Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases

Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize GM2 ganglioside by beta-hexosaminidase A (Hex A) due to mutations of the alpha subunit (Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B (beta beta homodimer) is also defective in Sandhoff disease. We previously developed mouse models of both diseases and showed that Hexa-/- (Tay-Sachs) mice remain asymptomatic to at least 1 year of age while Hexb-/- (Sandhoff) mice succumb to a profound neurodegenerative disease by 4-6 months of age. Here we find that neuron death in Hexb-/- mice is associated with apoptosis occurring throughout the CNS, while Hexa-/- mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated GM2 ganglioside or a derivative in triggering of the apoptotic cascade.      

Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP- sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.      

Presentation of cytosolic antigens via MHC class II molecules

Major histocompatibility (MHC) class II molecules function to present antigenic peptides to CD4 T lymphocytes. The pathways by which these molecules present exogenous antigens have been extensively studied. However by contrast, far less is known about the processing and trafficking of cytosolic antigens, which can also serve as an alternative source of ligands for MHC class II molecules. Self-proteins, tumor antigens, as well as viral proteins found within the cytosol of cells, can be presented via MHC class II molecules, resulting in the activation of specific CD4 T cells. Studies have begun to reveal unique steps as well as some similarities in the pathways for cytosolic and exogenous antigen presentation. Recent developments in this area are summarized here.     

Calculation of direct standard costs in the evaluation of new technologies: application to the treatment of acute myeloblastic leukemias

Financial incidence of new technology can be approached through the utilization of "direct standard cost". This method allows actualization of prices and permits the integration of new procedures. It is applied to acute non lymphoblastic leukemia.     

Involvement of calyculin A-sensitive phosphatase(s) in the differentiation of Trypanosoma cruzi trypomastigotes to amastigotes

Differentiation of the non-dividing trypomastigote form of Trypanosoma cruzi, the causative agent of Chagas disease, to the dividing amastigote form normally occurs in cytoplasm of infected cells. Here we show that calyculin A. a potent inhibitor of protein phosphatases 1 and 2A, induces at pH 7.5 extracellular transformation of long slender trypomastigotes to round amastigote-like forms which acquire characteristic features observed after the normal differentiation process: repositioning and structural changes of the kinetoplast, release of surface neuraminidase, and expression of amastigote-specific epitopes. Calyculin A inhibits parasite phosphatases and changes in the phosphorylation of specific proteins occur during the transformation process. As an exposure of trypomastigotes to calyculin A concentrations as low as 1 nM and for only 1-2 h is sufficient to induce transformation, the inhibition of calyculin A-sensitive phosphatase(s) appears to play a major role in initiating the trypomastigote differentiation.     

Perkutane Revaskulärisation von Nierenarterienstenosen Ballonangioplastie versus Stentimplantation

Renal artery stenosis (RAS) is the most common cause of secondary hypertension, with a prevalence of about 1% in the general population of people with hypertension. Severe arterial stenosis may also lead to impairment of excretory renal function. In experienced hands renal artery revascularization with or without stent implantation may be a safe and effective treatment in patients with sustained hypertension resistant to intensive antihypertensive treatment. Conventional balloon angioplasty of non-ostial RAS caused by fibromuscular dysplasia with a high technical and functional success rate may be the treatment of choice. However, there is continuous discussion concerning the utility of balloon angioplasty and renal stenting, respectively, in patients with atherosclerotic disease. At the time being, there are 3 randomized European trials ongoing to analyze the benefit of medical treatment versus percutaneous intervention. Several prospective studies dealing with renal artery stenting in ostial RAS found that the implantation of endoprostheses leads to much better morphologic longterm results as compared to those of balloon angioplasty alone and may be a safe and effective alternative to surgery. In addition, the functional results suggest that stent implantation in patients with mild or severe renal dysfunction may slow progression of renal failure and, thus delay the need for renal replacement therapy. It is to note that renal artery stenting does not impede any further surgical intervention. However, prior to any interventional treatment the indication of an eventual catheter procedure in patients with RAS should be discussed between experienced nephrologists and interventionalists based on clinical, functional and duplexsonographic data.