L-carnitine supplementation in the dialysis population: are Australian patients missing out?

It has been widely established that patients with end-stage renal disease undergoing chronic haemodialysis therapy exhibit low endogenous levels of L-carnitine and elevated acylcarnitine levels; however, the clinical implication of this altered carnitine profile is not as clear. It has been suggested that these disturbances in carnitine homeostasis may be associated with a number of clinical problems common in this patient population, including erythropoietin-resistant anaemia, cardiac dysfunction, and dialytic complications such as hypotension, cramps and fatigue. In January 2003, the Centers for Medicare and Medicaid Services (USA) implemented coverage of intravenous L-carnitine for the treatment of erythropoietin-resistant anaemia and/or intradialytic hypotension in patients with low endogenous L-carnitine concentrations. It has been estimated that in the period of 1998-2003, 3.8-7.2% of all haemodialysis patients in the USA received at least one dose of L-carnitine, with 2.7-5.2% of patients receiving at least 3 months of supplementation for one or both of these conditions. The use of L-carnitine within Australia is virtually non-existent, which leads us to the question: Are Australian haemodialysis patients missing out? This review examines the previous research associated with L-carnitine administration to chronic dialysis patients for the treatment of anaemia, cardiac dysfunction, dyslipidaemia and/or dialytic symptoms, and discusses whether supplementation is warranted within the Australian setting.     

Interaction of Felbamate with [H]DCKA-Labeled Strychnine-Insensitive Glycine Receptors in Human Postmortem Brain

The dicarbamate felbamate has been shown to be capable of competing for the binding of 5,7-[³H]dichlorokynurenic acid ([³H]DCKA) to strychnine-insensitive glycine receptors in sections of human postmortem brain. The IC₅₀ for this interaction was 305.8 μM and the inhibition was complete at 1 mM. Autoradiographic localization of [³H]DCKA binding revealed many regions of human brain in which strychnine-insensitive glycine receptors are manifest. The specific binding in most of these areas was markedly reduced in the presence of 625 μM felbamate. In many regions, [³H]DCKA binding was reduced to background in the presence of felbamate, but some areas retained binding by as much as 41% (i.e., the CA2 region of the hippocampus). This is in contrast to the binding of [³H]DCKA in the presence of carbamazepine, phenytoin, or valproic acid. The binding of the glycine receptor antagonist was not affected by any of these latter agents to the same degree as felbamate. Strychnine-insensitive glycine receptors represent a site of action of felbamate in the human brain.     

Tubular expression of intercellular adhesion molecule-1 during renal allograft rejection

Molecules responsible for adhesion between cells are known to play an important role in the immune response. The expression of one of these molecules, intercellular adhesion molecule-1 (ICAM-1), was examined on normal and allografted kidneys using a specific monoclonal antibody and an indirect immunoperoxidase technique. The expression of this molecule was compared to that of HLA class II antigens. On normal kidneys and most allograft biopsies taken immediately before implantation, ICAM-1 was expressed only on vascular endothelial cells (VEC) and parietal epithelium of Bowman's capsule. In the 11 kidneys where biopsies were available before and after transplantation, the appearance of rejection was associated with de novo expression of ICAM-1 on renal tubular epithelial cells that closely paralleled that of HLA class II antigens. In addition, an increase in endothelial cell expression of these molecules was also seen in rejection. In 23 random allograft biopsies, most of those with rejection showed tubular expression of both HLA class II antigens and ICAM-1. However, the presence of these molecules on tubules in several biopsies that did not show rejection limits the clinical usefulness of monitoring these antigens in posttransplant biopsies. The upregulation of these molecules is presumed to be secondary to the release of cytokines by cells infiltrating the allograft, although other mechanisms may be operating that explain the expression of these molecules in nonrejecting grafts.     

Preparative purification of the rat mast cell chymase. Characterization and Interaction with granule components

The rat mast cell granule chymotrypsinlike enzyme was purified to homogeneity from 1 M NaCl solubilized membrane and granule-rich fractions of concentrated rat peritoneal mast cells by a preparative technique utilizing chromatography on Dowex 1, filtration on Sephadex G-75, and affinity chromatography with D-tryptophan methyl ester. Acid disk gel electrophoresis of the purified chymase disclosed a single stained band with activity being eluted from a replicate sliced gel in the same region. SDS-polyacrylamide gel electrophoresis of purified protein gave a single stained band that did not change in position with reduction and alkylation. Mast cell chymase is thus a cationic protein of 25,000 mol wt composed of a single polypeptide chain. The apparent K(m) of the chymase for BTEE was 1.5 x 10(-3) M and the V(max) was 67.8 μmol/min per mg. The enzyme was inhibited by TPCK and not by TLCK. The chymase complexed with native macromolecular rat mast cell heparin in molar ratios of 12:1 and 16:1, and complete heparin uptake occurred at a 40:1 ratio of chymase to heparin. Chymase activity was partially masked by combination with heparin in the isolated granule or experimental chymase-heparin complex, and soluble purified chymase was inhibited by concentrations of 5-HT comparable to those present in mast cells. It is therefore possible that the active site of chymase in the mast cell granule is largely masked by the combined effects of macromolecular heparin and 5-HT.     

Adherence to secondary prophylaxis and disease recurrence in 536 Brazilian children with rheumatic fever

Background  

More than 15 million people worldwide have rheumatic fever (RF) and rheumatic heart disease due to RF. Secondary prophylaxis is a critical cost-effective intervention for preventing morbidity and mortality related to RF. Ensuring adequate adherence to secondary prophylaxis for RF is a challenging task. This study aimed to describe the rates of recurrent episodes of RF, quantify adherence to secondary prophylaxis, and examine the effects of medication adherence to the rates of RF in a cohort of Brazilian children and adolescents with RF.     

A novel population of progenitor cells expressing cannabinoid receptors in the subependymal layer of the adult normal and Huntington's disease human brain

Progenitor cells in the adult human brain subependymal layer are capable of producing new neurons and glial cells that may be useful as a source of cells for endogenous cell replacement for regions of the brain that undergo degeneration due to a neurodegenerative disease such as Huntington's disease, Parkinson's disease or Alzheimer's disease. We have previously demonstrated that in the human Huntington's disease brain there are increased numbers of progenitor cells proportional to the severity of the gene defect responsible for the disease and proportional to the severity of the pathology of the disease. One of the criticisms of a potential endogenous progenitor cell replacement therapy has been that the endogenous progenitor cells also contain the Huntington's disease gene and would therefore be just as susceptible to degeneration as those in the degenerate brain region. In the present study we have demonstrated the presence of cannabinoid CB1 receptors, which are preferentially lost in Huntington's disease, colocalised with the proliferative marker PCNA in the adult normal and Huntington's disease subependymal layer. This population of CB1 positive cells only colabels with PCNA and not with neuronal, glial, microglial or oligodendrocyte markers. These results indicate that the subependymal layer in Huntington's disease contains a subpopulation of proliferating cells that are also CB1 receptor positive and are thus not immediately susceptible to the neurodegenerative process that denudes the striatum of CB1 receptors. This finding raises the intriguing possibility that these cells could provide a suitable source of cells for the endogenous replacement of cells lost due to neurodegenerative disease.