No Evidence for Statin-induced Proteinuria in Healthy Volunteers as Assessed by Proteomic Analysis

In clinical studies of statins (class of drugs lowering plasma cholesterol levels), transient low-molecular-weight proteinuria was observed. The causes of statin-induced proteinuria in the patient background of those studies (cardiovascular and kidney disease) are multifactorial and, therefore, a matter of debate. In light of this, it seemed interesting to investigate the effect of statins on the urinary protein concentration and proteome in healthy volunteers. Six healthy volunteers were randomly treated with rosuvastatin (40 mg/day) or pravastatin (80 mg/day) in a double-blinded cross-over study. Total urinary protein concentration and the concentration of albumin/retinol-binding protein were analysed, after which the urinary proteome was investigated. From the results described in this study, it was concluded that statins do not induce major changes in the urinary protein concentration/proteome. High variability in the baseline urinary proteome/proteins among volunteers, however, made it very difficult to find subtle (possibly isolated to individuals) effects of statins

Low Doses of Cadmium Chloride and Methallothionein-1-Bound Cadmium Display Different Accumulation Kinetics and Induce Different Genes in Cells of the Human Nephron

Background/Aims: The present study was conducted to investigate the renal tubular handling of inorganic cadmium (Cd2+) by exposing primary human tubular cell cultures to physiologically relevant doses of cadmium chloride (CdCl2). Furthermore, the cellular accumulation of Cd2+ was compared to that of metallothionein-1-bound Cd (Cd7MT-1). Finally, this study aimed to investigate the effect of the accumulation of Cd (both Cd2+ and Cd7MT-1) in renal cells on the expression of genes relevant to nephrotoxic processes. Methods: Cd concentration was measured using atomic absorption spectrometry. mRNA expression was evaluated by quantitative real-time RT-PCR. Results: Cd2+ accumulated into human tubular cells in a concentration- and time-dependent way. Furthermore, cellular accumulation of Cd2+ was different from the cellular accumulation of Cd7MT-1, indicative for different uptake routes. Finally, mRNA expression of the genes encoding the anti-oxidative proteins metallothionein-1 (MT-1) and heme-oxygenase-1 (HO-1) as well as the pro-apoptotic Bcl-2-associated X protein (Bax) were upregulated by CdCl2 and not by Cd7MT1. Conclusion: In the presence of physiologically relevant Cd concentrations, tubular accumulation of the element in its inorganic form is different from that of Cd7MT-1. Furthermore, the tubular accumulation of inorganic Cd induces mRNA expression of genes of which the protein products may play a role in Cd-associated renal toxicity

Calcium oxalate crystal adherence to hyaluronan-, osteopontin-, and CD44-expressing injured/regenerating tubular epithelial cells in rat kidneys

Retention of crystals in the kidney is an essential early step in renal stone formation. Studies with renal tubular cells in culture indicate that hyaluronan (HA) and osteopontin (OPN) and their mutual cell surface receptor CD44 play an important role in calcium oxalate (CaOx) crystal binding during wound healing. This concept was investigated in vivo by treating rats for 1, 4, and 8 d with ethylene glycol (0.5 and 0.75%) in their drinking water to induce renal tubular cell damage and CaOx crystalluria. Tubular injury was morphologically scored on periodic acid-Schiff-stained renal tissue sections and tissue repair assessed by immunohistochemical staining for proliferating cell nuclear antigen. CaOx crystals were visualized in periodic acid-Schiff-stained sections by polarized light microscopy, and renal calcium deposits were quantified with von Kossa staining. HA was visualized with HA-binding protein and OPN and CD44 immunohistochemically with specific antibodies and quantified with an image analyzer system. Already after 1 d of treatment, both concentrations of ethylene glycol induced hyperoxaluria and CaOx crystalluria. At this point, there was neither tubular injury nor crystal retention in the kidney, and expression of HA, OPN, and CD44 was comparable to untreated controls. After 4 and 8 d of ethylene glycol, however, intratubular crystals were found adhered to injured/regenerating (proliferating cell nuclear antigen positive) tubular epithelial cells, expressing HA, OPN, and CD44 at their luminal membrane. In conclusion, the expression of HA, OPN, and CD44 by injured/regenerating tubular cells seems to play a role in retention of crystals in the rat kidney

Epoetin Delta Reduces Oxidative Stress in Primary Human Renal Tubular Cells

Erythropoietin (EPO) exerts (renal) tissue protective effects. Since it is unclear whether this is a direct effect of EPO on the kidney or not, we investigated whether EPO is able to protect human renal tubular epithelial cells (hTECs) from oxidative stress and if so which pathways are involved. EPO (epoetin delta) could protect hTECs against oxidative stress by a dose-dependent inhibition of reactive oxygen species formation. This protective effect is possibly related to the membranous expression of the EPO receptor (EPOR) since our data point to the membranous EPOR expression as a prerequisite for this protective effect. Oxidative stress reduction went along with the upregulation of renoprotective genes. Whilst three of these, heme oxygenase-1 (HO-1), aquaporin-1 (AQP-1), and B-cell CLL/lymphoma 2 (Bcl-2) have already been associated with EPO-induced renoprotection, this study for the first time suggests carboxypeptidase M (CPM), dipeptidyl peptidase IV (DPPIV), and cytoglobin (Cygb) to play a role in this process

Sharing knowledge: a new frontier for public-private partnerships in medicine

To help overcome the bottlenecks that limit the development of diagnostic and therapeutic products, academic and industrial researchers, patient organizations and charities, and regulatory and funding institutions should redefine the basis for sharing the knowledge collected in large-scale clinical and experimental studies

Preferential Transmission of the Alien Chromosome in a Durum Wheat-Agropyron Chromosome Addition Line

マカロニコムギ(Triticum durum cv. STEWART)に添加されたAgropyron elongatum, 2n=14の染色体e_1が常に次代に残される現象について取扱った。この現象はコムギゲノム内に生じた劣性接合子致死遺伝子の作用をe_1染色体が抑制することによって説明された。即ち, しわ種子は致死遺伝子をホモにもつ2n=28の種子で, 良種子はe_1染色体を含む添加型(2n=29)である。後者はe_1染色体による致死遺伝子作用の抑制のために, 正常に発芽し旺盛に生長する。しかし, 着粒種子の80%はe_1染色体を含まぬためしわ種子となり, 致死する。 / During an attempt to produce a set of substitution lines Agropyron elongatum (2n=14) to durum wheat cv. STEWART, a plant with 29 chromosomes was found in which a great majority of seeds set in a spike was shriveled and lethal. The selfed progenies of the plant had also 29 chromosomes and a lot of shriveled seeds without any exceptions. This implies that an alien chromosome continuously retains in the durum wheat background. From the observed segregation in F_1 and F_2 progenies resulting from the reciprocal crosses with the durum wheat, the preferential transmission might be explained as follows : 1. Zygotic lethal mutation has occurred spontaneously in wheat genomes. 2. An particular alien chromosome can suppress the lethal gene action. Therefore, it is possible that the alien chromosome, if present, makes the seed grow into matured plant. 3. The male gametes carring the lethal gene have an overwhelming competitive disadvantage to the normal gametes, but effect normally at the time of fertilization

The Wellesley News (04-20-1933)

https://repository.wellesley.edu/news/1945/thumbnail.jp

Reduced autonomic flexibility as a predictor for future anxiety in girls from the general population:The TRAILS study

The present present study investigated whether autonomic flexibility predicted future anxiety levels in adolescent boys and girls. This study is part of the TRacking Adolescents' Individual Lives Survey (TRAILS), a prospective cohort study of Dutch adolescents. The current study included a subsample of 965 individuals. Measures of autonomic flexibility, i.e., heart rate (HR) and respiratory sinus arrhythmia (RSA), were determined during the first assessment wave (T1: participants 10-12 years old). Self-reported anxiety was assessed at the first and second assessment wave (T2: participants 12-14 years old). Possible gender differences and co-occurring depressive problems were examined. In girls, low RSA predicted anxiety levels 2 years later. In boys, no associations between HR and RSA and future anxiety were found. We conclude that in adolescent girls from the general population, signs of reduced autonomic flexibility (i.e., low RSA) predict future anxiety levels. Since the effect size was small, at this point, RSA reactivity alone cannot be used to identify individuals at risk for anxiety, but should be regarded as one factor within a large group of risk factors. However, if the present findings are replicated in clinical studies, intervention programmes - in the future - aimed at normalising autonomic functioning may be helpful. (C) 2009 Elsevier Ireland Ltd. All rights reserved.</p

Switching from premixed insulin to glargine-based insulin regimen improves glycaemic control in patients with type 1 or type 2 diabetes: a retrospective primary care-based analysis

Background: Insulin glargine (glargine) and premixed insulins (premix) are alternative insulin treatments. This analysis evaluated glycaemic control in 528 patients with type 1 (n = 183) or type 2 (n = 345) diabetes, after switching from premix to a glargine-based regimen, using unselected general practice (GP) data. Methods: Data for this retrospective observational analysis were extracted from a UK GP database (The Health Improvement Network). Patients were required to have at least 12 months of available data, before and after, switching from premix to a glargine-based regimen. The principal analysis was the change in HbA1c after 12 months of treatment with glargine; secondary analyses included change in weight, bolus usage and total daily insulin dose. Inconsistent reporting of hypoglycemic episodes precludes reliable assessment of this outcome. Multivariate analyses were used to adjust for baseline characteristics and confounding variables. Results: Both cohorts showed significant reduction in mean HbA1c 12 months after the switch: by -0.67% (p < 0.001) in the type 1 cohort and by -0.53% (p < 0.001) in the type 2 cohort (adjusted data). The size of HbA1c improvement was positively correlated with baseline HbA1c; patients with a baseline HbA1c ≥ 10% had the greatest mean reduction in HbA1c, by -1.7% (p < 0.001) and -1.2% (p < 0.001), respectively. The proportion of patients receiving co-bolus prescriptions increased in the type 1 (mean 24.6% to 95.1%, p < 0.001) and type 2 (mean 16.2% to 73.9%, p < 0.001) cohorts. There was no significant change in weight in either cohort. Total mean insulin use increased in type 2 diabetes patients (from 0.67 ± 1.35 U/Kg to 0.88 ± 1.33 U/Kg, p < 0.001) with a slight decrease in type 1 diabetes patients (from 1.04 ± 2.51 U/Kg to 0.98 ± 2.58 U/Kg, p < 0.001). Conclusion: In everyday practice, patients with type 1 or type 2 diabetes inadequately controlled by premix insulins experienced significant improvement in glycaemic control over 12 months after switching to a glargine-based insulin regimen. These findings support the use of a basal-bolus glargine-based regimen in patients poorly controlled on premix.Peter Sharplin, Jason Gordon, John R Peters, Anthony P Tetlow, Andrea J Longman and Philip McEwa