Immunoglobulin-A distribution in glomerular disease: Analysis of immunofluorescence localization and pathogenetic significance

Immunoglobulin-A distribution in glomerular disease. Analysis of immunofluorescence localization and pathogenetic significance. Renal biopsies from 470 patients with various glomemlonephropathies were studied for patterns and frequency of glomerular bound IgA. Correlations of IgA with IgG, IgM, C3, and C4 were made. Glomerular deposits of IgA were observed in five of six cases of Henoch-Schoenlein anaphylactoid nephritis (83%), stalk proliferative glomerulonephritis (73%), lupus nephritis (60%), and focal proliferative glomerulonephritis (57 %). In addition, IgA was less frequently observed in diffuse (acute) proliferative (33%), membranoproliferative (42%), membranous (32%), focal sclerosing (25%) crescentic (26%), and chronic glomerulonephritides (23%) as well as malignant arterionephrosclerosis, amyloidosis, and a group of patients with minimal glomerular alteration and no determinable diagnosis (40%). IgA was not specifically associated with IgG or IgM in any one diagnostic category but was often present with both. Deposits containing C3 and C4 most closely paralleled those of IgG and/or IgM. Presence of IgA appeared to correlate with variable degrees of increased glomerular mesangial cellularity in “minimal”, stalk proliferative, and focal-segmental glomerular lesions. The cause and immunopathogenetic significance of mesangial or peripheral glomerular capillary localization of IgA is unknown. Though a number of apparent examples of what has been referred to as IgA-IgG nephropathy were observed in this study, this entity, characterized by mesangial deposits of IgA, IgG, and C3, could not always be specifically identified or differentiated on histopathologic criteria alone from a variety of other glomerulopathies in which variable proportions of IgA, IgG, IgM, C3, and C4 globulins were localized

The fidelity of DNA replication, particularly on GC-rich templates, is reduced by defects of the Fe-S cluster in DNA polymerase δ

Iron-sulfur clusters (4Fe-4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes. Met18p is required for the efficient insertion of iron-sulfur clusters into various proteins. met18 mutants have an elevated rate of deletions between short flanking repeats, consistent with increased DNA polymerase slippage. This phenotype is very similar to that observed in mutants of POL3 (encoding the catalytic subunit of Pol δ) that weaken binding of the iron-sulfur cluster. Comparable mutants of POL2 (Pol ϵ) do not elevate deletions. Further support for the conclusion that met18 strains result in impaired DNA synthesis by Pol δ are the observations that Pol δ isolated from met18 strains has less bound iron and is less processive in vitro than the wild-type holoenzyme

The Role of Public Health Institutions in Global Health System Strengthening Efforts: The US CDC's Perspective

Peter Bloland and colleagues from the US CDC lay out the agency's priorities for health systems strengthening efforts

Impacts of Waste from Concentrated Animal Feeding Operations on Water Quality

Waste from agricultural livestock operations has been a long-standing concern with respect to contamination of water resources, particularly in terms of nutrient pollution. However, the recent growth of concentrated animal feeding operations (CAFOs) presents a greater risk to water quality because of both the increased volume of waste and to contaminants that may be present (e.g., antibiotics and other veterinary drugs) that may have both environmental and public health importance. Based on available data, generally accepted livestock waste management practices do not adequately or effectively protect water resources from contamination with excessive nutrients, microbial pathogens, and pharmaceuticals present in the waste. Impacts on surface water sources and wildlife have been documented in many agricultural areas in the United States. Potential impacts on human and environmental health from long-term inadvertent exposure to water contaminated with pharmaceuticals and other compounds are a growing public concern. This work-group, which is part of the Conference on Environmental Health Impacts of Concentrated Animal Feeding Operations: Anticipating Hazards—Searching for Solutions, identified needs for rigorous ecosystem monitoring in the vicinity of CAFOs and for improved characterization of major toxicants affecting the environment and human health. Last, there is a need to promote and enforce best practices to minimize inputs of nutrients and toxicants from CAFOs into freshwater and marine ecosystems

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma

Altres ajuts: This trial was funded by Eli Lilly and Company.The online version of this article contains supplementary material, which is available to authorized users

Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts