Update on the role of rituximab in kidney diseases and transplant

INTRODUCTION: Pathological antibody production by B lymphocytes is characteristic of numerous primary and secondary glomerular diseases of the kidney. Specific and less toxic therapies that target antibody-producing B cells are therefore needed. Based on its property of selectively depleting CD20(+) B cells, rituximab is a therapeutic option for antibody-mediated kidney diseases and adds to the existing drug armamentarium for the treatment of a number of these disorders. AREAS COVERED: This article reviews the current use of rituximab in renal disease and transplantation, and includes discussion of the drug's potential role in conditions where traditional treatment has failed. A literature search using PubMed data base was undertaken using search words rituximab and kidney transplantation, glomerulonephritis, antibody production etc. EXPERT OPINION: Rituximab could be a beneficial drug in certain renal diseases and for complications related to kidney transplantation where conventional treatment has not been successful.     

Development and evaluation of a PCR assay for tracking the emergence and dissemination of Haitian variant ctxB in Vibrio cholerae O1 strains isolated from Kolkata, India

A PCR-based assay was developed to discriminate the classical, El Tor, and Haitian types of ctxB alleles. Our retrospective study using this newly developed PCR showed that Haitian ctxB first appeared in Kolkata during April 2006, and 93.3% of strains isolated during 2011 carried the new allele. Dendrogram analysis showed a pulsed-field gel electrophoresis (PFGE) pattern of the new variant strains isolated recently that was distinct from the PFGE pattern of the strains carrying classical ctxB that closely matched the 2006 to 2007 variant strains.     

Integration of β-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity

One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/β-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the β-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of β-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between β-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of β-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity.     

Prognosis for splicing factor PRPF8 retinitis pigmentosa,novel mutations and correlation between human and yeast phenotypes

PRPF8‐retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP‐causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8‐RP. Clinical data for 75 PRPF8‐RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8‐RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit. © 2010 Wiley‐Liss, Inc.     

Direct evidence for endothelial vascular endothelial growth factor receptor-1 function in nitric oxide-mediated angiogenesis

Vascular endothelial growth factor-A (VEGF) is critical for angiogenesis but fails to induce neovascularization in ischemic tissue lesions in mice lacking endothelial nitric oxide synthase (eNOS). VEGF receptor-2 (VEGFR-2) is critical for angiogenesis, although little is known about the precise role of endothelial VEGFR-1 and its downstream effectors in this process. Here we have used a chimeric receptor approach in which the extracellular domain of the epidermal growth factor receptor was substituted for that of VEGFR-1 (EGLT) or VEGFR-2 (EGDR) and transduced into primary cultures of human umbilical vein endothelial cells (HUVECs) using a retroviral system. Activation of HUVECs expressing EGLT or EGDR induced rapid phosphorylation of eNOS at Ser1177, release of NO, and formation of capillary networks, similar to VEGF. Activation of eNOS by VEGFR-1 was dependent on Tyr794 and was mediated via phosphatidylinositol 3-kinase, whereas VEGFR-2 Tyr951 was involved in eNOS activation via phospholipase Cgamma1. Consistent with these findings, the VEGFR-1-specific ligand placenta growth factor-1 activated phosphatidylinositol 3-kinase and VEGF-E, which is selective for VEGFR-2-activated phospholipase Cgamma1. Both VEGFR-1 and VEGFR-2 signal pathways converged on Akt, as dominant-negative Akt inhibited the NO release and in vitro tube formation induced following activation of EGLT and EGDR. The identification Tyr794 of VEGFR-1 as a key residue in this process provides direct evidence of endothelial VEGFR-1 in NO-driven in vitro angiogenesis. These studies provide new sites of modulation in VEGF-mediated vascular morphogenesis and highlight new therapeutic targets for management of vascular diseases.     

Defective homologous recombination in human cancers

Homologous recombination (HR) is a process by which DNA double strand breaks are repaired through the alignment of homologous sequences of DNA. Interest continues to increase in HR pathway function due to the development of new therapeutic agents which selectively exploit DNA damage repair pathways. Currently the most promising of these new agents are inhibitors of poly(ADP ribose) polymerase (PARP). The response of cancers known to be deficient in HR, due to BRCA1 or 2 mutations has been demonstrated, and a wider use of PARP inhibitors in cancers with mutations of other HR pathway genes has been suggested. With ongoing clinical studies into the use of PARP inhibitors, further understanding of the HR pathway, to allow patient selection by cancer biology, is now essential. Numerous studies have investigated individual aberrations of genes involved in the HR pathway. Here we collate this evidence to give an overview of the role of the HR pathway in human cancer.     

Renal replacement therapy in end-stage renal disease patients with chronic liver disease and ascites: role of peritoneal dialysis.

Chronic liver disease and cirrhosis account for several thousand deaths in the United States and often these patients have renal disease that progresses to end-stage renal disease (ESRD), necessitating renal replacement therapy. These patients provide significant challenges to their physicians, especially in the management of their ESRD with dialysis. ESRD patients with chronic liver disease and ascites are more difficult to manage on hemodialysis (HD) due to their hemodynamic status and risk of bleeding. Peritoneal dialysis (PD) offers them a viable alternative, along with a stable hemodynamic status and a lower risk of bleeding. The overall morbidity and mortality as well as the risk of peritonitis appear to be almost similar between cirrhotic and non-cirrhotic PD patients. In the absence of clinical trials comparing HD versus PD in such a population, and despite the limited clinical observations, the authors support PD as a viable and effective form of renal replacement therapy for patients with ESRD and associated chronic liver disease with cirrhosis and ascites.