N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress

During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure-activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure-activity relationships. A representative compound N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-10H-phenothiazine-10-carboxamide, (DT-PTZ-C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30-100-fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug-like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress. This article is protected by copyright. All rights reserved

Modeling early recovery of physical function following hip and knee arthroplasty

BACKGROUND: Information on early recovery after arthroplasty is needed to help benchmark progress and make appropriate decisions concerning patient rehabilitation needs. The purpose of this study was to model early recovery of physical function in patients undergoing total hip (THA) and knee (TKA) arthroplasty, using physical performance and self-report measures. METHODS: A sample of convenience of 152 subjects completed testing, of which 69 (mean age: 66.77 ± 8.23 years) underwent THA and 83 (mean age: 60.25 ± 11.19 years) TKA. Postoperatively, patients were treated using standardized care pathways and rehabilitation protocols. Using a repeated measures design, patients were assessed at multiple time points over the first four postoperative months. Outcome measures included the Lower Extremity Function Scale (LEFS), the physical function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC PF), the 6 minute walk test (6 MWT), timed up and go test (TUG) and a timed stair test (ST). Average recovery curves for each of the measures were characterized using hierarchical linear modeling. Predictors of recovery were sequentially modeled after validation of the basic developmental models. RESULTS: Slopes of recovery were greater in the first 6 to 9 weeks with a second-degree polynomial growth term (weeks squared) providing a reasonable fit for the data over the study interval. Different patterns of recovery were observed between the self-report measures of physical function and the performance measures. In contrast to the models for the WOMAC PF and the LEFS, site of arthroplasty was a significant predictor (p = 0.001) in all of the physical performance measure models with the patients post TKA initially demonstrating higher function. Site of arthroplasty (p = 0.025) also predicted the rate of change for patients post THA and between 9 to 11 weeks after surgery, the THA group surpassed the function of the patients post TKA. CONCLUSION: Knowledge about the predicted growth curves will assist clinicians in referencing patient progress, and determining the critical time points for measuring change. The study has contributed further evidence to highlight the benefit of using physical performance measures to learn about the patients' actual level of disability

A 2-year prospective study of patient-relevant outcomes in patients operated on for knee osteoarthritis with tibial osteotomy

BACKGROUND: Tibial osteotomy is a treatment for younger and/or physically active patients suffering from uni-compartmental knee osteoarthritis. The open wedge osteotomy by the hemicallotasis technique includes the use of external fixation. The use of external fixation has several advantages, as early mobilization and the opportunity for optimal correction. However, the hemicallotasis technique has also been described as a cumbersome procedure for the patient. The aim of this study was to prospectively evaluate patient-relevant outcomes during the first 2 post-operative years. Especially the treatment period, during which external fixation was used, was closely monitored. METHODS: In an uncontrolled study, fifty-eight consecutive patients, 30 men and 28 women (mean age 54 years) were operated on by the hemicallotasis technique were evaluated with the patient-relevant outcome measure Knee injury and Osteoarthritis Outcome Score (KOOS) preoperatively, during the treatment with external fixation, one week after removal of the external fixation, at 6 months, and at one and two years postoperatively. RESULTS: At the 2-year postoperative follow-up, all subscales of the KOOS were improved (p < 0.001), mostly in pain (41–80 on a 0–100 worst to best scale) and knee-related quality of life (21–61 on a 0–100 worst to best scale), compared to the preoperative status. Significant improvements in pain and other symptoms, function of daily life and quality of life were seen already during the treatment period (mean 98 ± 18 days) with the external fixation. More demanding functions such as kneeling, squatting, jumping and running, were improved first after extraction of the external fixation device and the pins. CONCLUSION: Tibial osteotomy by the hemicallotasis technique yields large improvement in self-rated pain, function and quality of life, which persists over two years. Surprisingly, large improvements occurred already during the immediate post-operative period when the external fixation was still used

Patient-reported outcome after rheumatoid arthritis-related surgery in the lower extremities: A report from the Swedish National Register of Rheuma Surgery (RAKIR)

Background and purpose Although decreasing with the development of effective pharmacological regimes, joint surgery has improved the function and quality of life of patients with rheumatoid arthritis (RA). Few studies have assessed patient-reported outcomes after RA surgery to the lower extremities. Here we report patient-relevant outcome after RA-related surgery based on the first data from the Swedish National Register of Rheuma Surgery (RAKIR). Patients and methods 258 RA patients (212 women) who had joint surgery performed at the Department of Orthopaedics, Spenshult Hospital between September 2007 and June 2009 were included. Mean age at surgery was 64 (20-86) years. The patients completed the SF-36 and HAQ questionnaires preoperatively and 6 months postoperatively, and 165 patients completed them after 12 months. Results Improvement was seen as early as at 6 months. At 12 months, 165 patients (141 women)-including hip (n = 15), knee (n = 27), foot (n = 102), and ankle (n = 21) patients-reported statistically significant improvements from preoperatively to 12 months postoperatively in HAQ (mean change: -0.11) and SF-36 subscales physical function (11), role physical (12), bodily pain (13), social functioning (6.4), and role emotional (9.4). Hip and knee patients reported the greatest improvements. Interpretation Orthopedic RA-related surgery of the lower extremities has a strong effect on pain and physical function. Improvement is evident as early as 6 months postoperatively and remains after 12 months

A Genome Wide Association Scan of Bovine Tuberculosis Susceptibility in Holstein-Friesian Dairy Cattle

peer-reviewedBackground: Bovine tuberculosis is a significant veterinary and financial problem in many parts of the world. Although many factors influence infection and progression of the disease, there is a host genetic component and dissection of this may enlighten on the wider biology of host response to tuberculosis. However, a binary phenotype of presence/absence of infection presents a noisy signal for genomewide association study. Methodology/Principal Findings: We calculated a composite phenotype of genetic merit for TB susceptibility based on disease incidence in daughters of elite sires used for artificial insemination in the Irish dairy herd. This robust measure was compared with 44,426 SNP genotypes in the most informative 307 subjects in a genome wide association analysis. Three SNPs in a 65 kb genomic region on BTA 22 were associated (i.e. p,1025, peaking at position 59588069, p = 4.0261026) with tuberculosis susceptibility. Conclusions/Significance: A genomic region on BTA 22 was suggestively associated with tuberculosis susceptibility; it contains the taurine transporter gene SLC6A6, or TauT, which is known to function in the immune system but has not previously been investigated for its role in tuberculosis infection

Evolutionary Determinants of Genetic Variation in Susceptibility to Infectious Diseases in Humans

Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology

Risk factor screening to identify women requiring oral glucose tolerance testing to diagnose gestational diabetes : a systematic review and meta-analysis and analysis of two pregnancy cohorts

BACKGROUND: Easily identifiable risk factors including: obesity and ethnicity at high risk of diabetes are commonly used to indicate which women should be offered the oral glucose tolerance test (OGTT) to diagnose gestational diabetes (GDM). Evidence regarding these risk factors is limited however. We conducted a systematic review (SR) and meta-analysis and individual participant data (IPD) analysis to evaluate the performance of risk factors in identifying women with GDM. METHODS: We searched MEDLINE, Medline in Process, Embase, Maternity and Infant Care and the Cochrane Central Register of Controlled Trials (CENTRAL) up to August 2016 and conducted additional reference checking. We included observational, cohort, case-control and cross-sectional studies reporting the performance characteristics of risk factors used to identify women at high risk of GDM. We had access to IPD from the Born in Bradford and Atlantic Diabetes in Pregnancy cohorts, all pregnant women in the two cohorts with data on risk factors and OGTT results were included. RESULTS: Twenty nine published studies with 211,698 women for the SR and a further 14,103 women from two birth cohorts (Born in Bradford and the Atlantic Diabetes in Pregnancy study) for the IPD analysis were included. Six studies assessed the screening performance of guidelines; six examined combinations of risk factors; eight evaluated the number of risk factors and nine examined prediction models or scores. Meta-analysis using data from published studies suggests that irrespective of the method used, risk factors do not identify women with GDM well. Using IPD and combining risk factors to produce the highest sensitivities, results in low specificities (and so higher false positives). Strategies that use the risk factors of age (>25 or >30) and BMI (>25 or 30) perform as well as other strategies with additional risk factors included. CONCLUSIONS: Risk factor screening methods are poor predictors of which pregnant women will be diagnosed with GDM. A simple approach of offering an OGTT to women 25 years or older and/or with a BMI of 25kg/m2 or more is as good as more complex risk prediction models. Research to identify more accurate (bio)markers is needed. Systematic Review Registration: PROSPERO CRD42013004608

Comparing regional organizations in global multilateral institutions:ASEAN, the EU and the UN

Structural change brought about by the end of the Cold War and accelerated globalisation have transformed the global environment. A global governance complex is emerging, characterised by an ever-greater functional and regulatory role for multilateral organisations such as the United Nations (UN) and its associated agencies. The evolving global governance framework has created opportunities for regional organisations to participate as actors within the UN (and other multilateral institutions). This article compares the European Union (EU) and Association of Southeast Asian Nations (ASEAN) as actors within the UN network. It begins by extrapolating framework conditions for the emergence of EU and ASEAN actorness from the literature. The core argument of this article is that EU and ASEAN actorness is evolving in two succinct stages: Changes in the global environment create opportunities for the participation of regional organisations in global governance institutions, exposing representation and cohesion problems at the regional level. In response, ASEAN and the EU have initiated processes of institutional adaptation