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.     

Tau positron emission tomography,cerebrospinal fluid and plasma biomarkers of neurodegeneration,and neurocognitive testing: an exploratory study of participants with myotonic dystrophy type 1

Journal of Neurology - To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1). We recruited twelve...     

Invasion pathways and malaria severity in Kenyan Plasmodium falciparum clinical isolates

The invasion of erythrocytes by Plasmodium falciparum occurs through multiple pathways that can be studied in vitro by examining the invasion of erythrocytes treated with enzymes such as neuraminidase, trypsin, and chymotrypsin. We have studied the invasion pathways used by 31 Kenyan P. falciparum isolates from children with uncomplicated or severe malaria. Six distinct invasion profiles were detected, out of eight possible profiles. The majority of isolates (23 of 31) showed neuraminidase-resistant, trypsin-sensitive invasion, characteristic of the pathway mediated by an unknown parasite ligand and erythrocyte receptor "X." The neuraminidase-sensitive, trypsin-sensitive phenotype consistent with invasion mediated by the binding of parasite ligand erythrocyte binding antigen 175 to glycophorin A, the most common invasion profile in a previous study of Gambian field isolates, was seen in only 3 of 31 Kenyan isolates. No particular invasion profile was associated with severe P. falciparum malaria, and there was no significant difference in the levels of inhibition by the various enzyme treatments between isolates from children with severe malaria and those from children with uncomplicated malaria (P, >0.1 for all enzymes; Mann-Whitney U test). These results do not support the hypothesis that differences in invasion phenotypes play an important role in malaria virulence and indicate that considerable gaps remain in our knowledge of the molecular basis of invasion pathways in natural P. falciparum infections.     

Social recognition memory requires protein synthesis after reactivation

Recent evidence indicates that reactivation of consolidated memories returns them to a protein-synthesis-dependent state called reconsolidation. The hypothesis that memories reconsolidate has never been assessed in social memory. The authors tested whether sheep (Ovis aries) mothers' memory of their lambs undergoes reconsolidation upon reactivation. After 7 days of mother-young contact, ewes were separated from their lambs for 8 hr, after which the lambs were reintroduced to their mothers for a 10-min reactivation session. Before reactivation, mothers received a subcutaneous injection of either the protein-synthesis inhibitor cycloheximide (CY, 1 mg/kg) or vehicle. Mothers' lamb memory was tested 1 hr (short-term memory [STM]) or 16 hr (long-term memory [LTM]) after reactivation. Mothers treated with CY exhibited intact STM but deficient LTM. CY injection without reactivation or before presentation of an alien lamb induced no deficit in LTM. CY-induced LTM deficit was alleviated by (a) introducing a reminder just before the LTM test, (b) extending mother-young contact, and (c) preventing suckling by the familiar lamb during reactivation. Thus, reconsolidation can be shown to exist in social memory, and some of its boundary conditions are discussed.     

Allogeneic bone marrow transplantation in mevalonic aciduria

Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.     

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.