Rationale and design of the balANZ trial: A randomised controlled trial of low GDP, neutral pH versus standard peritoneal dialysis solution for the preservation of residual renal function

<p>Abstract</p> <p>Background</p> <p>The main hypothesis of this study is that neutral pH, low glucose degradation product (GDP) peritoneal dialysis (PD) fluid better preserves residual renal function in PD patients over time compared with conventional dialysate.</p> <p>Methods/Design</p> <p>Inclusion criteria are adult PD patients (CAPD or APD) aged 18-81 years whose first dialysis was within 90 days prior to or following enrolment and who have a residual GFR ≥ 5 ml/min/1.73 m², a urine output ≥ 400 ml/day and an ability to understand the nature and requirements of this trial. Pregnant or lactating patients or individuals with an active infection at the time of enrolment, a contra-indication to PD or participation in any other clinical trial where an intervention is designed to moderate rate of change of residual renal function are excluded. Patients will be randomized 1:1 to receive either neutral pH, low GDP dialysis solution (Balance^®) or conventional dialysis solution (Stay.safe^®) for a period of 2 years. During this 2 year study period, urinary urea and clearance measurements will be performed at 0, 3, 6, 9, 12, 18 and 24 months. The primary outcome measure will be the slope of residual renal function decline, adjusted for centre and presence of diabetic nephropathy. Secondary outcome measures will include time from initiation of peritoneal dialysis to anuria, peritoneal small solute clearance, peritoneal transport status, peritoneal ultrafiltration, technique survival, patient survival, peritonitis rates and adverse events. A total of 185 patients has been recruited into the trial.</p> <p>Discussion</p> <p>This investigator-initiated study has been designed to provide evidence to help nephrologists determine the optimal dialysis solution for preserving residual renal function in PD patients.</p> <p>Trial Registration</p> <p>Australian New Zealand Clinical Trials Registry Number: ACTRN12606000044527</p

Transcription and Translation Products of the Cytolysin Gene psm-mec on the Mobile Genetic Element SCCmec Regulate Staphylococcus aureus Virulence

The F region downstream of the mecI gene in the SCCmec element in hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) contains two bidirectionally overlapping open reading frames (ORFs), the fudoh ORF and the psm-mec ORF. The psm-mec ORF encodes a cytolysin, phenol-soluble modulin (PSM)-mec. Transformation of the F region into the Newman strain, which is a methicillin-sensitive S. aureus (MSSA) strain, or into the MW2 (USA400) and FRP3757 (USA300) strains, which are community-acquired MRSA (CA-MRSA) strains that lack the F region, attenuated their virulence in a mouse systemic infection model. Introducing the F region to these strains suppressed colony-spreading activity and PSMα production, and promoted biofilm formation. By producing mutations into the psm-mec ORF, we revealed that (i) both the transcription and translation products of the psm-mec ORF suppressed colony-spreading activity and promoted biofilm formation; and (ii) the transcription product of the psm-mec ORF, but not its translation product, decreased PSMα production. These findings suggest that both the psm-mec transcript, acting as a regulatory RNA, and the PSM-mec protein encoded by the gene on the mobile genetic element SCCmec regulate the virulence of Staphylococcus aureus

Aetiology and risk factors of musculoskeletal disorders in physically active conscripts: a follow-up study in the Finnish Defence Forces

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal disorders (MSDs) are the main reason for morbidity during military training. MSDs commonly result in functional impairment leading to premature discharge from military service and disabilities requiring long-term rehabilitation. The purpose of the study was to examine associations between various risk factors and MSDs with special attention to the physical fitness of the conscripts.</p> <p>Methods</p> <p>Two successive cohorts of 18 to 28-year-old male conscripts (<it>N </it>= 944, median age 19) were followed for six months. MSDs, including overuse and acute injuries, treated at the garrison clinic were identified and analysed. Associations between MSDs and risk factors were examined by multivariate Cox's proportional hazard models.</p> <p>Results</p> <p>During the six-month follow-up of two successive cohorts there were 1629 MSDs and 2879 health clinic visits due to MSDs in 944 persons. The event-based incidence rate for MSD was 10.5 (95% confidence interval (CI): 10.0-11.1) per 1000 person-days. Most MSDs were in the lower extremities (65%) followed by the back (18%). The strongest baseline factors associated with MSDs were poor result in the combined outcome of a 12-minute running test and back lift test (hazard ratio (HR) 2.9; 95% CI: 1.9-4.6), high waist circumference (HR 1.7; 95% CI: 1.3-2.2), high body mass index (HR 1.8; 95% CI: 1.3-2.4), poor result in a 12-minute running test (HR 1.6; 95% CI: 1.2-2.2), earlier musculoskeletal symptoms (HR 1.7; 95% CI: 1.3-2.1) and poor school success (educational level and grades combined; HR 2.0; 95% CI: 1.3-3.0). In addition, risk factors of long-term MSDs (≥10 service days lost due to one or several MSDs) were analysed: poor result in a 12-minute running test, earlier musculoskeletal symptoms, high waist circumference, high body mass index, not belonging to a sports club and poor result in the combined outcome of the 12-minute running test and standing long jump test were strongly associated with long-term MSDs.</p> <p>Conclusions</p> <p>The majority of the observed risk factors are modifiable and favourable for future interventions. An appropriate intervention based on the present study would improve both aerobic and muscular fitness prior to conscript training. Attention to appropriate waist circumference and body mass index would strengthen the intervention. Effective results from well-planned randomised controlled studies are needed before initiating large-scale prevention programmes in a military environment.</p

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

Following spinal cord injury (SCI), semaphorin 3A (Sema3A) prevents axonal regeneration through binding to the neuropilin-1 (NRP-1)/PlexinA4 receptor complex. Here, we show that galectin-1 (Gal-1), an endogenous glycan-binding protein, selectively bound to the NRP-1/PlexinA4 receptor complex in injured neurons through a glycan-dependent mechanism, interrupts the Sema3A pathway and contributes to axonal regeneration and locomotor recovery after SCI. Although both Gal-1 and its monomeric variant contribute to de-activation of microglia, only high concentrations of wild-type Gal-1 (which co-exists in a monomer-dimer equilibrium) bind to the NRP-1/PlexinA4 receptor complex and promote axonal regeneration. Our results show that Gal-1, mainly in its dimeric form, promotes functional recovery of spinal lesions by interfering with inhibitory signals triggered by Sema3A binding to NRP-1/PlexinA4 complex, supporting the use of this lectin for the treatment of SCI patients.Fil: Quintá, Héctor Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Pasquini, Juana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Pasquini, Laura Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; Argentin

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings