Biological variation of established and novel biomarkers for atherosclerosis: Results from a prospective, parallel-group cohort study.

BACKGROUND: Biomarkers are a promising tool for the management of patients with atherosclerosis, but their variation is largely unknown. We assessed within-subject and between-subject biological variation of biomarkers in peripheral artery disease (PAD) patients and healthy controls, and defined which biomarkers have a favorable variation profile for future studies. METHODS: Prospective, parallel-group cohort study, including 62 patients with stable PAD (79% men, 65±7years) and 18 healthy control subjects (44% men, 57±7years). Blood samples were taken at baseline, and after 3-, 6-, and 12-months. We calculated within-subject (CVI) and between-subject (CVG) coefficients of variation and intra-class correlation coefficient (ICC). RESULTS: Mean levels of D-dimer, hs-CRP, IL-6, IL-8, MMP-9, MMP-3, S100A8/A9, PAI-1, sICAM-1, and sP-selectin levels were higher in PAD patients than in healthy controls (P≤.05 for all). CVI and CVG of the different biomarkers varied considerably in both groups. An ICC≥0.5 (indicating moderate-to-good reliability) was found for hs-CRP, D-Dimer, E-selectin, IL-10, MCP-1, MMP-3, oxLDL, sICAM-1 and sP-selectin in both groups, for sVCAM in healthy controls and for MMP-9, PAI-1 and sCD40L in PAD patients. CONCLUSIONS: Single biomarker measurements are of limited utility due to large within-subject variation, both in PAD patients and healthy subjects. D-dimer, hs-CRP, MMP-9, MMP-3, PAI-1, sP-selectin and sICAM-1 are biomarkers with both higher mean levels in PAD patients and a favorable variation profile making them most suitable for future studies.

Salt, blood pressure and cardiovascular risk : what is the most adequate preventive strategy? A Swiss perspective

Among the various strategies to reduce the incidence of non-communicable diseases reduction of sodium intake in the general population has been recognized as one of the most cost-effective means because of its potential impact on the development of hypertension and cardiovascular diseases. Yet, this strategic health recommendation of the WHO and many other international organizations is far from being universally accepted. Indeed, there are still several unresolved scientific and epidemiological questions that maintain an ongoing debate. Thus what is the adequate low level of sodium intake to recommend to the general population and whether national strategies should be oriented to the overall population or only to higher risk fractions of the population such as salt-sensitive patients are still discussed. In this paper, we shall review the recent results of the literature regarding salt, blood pressure and cardiovascular risk and we present the recommendations recently proposed by a group of experts of Switzerland. The propositions of the participating medical societies are to encourage national health authorities to continue their discussion with the food industry in order to reduce the sodium intake of food products with a target of mean salt intake of 5-6 grams per day in the population. Moreover, all initiatives to increase the information on the effect of salt on health and on the salt content of food are supported.

MHC/Peptide-Specific Interaction of the Humoral Immune System: A New Category of Antibodies.

Abs bind to unprocessed Ags, whereas cytotoxic CD8(+) T cells recognize peptides derived from endogenously processed Ags presented in the context of class I MHC complexes. We screened, by ELISA, human sera for Abs reacting specifically with the influenza matrix protein (IMP)-derived peptide58-66 displayed by HLA-A*0201 complexes. Among 653 healthy volunteers, blood donors, and women on delivery, high-titered HLA-A*0201/IMP58-66 complex-specific IgG Abs were detected in 11 females with a history of pregnancies and in 1 male, all HLA-A*0201(-). These Abs had the same specificity as HLA-A*0201/IMP58-66-specific cytotoxic T cells and bound neither to HLA-A*0201 nor the peptide alone. No such Abs were detected in HLA-A*0201(+) volunteers. These Abs were not cross-reactive to other self-MHC class I alleles displaying IMP58-66, but bound to MHC class I complexes of an HLA nonidentical offspring. HLA-A*0201/IMP58-66 Abs were also detected in the cord blood of newborns, indicating that HLA-A*0201/IMP58-66 Abs are produced in HLA-A*0201(-) mothers and enter the fetal blood system. That Abs can bind to peptides derived from endogenous Ags presented by MHC complexes opens new perspectives on interactions between the cellular and humoral immune system.

Testing Local Adaptation in a Natural Great Tit-Malaria System: An Experimental Approach.

Finding out whether Plasmodium spp. are coevolving with their vertebrate hosts is of both theoretical and applied interest and can influence our understanding of the effects and dynamics of malaria infection. In this study, we tested for local adaptation as a signature of coevolution between malaria blood parasites, Plasmodium spp. and its host, the great tit, Parus major. We conducted a reciprocal transplant experiment of birds in the field, where we exposed birds from two populations to Plasmodium parasites. This experimental set-up also provided a unique opportunity to study the natural history of malaria infection in the wild and to assess the effects of primary malaria infection on juvenile birds. We present three main findings: i) there was no support for local adaptation; ii) there was a male-biased infection rate; iii) infection occurred towards the end of the summer and differed between sites. There were also site-specific effects of malaria infection on the hosts. Taken together, we present one of the few experimental studies of parasite-host local adaptation in a natural malaria system, and our results shed light on the effects of avian malaria infection in the wild.

NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability. © 2015 Wiley Periodicals, Inc.

Towards actionable international comparisons of health system performance: expert revision of the OECD framework and quality indicators.

OBJECTIVE: To review and update the conceptual framework, indicator content and research priorities of the Organisation for Economic Cooperation and Development's (OECD) Health Care Quality Indicators (HCQI) project, after a decade of collaborative work. DESIGN: A structured assessment was carried out using a modified Delphi approach, followed by a consensus meeting, to assess the suite of HCQI for international comparisons, agree on revisions to the original framework and set priorities for research and development. SETTING: International group of countries participating to OECD projects. PARTICIPANTS: Members of the OECD HCQI expert group. RESULTS: A reference matrix, based on a revised performance framework, was used to map and assess all seventy HCQI routinely calculated by the OECD expert group. A total of 21 indicators were agreed to be excluded, due to the following concerns: (i) relevance, (ii) international comparability, particularly where heterogeneous coding practices might induce bias, (iii) feasibility, when the number of countries able to report was limited and the added value did not justify sustained effort and (iv) actionability, for indicators that were unlikely to improve on the basis of targeted policy interventions. CONCLUSIONS: The revised OECD framework for HCQI represents a new milestone of a long-standing international collaboration among a group of countries committed to building common ground for performance measurement. The expert group believes that the continuation of this work is paramount to provide decision makers with a validated toolbox to directly act on quality improvement strategies.

Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood-brain barrier.

There is an increasing need to develop improved systems for predicting the safety of xenobiotics. However, to move beyond hazard identification the available concentration of the test compounds needs to be incorporated. In this study cyclosporine A (CsA) was used as a model compound to assess the kinetic profiles in two rodent brain cell cultures after single and repeated exposures. CsA induced-cyclophilin B (Cyp-B) secretion was also determined as CsA-specific pharmacodynamic endpoint. Since CsA is a potent p-glycoprotein substrate, the ability of this compound to cross the blood-brain barrier (BBB) was also investigated using an in vitro bovine model with repeated exposures up to 14days. Finally, CsA uptake mechanisms were studied using a parallel artificial membrane assay (PAMPA) in combination with a Caco-2 model. Kinetic results indicate a low intracellular CsA uptake, with no marked bioaccumulation or biotransformation. In addition, only low CsA amounts crossed the BBB. PAMPA and Caco-2 experiments revealed that CsA is mostly trapped to lipophilic compartments and exits the cell apically via active transport. Thus, although CsA is unlikely to enter the brain at cytotoxic concentrations, it may cause alterations in electrical activity and is likely to increase the CNS concentration of other compounds by occupying the BBBs extrusion capacity. Such an integrated testing system, incorporating BBB, brain culture models and kinetics could be applied for assessing neurotoxicity potential of compounds.

Influence of transport and time on blood variables commonly measured for the athlete biological passport.

Some recent studies have characterized the stability of blood variables commonly measured for the Athlete Biological Passport. The aim of this study was to characterize the impact of different shipments conditions and the quality of the results returned by the haematological analyzer. Twenty-two healthy male subjects provided five EDTA tubes each. Four shipment conditions (24, 36, 48, 72 h) under refrigerated conditions were tested and compared to a set of samples left in the laboratory also under refrigerated conditions (group control). All measurements were conducted using two Sysmex XT-2000i analyzers. Haemoglobin concentration, reticulocytes percentage, and OFF-score numerical data were the same for samples analyzed just after collection and after a shipment under refrigerated conditions up to 72 h. Detailed information reported especially by the differential (DIFF) channel scatterplot of the Sysmex XT-2000i indicated that there were signs of blood deterioration, but were not of relevance for the variables used in the Athlete Biological Passport. As long as the cold chain is guaranteed, the time delay between the collection and the analyses of blood variables can be extended. Copyright© 2015 John Wiley & Sons, Ltd.