An open-label, sequential, dose-finding study of peginesatide for the maintenance treatment of anemia in chronic hemodialysis patients

ABSTRACT: BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. The primary objective of this phase 2 dose-finding study was to determine the once-monthly peginesatide dosing strategy that would maintain hemoglobin within [PLUS-MINUS SIGN]1.0 g/dL of baseline values after conversion from epoetin alfa; the safety of peginesatide was evaluated concurrently. METHODS: Chronic hemodialysis patients on stable regimens of epoetin alfa were sequentially assigned to cohorts that differed on (1) how the peginesatide starting dose was determined (using a single epoetin alfa--to-peginesatide dose conversion ratio or a tiered, weight-based or absolute-dose conversion table) and on (2) whether or not a 1-week erythropoiesis-stimulating agent-free interval was used. Peginesatide doses were titrated to maintain hemoglobin levels within [PLUS-MINUS SIGN]1.0 g/dL from baseline. RESULTS: A total of 164 patients were enrolled and received intravenous peginesatide every 4 weeks for up to 6 doses; the duration of the study including follow-up was [LESS-THAN OR EQUAL TO]29 weeks. Overall, the proportion of patients with hemoglobin levels within [PLUS-MINUS SIGN]1.0 g/dL of baseline increased over the course of the study from 39% (Weeks 2--13) to 54% (Weeks 18--25). Cohorts that used tiered dose conversion tables trended towards having more stable peginesatide doses than did those cohorts that used a single dose conversion ratio. Moreover, cohorts that used an erythropoiesis-stimulating agent-free interval did not have the substantial initial increase in hemoglobin levels that was seen in those cohorts that did not use such an interval. In this study, the safety profile of peginesatide was consistent with those of marketed erythropoiesis-stimulating agents. CONCLUSIONS: The results of this study were used to guide the dosing regimens used subsequently in phase 3 studies. Once-monthly peginesatide is feasible in hemodialysis patients.Trial registrationClinicalTrials.gov registration: NCT00228449.     

Layer-specific diffusion weighted imaging in human primary visual cortex in vitro

One of the most prominent characteristics of the human neocortex is its laminated structure. The first person to observe this was Francesco Gennari in the second half the 18th century: in the middle of the depth of primary visual cortex, myelinated fibres are so abundant that he could observe them with bare eyes as a white line. Because of its saliency, the stria of Gennari has a rich history in cyto- and myeloarchitectural research as well as in magnetic resonance (MR) microscopy. In the present paper we show for the first time the layered structure of the human neocortex with ex vivo diffusion weighted imaging (DWI). To achieve the necessary spatial and angular resolution, primary visual cortex samples were scanned on an 11.7 T small-animal MR system to characterize the diffusion properties of the cortical laminae and the stria of Gennari in particular. The results demonstrated that fractional anisotropy varied over cortical depth, showing reduced anisotropy in the stria of Gennari, the inner band of Baillarger and the deepest layer of the cortex. Orientation density functions showed multiple components in the stria of Gennari and deeper layers of the cortex. Potential applications of layer-specific diffusion imaging include characterization of clinical abnormalities, cortical mapping and (intra)cortical tractography. We conclude that future high-resolution in vivo cortical DWI investigations should take into account the layer-specificity of the diffusion properties.     

Toluene and methylethylketone: effect of combined exposure on their metabolism in rat

1.?Multiple exposures are ubiquitous in industrial environments. In this article, we highlight the risks faced by workers and complete the data available on the metabolic impact of a common mixture: toluene (TOL) and methylethylketone (MEK).

2.?Rats were exposed by inhalation under controlled conditions either to each solvent individually, or to mixtures of the two. How the interaction between the two solvents affected their fate in the blood and brain, their main relevant urinary metabolites (o-cresol, benzylmercapturic acid for TOL and 2,3-butanediols for MEK) and their hepatic metabolism were investigated.

3.?Although the cytochrome P450 concentration was unchanged, and the activities of CYP1A2 and CYP2E1 isoforms were not additively or synergistically induced by co-exposure, TOL metabolism was inhibited by the presence of MEK (and vice versa). Depending on the relative proportions of each compound in the mixture, this sometimes resulted in a large increase in blood and brain concentrations. Apart from extreme cases (unbalanced mixtures), the amount of o-cresol and benzylmercapturic acid (and to a lesser extent 2,3-butanediols) excreted were proportional to the blood solvent concentrations.

4.?In a co-exposure context, ortho-cresol and benzylmercapturic acid can be used as urinary biomarkers in biomonitoring for employees to relatively accurately assess TOL exposure.     

Anti-phospholipid antibodies in diabetes mellitus.

The presence of autoantibodies to phospholipids may be associated with various pathological disorders; diabetes could be one of them because of the changes occurring in lipid metabolism but there are only few reports examining this question, and they are not always leading to the same conclusions because of the differences in the procedures or in the phospholipids tested. We carried out a systematic comparative study of diabetic serum antibody binding to all phospholipids, anionic and zwitterionic, by a quantitative ELISA. The implication of the hydrophobic moiety of the lipids was also studied: the presence of autoantibodies to the fatty acyl chains was investigated. Our results show the presence of anti-phospholipid antibodies in diabetic sera, particularly anti-phosphatidylinositol and anti-phosphatidylcholine which have never been tested before, and appear to be associated with macroangiopathic complications. The antigenic epitopes are mainly the polar heads as no antibody binding to the hydrophobic moiety was observed. We discuss the relation of those antibodies to the angiopathic complications and to the direct effects of hyperglycemia on lipid antigenicity.     

Cocaine use in Europe - a multi-centre study. Methodology and prevalence estimates

An increase in the use of cocaine and crack in several parts of Europe has raised the question whether this trend is similar to that of the USA in the 1980s. However, research in the field of cocaine use in Europe has been only sporadic. Therefore, a European multi-centre and multi-modal project was designed to study specific aspects of cocaine and crack use in Europe, in order to develop guidelines for public health strategies. Data on prevalence rates were analysed for the general population and for specific subgroups. Despite large differences between countries in the prevalence of cocaine use in the general population, most countries show an increase in the last few years. The highest rate with a lifetime prevalence of 5.2% was found for the United Kingdom, although with a plateau effect around the year 2000. With regard to specific subgroups, three groups seem to show a higher prevalence than the general population: (1) youth, especially in the party scene; (2) socially marginalized groups, such as homeless and prostitutes or those found in open drug scenes; (3) opiate-dependent patients in maintenance treatment who additionally use cocaine. Specific strategies need to be developed to address problematic cocaine use in these subgroups.     

Proteinase-activated receptor-2: physiological and pathophysiological roles

Protease-activated receptor 2 (PAR2) is the second member of a new subfamily of G-protein coupled receptors: the protease-activated receptors (PARs). At present, four different PARs have been cloned and all of them share the same basic mechanism of activation. A serine protease cleaves the extended, extracellular N-terminus of the receptor at a specific site within the protein chain to expose an N-terminal tethered ligand domain, which binds to and activates the cleaved receptor. In this manner, trypsin and mast cell beta-tryptase activate PAR2. PARs are single use receptors because proteolytic activation is irreversible and the cleaved receptors are degraded in lysosomes. Thus, PARs play important roles in emergency situations, such as trauma and inflammation. Emerging evidence indicates that PAR2 is involved in the cardiovascular, pulmonary and gastrointestinal systems, where it controls inflammation and nociception. Work with selective agonists and knockout animals suggests a contribution of PAR2 to certain inflammatory diseases. Therefore, selective antagonists or agonists of these receptors may be useful therapeutic agents for the treatment of human diseases.     

Breastfeeding Practices in Relation to Country of Origin Among Women Living in Denmark: A Population-Based Study

The objective of this study was to describe breastfeeding practices and to compare the risk of suboptimal breastfeeding of women living in Denmark according to country of origin, and further to examine how socio-economic position and duration of stay in the country affected this risk. Information on breastfeeding of 42,420 infants born 2002–2009 and living in eighteen selected Danish municipalities was collected from the Danish Health Visitor’s Child Health Database. The data was linked with data on maternal socio-demographic information from Danish population-covering registries. Suboptimal breastfeeding was defined as <4 months of full breastfeeding as described by the Danish Health and Medicines Authority. We used logistic regression to model the crude associations between suboptimal breastfeeding and country of origin, and taking maternal age and parity, and a variety of parental socio-economic measures into account. Suboptimal breastfeeding was more frequent among non-Western migrant women than among women of Danish origin. Women who were descendants of Turkish and Pakistani immigrants had a higher risk of suboptimal breastfeeding as compared to the group of women who had migrated from the same countries, suggesting that acculturation did not favor breastfeeding. For all but the group of women who had migrated from Pakistan, adjustment for socio-demographic indicators (age, parity, education, attachment to labour market, and income) eliminated the increased risk of suboptimal breastfeeding. There was no evidence for differences in the breastfeeding support provided at hospital level according to migrant status. Suboptimal breastfeeding was more frequent among women who were non-Nordic migrants and descendants of migrants than among women with Danish origin.