Trace elements in end-stage renal disease – unfamiliar territory to be revealed

Although associated with unfavorable outcomes in the general population, abnormal blood levels of various trace elements have not been consistently studied in the end-stage renal disease population (with the notable exception of aluminum). This is surprising, as the uremic patient treated by chronic dialysis loses one major route of trace element excretion and is exposed systematically to a foreign environment (the dialysis fluid) possibly contaminated with significant amounts of potential deleterious trace elements. Moreover, some biological important trace elements may be lost through the dialysis membrane. Most studies to date demonstrated significantly altered blood levels of trace elements in ESRD patients compared to healthy controls. However, the biological impact of these abnormalities in renal disease is largely unknown and should be clarified by future studies. A further step would be the design of well-controlled randomized interventional studies, examining the potential therapeutic benefit of supplementing one or more trace elements in ESRD patients, a population characterized by an impressive mortality due to cardiovascular, infectious and neoplasic disease

Structural and biophysical properties of the integrin-associated cytoskeletal protein talin

Talin is a large cytoskeletal protein (2541 amino acid residues) which plays a key role in integrin-mediated events that are crucial for cell adhesion, migration, proliferation and survival. This review summarises recent work on the structure of talin and on some of the structurally better defined interactions with other proteins. The N-terminal talin head (approx. 50 kDa) consists of an atypical FERM domain linked to a long flexible rod (approx. 220 kDa) made up of a series of amphipathic helical bundle domains. The F3 FERM subdomain in the head binds the cytoplasmic tail of integrins, but this interaction can be inhibited by an interaction of F3 with a helical bundle in the talin rod, the so-called “autoinhibited form” of the molecule. The talin rod contains a second integrin-binding site, at least two actin-binding sites and a large number of binding sites for vinculin, which is important in reinforcing the initial integrin–actin link mediated by talin. The vinculin binding sites are defined by hydrophobic residues buried within helical bundles, and these must unfold to allow vinculin binding. Recent experiments suggest that this unfolding may be mediated by mechanical force exerted on the talin molecule by actomyosin contraction

Physiological and Behavioural Responses to Noxious Stimuli in the Atlantic Cod (Gadus morhua)

In the present study, our aim was to compare physiological and behavioural responses to different noxious stimuli to those of a standardized innocuous stimulus, to possibly identify aversive responses indicative of injury detection in a commercially important marine teleost fish, the Atlantic cod. Individual fish were administered with a noxious stimulus to the lip under short-term general anaesthesia (MS-222). The noxious treatments included injection of 0.1% or 2% acetic acid, 0.005% or 0.1% capsaicin, or piercing the lip with a commercial fishing hook. Counts of opercular beat rate (OBR) at 10, 30, 60, 90 and 120 min and observations of behaviour at 30 and 90 min post-treatment were compared with pre-treatment values and with control fish injected with physiological saline, an innocuous stimulus. Circulatory levels of physiological stress indicators were determined in all fish at 120 minutes post-treatment. All treatments evoked temporarily increased OBR that returned to pre-treatment levels at 60 minutes (saline, 0.005% capsaicin, hook), 90 minutes (0.1% acetic acid, 0.1% capsaicin), or 120 minutes (2% acetic acid), but with no significant differences from the control group at any time point. Fish treated with 0.1% and 2% acetic acid and 0.1% capsaicin displayed increased hovering close to the bottom of the aquaria and fish given 2% acetic acid and 0.1% capsaicin also displayed a reduced use of shelter. The only effect seen in hooked fish was brief episodes of lateral head shaking which were not seen pre-treatment or in the other groups, possibly reflecting a resiliency to tissue damage in the mouth area related to the tough nature of the Atlantic cod diet. There were no differences between groups in circulatory stress indicators two hours after treatment. This study provides novel data on behavioural indicators that could be used to assess potentially aversive events in Atlantic cod

Immunosuppressive treatments for immunoglobulin A nephropathy: A meta-analysis of randomized controlled trials

Immunoglobulin A (IgA) nephropathy is a worldwide disease that causes end-stage kidney disease (ESRD) in up to 15-20% of affected patients within 10 years from the apparent onset of disease and in up to 30-40% of individuals within 20 years from diagnosis. No specific treatment has been established and there is wide variation in current practice. This systematic review evaluates the use of immunosuppressive agents to treat patients with IgA nephropathy. The Cochrane Renal Group Specialized Register, Cochrane Controlled Trial Registry, MEDLINE, EMBASE and article reference lists were searched for randomized or quasi randomized trials. Two independent reviewers assessed studies for inclusion criteria (biopsy proven IgA nephropathy, randomized trial, use of immunosuppressive agents) and extracted data regarding the effects of immunosuppressive agents on ESRD, doubling of serum creatinine, glomerular filtration rate, urinary protein excretion and side-effects. Data were analysed with a random effects model. The published trials were few (13 trials, 623 patients) and were generally of poor quality. Compared with placebo, steroids were associated with a lower risk of progression to ESRD (six trials, 341 patients, RR 0.44, 95% Cl 0.25-0.80) and lower end-of-trial proteinuria (six trials, 263 patients, weighted mean difference (WMD) -0.49 g/day, 95% Cl -0.25 to -0.72). Treatment with alkylating agents significantly reduced end of treatment proteinuria (two trials, 122 patients, WMD -0.94, 95% Cl -0.46 to -1.43). Although the optimal management of patients with IgA nephropathy remains uncertain because of limitations with the existing published data, immunosuppressive agents are a promising strategy and should be investigated further

Non-immunosuppressive treatment for IgA nephropathy

IgA nephropathy (IgAN) is the most common primary glomerular disease with approximately 30% to 40% of patients progressing to end-stage kidney disease (ESKD) within 20 years. The most common regimens include immunosuppressive agents, however the risks of long-term treatment often outweigh the potential benefits. Non-immunosuppressive options, including fish oils, anticoagulants, antihypertensive agents and tonsillectomy have also been examined but not reviewed systematically. To assess the benefits and harms of non-immunosuppressive treatments for treating IgAN in adults and children. In July 2010 we searched the Cochrane Renal Group's specialised register, CENTRAL (in The Cochrane Library), MEDLINE (from 1966) and EMBASE (from 1980). We also searched reference lists of included studies, review articles and contacted local and international experts. Randomised controlled trials (RCTs) of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included. Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model. We included 56 studies (2838 participants). Antihypertensive agents were the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or combinations of both, versus other antihypertensives and other agents. The benefits of antihypertensive agents, particularly inhibitors of the renin angiotensin system, appear to potentially outweigh the harms in patients with IgAN. The benefits are largely manifest as a reduction in proteinuria, a surrogate outcome. There is no evidence that treatment with any of the antihypertensive agents evaluated affect major renal and/or cardiovascular endpoints or long-term mortality risk beyond the benefit that arises from controlling hypertension in patients with IgAN. The RCT evidence is insufficiently robust to demonstrate efficacy for any of the other non-immunosuppressive therapies evaluated here. IgAN remains a disease in search of adequately powered RCTs to reliably inform clinical practice. More and better evidence is needed to understand the magnitude of benefit and the possible risks of anti-hypertensive or more specifically of ACEi/ARB therapy alone or in combination and which specific types of patients with the IgAN might have the greatest potential for benefit. For other non-immunosuppressive therapies, where neither benefit nor significant harm has yet to be demonstrated, there remains some justification for further exploration of the potential benefits