Super selective intra-arterial cerebral infusion of modern chemotherapeutics after blood–brain barrier disruption: where are we now,and where we are going

Journal of Neuro-Oncology - Intra-arterial (IA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration...     

Patterns of relapse after successful completion of initial therapy in primary central nervous system lymphoma: a case series

Journal of Neuro-Oncology - Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin’s lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of...     

Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells

Both the rate of overall translation and the specific acceleration of proinsulin synthesis are known to be glucose-regulated processes in the beta-cell. In this study, we propose that glucose-induced stimulation of overall translation in beta-cells depends on a protein phosphatase-1-mediated decrease in serine-51 phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha), a pivotal translation initiation factor. The decrease was rapid and detectable within 15 min and proportional to the range of glucose concentrations that also stimulate translation. Lowered net eIF2alpha phosphorylation was not associated with a detectable decrease in activity of any eIF2alpha kinase. Moreover, okadaic acid blocked glucose-induced eIF2alpha dephosphorylation, suggesting that the net effect was mediated by a protein phosphatase. Experiments with salubrinal on intact cells and nuclear inhibitor of protein phosphatase-1 (PP1) on cell extracts suggested that this phosphatase was PP1. The net effect contained, however, a component of glucose-induced folding load in the endoplasmic reticulum because coincubation with cycloheximide further amplified the effect of glucose on eIF2alpha dephosphorylation. Thus, the steady-state level of eIF2alpha phosphorylation in beta-cells is the result of a balance between folding-load-induced phosphorylation and PP1-dependent dephosphorylation. Because defects in the pancreatic endoplasmic reticulum kinase-eIF2alpha signaling system lead to beta-cell failure and diabetes, deregulation of the PP1 system could likewise lead to cellular dysfunction and disease.     

Risk of Vancomycin-induced Nephrotoxicity in the Population With Chronic Kidney Disease

The antibiotic vancomycin has been available since the 1950s but has been used more commonly since the early 1980s because of the widespread appearance of methicillin-resistant Staphylococcus aureus. Infectious Diseases Society of America guidelines recommend achieving vancomycin trough levels of 10 to 20 μg/mL. Usage of vancomycin in high dosages especially ≥4 g/d has led to an increase in the incidence of vancomycin-induced nephrotoxicity, particularly in patients with chronic kidney disease (CKD). This review focuses on the impact of vancomycin-induced nephrotoxicity in patients with CKD. Patients with CKD are at increased risk of developing acute kidney injury and subsequently requiring renal replacement therapy. There is substantial need for vancomycin pharmacokinetic studies to be performed in the population with CKD to develop an optimum vancomycin nomogram in these patients. At present, tight monitoring of vancomycin trough levels in the population with CKD is recommended to help prevent acute kidney injury and its associated high morbidity, mortality and health care costs.