Increased Glucose Transport into Neurons Rescues A? Toxicity in Drosophila

Glucose hypometabolism is a prominent feature of the brains of patients with Alzheimer's disease (AD). Disease progression is associated with a reduction in glucose transporters in both neurons and endothelial cells of the blood-brain barrier. However, whether increasing glucose transport into either of these cell types offers therapeutic potential remains unknown. Using an adult-onset Drosophila model of A? (amyloid beta) toxicity, we show that genetic overexpression of a glucose transporter, specifically in neurons, rescues lifespan, behavioral phenotypes, and neuronal morphology. This amelioration of A? toxicity is associated with a reduction in the protein levels of the unfolded protein response (UPR) negative master regulator Grp78 and an increase in the UPR. We further demonstrate that genetic downregulation of Grp78 activity also protects against A? toxicity, confirming a causal effect of its alteration on AD-related pathology. Metformin, a drug that stimulates glucose uptake in cells, mimicked these effects, with a concomitant reduction in Grp78 levels and rescue of the shortened lifespan and climbing defects of A?-expressing flies. Our findings demonstrate a protective effect of increased neuronal uptake of glucose against A? toxicity and highlight Grp78 as a novel therapeutic target for the treatment of AD

Deletion of endogenous Tau proteins is not detrimental in Drosophila

Human Tau (hTau) is a highly soluble and natively unfolded protein that binds to microtubules within neurons. Its dysfunction and aggregation into insoluble paired helical filaments is involved in the pathogenesis of Alzheimer’s disease (AD), constituting, together with accumulated β-amyloid (Aβ) peptides, a hallmark of the disease. Deciphering both the loss-of-function and toxic gain-of-function of hTau proteins is crucial to further understand the mechanisms leading to neurodegeneration in AD. As the fruit fly Drosophila melanogaster expresses Tau proteins (dTau) that are homologous to hTau, we aimed to better comprehend dTau functions by generating a specific tau knock-out (KO) fly line using homologous recombination. We observed that the specific removal of endogenous dTau proteins did not lead to overt, macroscopic phenotypes in flies. Indeed, survival, climbing ability and neuronal function were unchanged in tau KO flies. In addition, we did not find any overt positive or negative effect of dTau removal on human Aβ-induced toxicity. Altogether, our results indicate that the absence of dTau proteins has no major functional impact on flies, and suggests that our tau KO strain is a relevant model to further investigate the role of dTau proteins in vivo, thereby giving additional insights into hTau functions

Five-year follow-up after live donor nephrectomy cross-sectional and longitudinal analysis of a prospective cohort within the era of extended donor eligibility criteria

Item does not contain fulltextTo establish the outcome of live kidney donors 5 years after donation, we investigated the risk for progressive renal function decline and quality of life (QoL). Data on estimated glomerular filtration rate (eGFR), creatinine, hypertension, QoL and survival were assessed in a prospective cohort of 190 donors, who donated between 2008 and 2010. Data were available for >90%. The mean age predonation was 52.8 +/- 11.5 years, 30 donors having pre-existent hypertension. The mean follow-up was 5.1 +/- 0.9 years. Eight donors had died due to non-donation-related causes. After 5 years, the mean eGFR was 60.2 (95% CI 58.7-62.7) ml/min/1.73 m2 , with a median serum creatinine of 105.1 (95% CI 102.5-107.8) mumol/l. eGFR decreased to 33.6% and was longitudinally lower among men than women and declining with age (P < 0.001), without any association on QoL. Donors with pre-existent and new-onset hypertension demonstrated no progressive decline of renal function overtime compared to nonhypertensives. No donors were found with proteinuria, microalbuminuria or at risk for end-stage renal disease. After an initial decline postdonation, renal function remained unchanged overtime. Men and ageing seem to affect renal function overtime, while decreased renal function did not affect QoL. These data support further stimulation of living kidney donation programmes as seen from the perspective of donor safety

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats in Drosophila caused adult-onset neurodegeneration attributable to poly-(glycine-arginine) proteins. Thus, expanded repeats promoted neurodegeneration through neurotoxic proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence showed both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration

Developing research priorities for nurses working in the gynaecology setting in Western Australia

Background: Nurses working in clinical settings are instrumental to translating research into practice. The Delphi approach has been used by clinicians worldwide to set research agendas relevant to their clinical work. Aim: To identify nursing research priorities at the tertiary women's hospital in Western Australia and to develop an agenda for gynaecological nursing research. Methods: A three-round Delphi study was used. Round one incorporated an open-ended questionnaire to generate ideas or issues important to gynaecology nurses. During round two, the 32 topics generated from the first round were prioritised into 12 topics with a final ranking performed in round three. Findings: Fifty-four nurses who work in gynaecology clinical areas at the study hospital were invited to participate with 18 (33.3%) participating in round one, 41 (75.9%) in round two and 40 nurses (74.1%) in the final round. The highest ranked research priorities were: managing trial of void; providing compassionate care to women who experience pregnancy loss - the role of the gynaecological nurse; and understanding a woman's journey of treatment following a diagnosis of gynaecological cancer. Discussion: We explore potential factors from the literature around the identified gynaecology research topics plus challenges around the generation and translation of evidence into clinical practice. Conclusion: Establishing a partnership between researchers and gynaecology nurses has contributed to the development of a nursing research agenda. We anticipate that using the Delphi approach may facilitate future collaboration in implementing this research agenda and translating the findings into clinical practice