From secondary to primary prevention of progressive renal disease: The case for screening for albuminuria

From secondary to primary prevention of progressive renal disease: The case for screening for albuminuria. Many subjects nowadays present with end-stage renal failure and its attendant cardiovascular complications without known prior renal damage. In this report we review the evidence available to strongly suggest that the present practice of secondary prevention in those with known prior renal disease should be extended to primary prevention for those subjects in the general population who are at risk for progressive renal failure, but who had never suffered from a primary renal disease. We show that such subjects can be detected by screening for albuminuria. Elevated urinary albumin loss is an indicator not only of poor renal, but also of poor cardiovascular prognosis. In addition to diabetic subjects who are at risk for albuminuria, we also show that hypertensive, obese, and smoking subjects are more susceptible. We suggest that therapies that have been shown to lower albumin excretion, such as ACE inhibitors, angiotensin II receptor antagonists, and statins be started early in such patients to prevent them from developing clinical renal disease and its attendant cardiovascular complications

Emergency department visits for acute asthma by adults who ran out of their inhaled medications

This study was designed to determine the percentage of asthma-related emergency department (ED) visits made by patients who recently ran out of their inhaled short-acting beta-agonists or inhaled corticosteroids and to characterize this understudied patient population. A secondary analysis was performed of data from four ED-based multicenter studies of acute asthma during 1996–1998 (n = 64 EDs). In each study, consecutive adult patients, aged 18–54 years, with acute asthma underwent a structured interview that assessed running out of inhaled medications. The analytic cohort comprised 1095 adults. Overall, 324 patients (30%; 95% confidence interval [CI], 27–32%) ran out of either of their inhaled beta-agonists or inhaled corticosteroids during the week before their index ED visit; 311 (28%; 95% CI, 26–31%) ran out of inhaled beta-agonists per se. Among a subset of 518 patients on inhaled corticosteroids, 55 patients (11%; 95% CI, 8–14%) ran out of inhaled corticosteroids. In the multivariable model, predictors of running out of an asthma medication were male sex, non-Hispanic black race, Hispanic ethnicity, no insurance, lower household income, and use of EDs as the preferred source of asthma prescriptions (all p < 0.05). Among patients who ran out of medications, 49% (95% CI, 43–55%) ran out of inhaled beta-agonists and 72% (95% CI, 58–84%) ran out of inhaled corticosteroids, before onset of their acute asthma symptoms. In 1095 adult ED patients with acute asthma, we found that 30% ran out of their inhaled asthma medications before the ED visit. Asthma patients who ran out of medications had sociodemographic characteristics that may help with identification of preventable ED visits. Multifaceted strategies needed to ensure optimal use of inhaled medications are warranted

Wittgenstein's Thought Experiments and Relativity Theory

In this paper, I discuss the similarity between Wittgenstein’s use of thought experiments and Relativity Theory. I begin with introducing Wittgenstein’s idea of “thought experiments” and a tentative classification of different kinds of thought experiments in Wittgenstein’s work. Then, after presenting a short recap of some remarks on the analogy between Wittgenstein’s point of view and Einstein’s, I suggest three analogies between the status of Wittgenstein’s mental experiments and Relativity theory: the topics of time dilation, the search for invariants, and the role of measuring tools in Special Relativity. This last point will help to better define Wittgenstein’s idea of description as the core of his philosophical enterprise

Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy

Background: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. Methods: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. Results: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). Conclusions: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated

Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays

BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. METHODOLOGY/PRINCIPAL FINDINGS: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. CONCLUSIONS/SIGNIFICANCE: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatibility gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches

Solvent-selective routing for centrifugally automated solid-phase purification of RNA

The final publication is available at Springer via https://doi.org/10.1007/s10404-014-1477-9.We present a disc-based module for rotationally controlled solid-phase purification of RNA from cell lysate. To this end, multi-stage routing of a sequence of aqueous and organic liquids into designated waste and elution reservoirs is implemented by a network of strategically placed, solvent-selective composite valves. Using a bead-based stationary phase at the entrance of the router, we show that total RNA is purified with high integrity from cultured MCF7 and T47D cell lines, human leucocytes and Haemophilus influenzae cell lysates. Furthermore, we demonstrate the broad applicability of the device through the in vitro amplification of RNA purified on-disc using RT-PCR and NASBA. Our novel router will be at the pivot of a forthcoming, fully integrated and automated sample preparation system for RNA-based analysis.Peer reviewe