Abeta-degrading endopeptidase,neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology

Metabolism of amyloid-beta peptide (Abeta) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Since neprilysin is the only rate-limiting catabolic peptidase proven by reverse genetics to participate in Abeta metabolism in vivo, we performed detailed immunohistochemical analysis of neprilysin in mouse brain using neprilysin-deficient mice as a negative control. The aim was to assess, at both the cellular and subcellular levels, where Abeta undergoes neprilysin-dependent degradation in the brain and how neprilysin localization relates to Abeta pathology in amyloid precursor protein (APP)-transgenic mice. In hippocampus, neprilysin was present in the stratum pyramidale and stratum lacunosum-moleculare of the CA1-3 fields and the molecular layer of the dentate gyrus. Confocal double immunofluorescence analyses revealed the subcellular localization of neprilysin along axons and at synapses. This observation suggests that after synthesis in the soma, neprilysin, a type II membrane-associated protein, is axonally transported to the terminals, where Abeta degradation is likely to take place. Among various cell types, GABAergic and metabotropic glutamate 2/3 receptor-positive neurons but not catecholaminergic or cholinergic neurons, expressed neprilysin in hippocampus and neocortex, implying the presence of a cell type-specific mechanism that regulates neprilysin gene expression. As expected, Abeta deposition correlated inversely with neprilysin expression in TgCRND8 APP-transgenic mice. These observations not only support the notion that neprilysin functions as a major Abeta-degrading enzyme in the brain but also suggest that down-regulation of neprilysin activity, which may be caused by aging, is likely to elevate local concentrations of Abeta at and around neuronal synapses.     

Heterogeneity of structural abnormalities in the 7q31.3 approximately q34 region in myeloid malignancies

Abnormalities in the long arm of chromosome 7 are a frequent chromosomal aberration in myeloid disorders. Most studies have focused on the analysis of del(7q), demonstrating the presence of several minimal deleted regions in 7q22 approximately q31. By contrast, few studies in myeloid disorders have been devoted to the analysis of translocations, either balanced or unbalanced, involving 7q. In this study, we used fluorescence in situ hybridization (FISH) to characterize the 7q31.3 approximately q34 region (markers D7S480-D7S2227) in patients with deletion or translocation of 7q. A total of 910 cases of myeloid disorders were studied by conventional cytogenetics. Fifty-eight (6%) patients had structural aberrations of 7q. FISH studies were carried out in the 27 patients with involvement of 7q31 approximately q34: 14 cases had an acute myelogenous leukemia and 13 cases had a myelodysplastic syndrome. FISH analysis revealed the existence of high complexity in the 7q31.3 approximately q34 region in patients with unbalanced translocations. No breakpoints in 7q31.3 approximately q34 were found in the cases with deletion or balanced translocation. Nevertheless, studies of unbalanced translocations showed several breakpoints in markers D7S480-D7S2227, which delineate a commonly altered region. The complexity of 7q rearrangements suggests that a synergy of different genetic factors, rather than the alteration of a single tumor suppressor gene, could be involved in the pathogenesis of del(7q) in myeloid disorders.     

Saquinavir plus ritonavir reduce viral load by 99.9 percent

A combination of two protease inhibitors, saquinavir (Invirase) and ritonavir (Norvir), may produce a median drop in viral load of 99.9 percent. Several dosage variations were tested. The most common side effects of the combination regimen included tingling around the mouth, diarrhea, fatigue, and nausea. A low level of toxicity was found. This combination may be used for people who have failed other protease inhibitor therapy or have developed a resistance to nucleoside analogues.     

Banish those side effects

Although many AIDS patients suffer side effects from their medications, not all do, and many side effects can be managed. Many patients suffer needless pain because physicians are reluctant to prescribe potentially addictive drugs. Patients may find relaxation techniques helpful in managing nausea, and should vary the use of their drugs to avoid developing an aversion to its taste. Patients should also ask for medications that can alleviate the side effects associated with some drugs.     

Understanding and treating protease paunch

The changes and complications in metabolic status and lipodystrophy stemming from HIV treatment are examined. Research results from international conferences are discussed; topics include mechanisms of action and outcomes of recent treatments for lipodystrophy. These therapies cite the benefits of diet and exercise and the use of liposuction. Also examined are studies that investigated the effects of switching HIV protease drugs. Concluding comments address the possible connection between heart disease and lipodystrophy.     

A look at lab numbers

Lab analyses show that children with HIV differ in disease characteristics from HIV-infected adults. In children, viral load and T-cells are higher initially, but gradually decline and achieve a plateau by age six. Like adults, both T-cells and two separate viral load levels must be considered when deciding on therapy. CD4+ cell counts below 25 percent of normal age levels warrant therapy. There is a substantial overlap in viral load levels in the first year of life between children who have rapid disease progression and those who do not. One study revealed that the average viral load for the first year of life was 185,000. For children below 2 years of age, viral load needs to multiply or decrease by five times to be considered a significant change, compared to a threefold difference for persons more than 2 years of age.     

Norvir capsules-soon?

Abbott Laboratories reports that it expects to put its Norvir (Ritonavir) capsules back on the market around July. Abbott reported a manufacturing problem with the capsule last year. The company cited the FDA requirements of 6-month stability data before re-introduction.