Abstract. The fate of octogenarians reaching end-stage renal disease (ESRD) is poorly defined, and implicit dialysis rationing may be practiced in this age group. The main objectives of this study were to analyze the characteristics of pre-ESRD octogenarians offered dialysis or not and to identify factors influencing mortality while on dialysis, to improve prognosis assessment and decision-making. In this single-center cohort, 146 consecutive pre-ESRD octogenarians were referred to a nephrology unit over a 12-yr period (1989 to 2000). Main outcome measures were baseline characteristics of patients offered dialysis and conservative therapy and overall and 1-yr survival according to effective treatment. A therapeutic decision was made for 144 patients. Octogenarians who were not proposed dialysis (n ϭ 37) differed from those who were proposed dialysis (n ϭ 107) mainly in terms of social isolation (43.3% versus 14.7%; P ϭ 0.03), late nephrologic referral (51.4% versus 28.9%; P ϭ 0.01), Karnofsky score (55 Ϯ 18 versus 63 Ϯ 20; P ϭ 0.03), and diabetic status (22.2% versus 6.5%, P ϭ 0.008). Six patients refused the dialysis proposal.During the 12-yr observation period, 99 patients died (68.7%). Median survival was 28.9 mo (95% CI, 24 to 38) in patients undergoing dialysis, compared with 8.9 mo (95% CI, 4 to
A common T17A polymorphism in the signal peptide of the cytotoxic T-lymphocyte antigen 4 (CTLA-4), a T-cell receptor that negatively regulates immune responses, is associated with risk for autoimmune disease. Because the polymorphism is absent from the mature protein, we hypothesized that its biological effect must involve early stages of protein processing, prior to signal peptide cleavage. Constructs representing the two alleles were compared by in vitro translation, in the presence of endoplasmic reticulum membranes. We studied glycosylation by endoglycosidase H digestion and glycosylation mutant constructs, cleavage of peptide with inhibitors, and membrane integration by ultracentrifugation and proteinase K sensitivity. A major cleaved and glycosylated product was seen for both alleles of the protein but a band representing incomplete glycosylation was markedly more abundant in the predisposing Ala allele (32.7 ؎ 1.0 versus 10.6% ؎ 1.2 for Thr, p < 10 ؊9 ). In addition, differential intracellular/surface partitioning was studied with co-transfection of the alleles fused to distinct fluorescent proteins in COS-1 cells. By quantitative confocal microscopy we found a higher ratio of cell surface/total CTLAThr 17 versus CTLAAla 17 (p ؍ 0.01). Our findings corroborate observations, in other proteins, that the signal peptide can determine the efficiency of post-translational modifications other than cleavage and suggest inefficient processing of the autoimmunity predisposing Ala allele as the explanation for the genetic effect.
Background: Oncotype DX™ is a clinically validated, high-complexity, multianalyte reverse transcription-PCR genomic test that predicts the likelihood of breast cancer recurrence in early-stage, node-negative, estrogen receptor-positive breast cancer. The Recurrence Score™ (RS) provides a more accurate, reproducible measure of breast cancer aggressiveness and therapeutic responsiveness than standard measures. Individualized patient management requires strict performance criteria for clinical laboratory tests. We therefore investigated the analytical performance of the assay. Methods: Assays used a pooled RNA sample from fixed paraffin-embedded tissues to evaluate the analytical performance of a 21-gene panel with respect to amplification efficiency, precision, linearity, and dynamic range, as well as limits of detection and quantification. Performance variables were estimated from assays carried out with sample dilutions. In addition, individual patient samples were used to test the optimized assay for reproducibility and sources of imprecision. Results: Assay results defined acceptable operational performance ranges, including an estimated maximum deviation from linearity of <1 cycle threshold (C T ) units over a >2000-fold range of RNA concentrations, with a mean quantification bias of 0.3% and CVs of 3.2%-5.7%. An analysis of study design showed that assay imprecision
This dual potential of NAC to inhibit phagocyte oxidative responses induced by HSA-AOPP without affecting those mediated by compounds mimicking pathogens supports the proposal of a therapeutic trial with NAC aimed at reducing oxidative stress-related inflammation in hemodialysis patients.
This study provides suggestive evidence that longer duration of regular nephrological care in the predialysis period, at least for several years prior to the start of dialysis, is associated with a better long-term survival on dialysis. Such data strongly support the argument for early referral and regular nephrological care of chronic renal failure patients.
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