% CI, 1.43-1249.31). A leucocitúria foi individualmente e independentemente associada a hipomagnesemia OR 8.37 (95% CI, 1.40-49.97). Conclusão: A presença de hipomagnesémia nos nossos doentes com lúpus eritematoso sistémico foi elevada. Não encontrámos associação entre os níveis de magnésio sérico e os parâmetros inflamatórios. A comorbilidade crescente e a leucocitúria foram preditores independentes de hipomagnesémia. A associação de leucocitúria e hematúria com magnésio sérico mais baixo pode sugerir uma relação com maior atividade da doença

Exploring the Free Energy Landscape: From Dynamics to Networks and Back

The knowledge of the Free Energy Landscape topology is the essential key to understand many biochemical processes. The determination of the conformers of a protein and their basins of attraction takes a central role for studying molecular isomerization reactions. In this work, we present a novel framework to unveil the features of a Free Energy Landscape answering questions such as how many meta-stable conformers are, how the hierarchical relationship among them is, or what the structure and kinetics of the transition paths are. Exploring the landscape by molecular dynamics simulations, the microscopic data of the trajectory are encoded into a Conformational Markov Network. The structure of this graph reveals the regions of the conformational space corresponding to the basins of attraction. In addition, handling the Conformational Markov Network, relevant kinetic magnitudes as dwell times or rate constants, and the hierarchical relationship among basins, complete the global picture of the landscape. We show the power of the analysis studying a toy model of a funnel-like potential and computing efficiently the conformers of a short peptide, the dialanine, paving the way to a systematic study of the Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press

How Academic Biologists and Physicists View Science Outreach

Scholars and pundits alike argue that U.S. scientists could do more to reach out to the general public. Yet, to date, there have been few systematic studies that examine how scientists understand the barriers that impede such outreach. Through analysis of 97 semi-structured interviews with academic biologists and physicists at top research universities in the United States, we classify the type and target audiences of scientists’ outreach activities. Finally, we explore the narratives academic scientists have about outreach and its reception in the academy, in particular what they perceive as impediments to these activities. We find that scientists’ outreach activities are stratified by gender and that university and disciplinary rewards as well as scientists’ perceptions of their own skills have an impact on science outreach. Research contributions and recommendations for university policy follow

A method for studying protistan diversity using massively parallel sequencing of V9 hypervariable regions of small-subunit ribosomal RNA genes

© 2009 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 4 (2009): e6372, doi:10.1371/journal.pone.0006372.Massively parallel pyrosequencing of amplicons from the V6 hypervariable regions of small-subunit (SSU) ribosomal RNA (rRNA) genes is commonly used to assess diversity and richness in bacterial and archaeal populations. Recent advances in pyrosequencing technology provide read lengths of up to 240 nucleotides. Amplicon pyrosequencing can now be applied to longer variable regions of the SSU rRNA gene including the V9 region in eukaryotes. We present a protocol for the amplicon pyrosequencing of V9 regions for eukaryotic environmental samples for biodiversity inventories and species richness estimation. The International Census of Marine Microbes (ICoMM) and the Microbial Inventory Research Across Diverse Aquatic Long Term Ecological Research Sites (MIRADA-LTERs) projects are already employing this protocol for tag sequencing of eukaryotic samples in a wide diversity of both marine and freshwater environments. Massively parallel pyrosequencing of eukaryotic V9 hypervariable regions of SSU rRNA genes provides a means of estimating species richness from deeply-sampled populations and for discovering novel species from the environment.This work was supported by grants from the W.M. Keck Foundation and the Woods Hole Center for Oceans and Human Health from the National Institutes of Health and National Science Foundation (NIH/NIEHS 1 P50 ES012742-01 and NSF/OCE 0430724-J) (LAZ and SH)