Definition and characterization of localised meningitis epidemics in Burkina Faso: a longitudinal retrospective study

<p>Abstract</p> <p>Background</p> <p>The epidemiology of meningococcal meningitis in the African meningitis belt is characterised by seasonality, localised epidemics and epidemic waves. To facilitate research and surveillance, we aimed to develop a definition for localised epidemics to be used in real-time surveillance based on weekly case reports at the health centre level.</p> <p>Methods</p> <p>We used national routine surveillance data on suspected meningitis from January 2004 to December 2008 in six health districts in western and central Burkina Faso. We evaluated eight thresholds composed of weekly incidence rates at health centre level for their performance in predicting annual incidences of 0.4%and 0.8% in health centre areas. The eventually chosen definition was used to describe the spatiotemporal epidemiology and size of localised meningitis epidemics during the included district years.</p> <p>Results</p> <p>Among eight weekly thresholds evaluated, a weekly incidence rate of 75 cases per 100,000 inhabitants during at least two consecutive weeks with at least 5 cases per week had 100% sensitivity and 98% specificity for predicting an annual incidence of at least 0.8% in health centres. Using this definition, localised epidemics were identified in all but one years during 2004-2008, concerned less than 10% of the districts' population and often were geographically dispersed. Where sufficient laboratory data were available, localised epidemics were exclusively due to meningococci.</p> <p>Conclusions</p> <p>This definition of localised epidemics a the health centre level will be useful for risk factor and modelling studies to understand the meningitis belt phenomenon and help documenting vaccine impact against epidemic meningitis where no widespread laboratory surveillance exists for quantifying disease reduction after vaccination.</p

Dynamic and Polarized Muscle Cell Behaviors Accompany Tail Morphogenesis in the Ascidian Ciona intestinalis

BACKGROUND: Axial elongation is a key morphogenetic process that serves to shape developing organisms. Tail extension in the ascidian larva represents a striking example of this process, wherein paraxially positioned muscle cells undergo elongation and differentiation independent of the segmentation process that characterizes the formation of paraxial mesoderm in vertebrates. Investigating the cell behaviors underlying the morphogenesis of muscle in ascidians may therefore reveal the evolutionarily conserved mechanisms operating during this process. METHODOLOGY/PRINCIPLE FINDINGS: A live cell imaging approach utilizing subcellularly-localized fluorescent proteins was employed to investigate muscle cell behaviors during tail extension in the ascidian Ciona intestinalis. Changes in the position and morphology of individual muscle cells were analyzed in vivo in wild type embryos undergoing tail extension and in embryos in which muscle development was perturbed. Muscle cells were observed to undergo elongation in the absence of positional reorganization. Furthermore, high-speed high-resolution live imaging revealed that the onset and progression of tail extension were characterized by the presence of dynamic and polarized actin-based protrusive activity at the plasma membrane of individual muscle cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that in the Ciona muscle, tissue elongation resulted from gradual and coordinated changes in cell geometry and not from changes in cell topology. Proper formation of muscle cells was found to be necessary not only for muscle tissue elongation, but also more generally for completion of tail extension. Based upon the characterized dynamic changes in cell morphology and plasma membrane protrusive activity, a three-phase model is proposed to describe the cell behavior operating during muscle morphogenesis in the ascidian embryo

Emergence of Epidemic Neisseria meningitidis Serogroup X Meningitis in Togo and Burkina Faso

Serogroup X meningococci (NmX) historically have caused sporadic and clustered meningitis cases in sub-Saharan Africa. To study recent NmX epidemiology, we analyzed data from population-based, sentinel and passive surveillance, and outbreak investigations of bacterial meningitis in Togo and Burkina Faso during 2006–2010. Cerebrospinal fluid specimens were analyzed by PCR. In Togo during 2006–2009, NmX accounted for 16% of the 702 confirmed bacterial meningitis cases. Kozah district experienced an NmX outbreak in March 2007 with an NmX seasonal cumulative incidence of 33/100,000. In Burkina Faso during 2007–2010, NmX accounted for 7% of the 778 confirmed bacterial meningitis cases, with an increase from 2009 to 2010 (4% to 35% of all confirmed cases, respectively). In 2010, NmX epidemics occurred in northern and central regions of Burkina Faso; the highest district cumulative incidence of NmX was estimated as 130/100,000 during March–April. Although limited to a few districts, we have documented NmX meningitis epidemics occurring with a seasonal incidence previously only reported in the meningitis belt for NmW135 and NmA, which argues for development of an NmX vaccine

NCAM180 Regulates Ric8A Membrane Localization and Potentiates β-Adrenergic Response

Cooperation between receptors allows integrated intracellular signaling leading to appropriate physiological responses. The Neural Cell Adhesion Molecule (NCAM) has three main isoforms of 120, 140 and 180 kDa, with adhesive and signaling properties, but their respective functions remains to be fully identified. Here we show that the human NCAM180 intracellular domain is a novel interactor of the human guanosine exchange factor (GEF) Ric8A using the yeast two hybrid system and immunoprecipitation. Furthermore, NCAM, Ric8A and Gαs form a tripartite complex. Colocalization experiments by confocal microscopy revealed that human NCAM180 specifically induces the recruitment of Ric8A to the membrane. In addition, using an in vitro recombinant system, and in vivo by comparing NCAM knock-out mouse brain to NCAM heterozygous and wild type brains, we show that NCAM expression dose dependently regulates Ric8A redistribution in detergent resistent membrane microdomains (DRM). Previous studies have demonstrated essential roles for Ric8 in Gα protein activity at G protein coupled receptors (GPCR), during neurotransmitter release and for asymmetric cell division. We observed that inhibition of Ric8A by siRNA or its overexpression, decreases or increases respectively, cAMP production following β-adrenergic receptor stimulation. Furthermore, in human HEK293T recombinant cells, NCAM180 potentiates the Gαs coupled β-adrenergic receptor response, in a Ric8A dependent manner, whereas NCAM120 or NCAM140 do not. Finally, in mouse hippocampal neurons expressing endogenously NCAM, NCAM is required for the agonist isoproterenol to induce cAMP production, and this requirement depends on Ric8A. These data illustrate a functional crosstalk between a GPCR and an IgCAM in the nervous system

Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1cM of major candidate genes, namely APOB (LOD =2.1), LDLR (LOD =1.9) and APOE (LOD =1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate. © 2005 Nature Publishing Group. All rights reserved

Cholesterol and Lipoprotein Dynamics in a Hibernating Mammal

Hibernating mammals cease feeding during the winter and rely primarily on stored lipids to fuel alternating periods of torpor and arousal. How hibernators manage large fluxes of lipids and sterols over the annual hibernation cycle is poorly understood. The aim of this study was to investigate lipid and cholesterol transport and storage in ground squirrels studied in spring, summer, and several hibernation states. Cholesterol levels in total plasma, HDL and LDL particles were elevated in hibernators compared with spring or summer squirrels. Hibernation increased plasma apolipoprotein A-I expression and HDL particle size. Expression of cholesterol 7 alpha-hydroxylase was 13-fold lower in hibernators than in active season squirrels. Plasma triglycerides were reduced by fasting in spring but not summer squirrels. In hibernators plasma β-hydroxybutyrate was elevated during torpor whereas triglycerides were low relative to normothermic states. We conclude that the switch to a lipid-based metabolism during winter, coupled with reduced capacity to excrete cholesterol creates a closed system in which efficient use of lipoproteins is essential for survival

Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naive animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems

Secret worlds, democratization and election observation in Malawi

ASC – Publicaties niet-programma gebonde

Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine