Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy

Acknowledgments Blood biochemistry analysis and serum analysis were performed by the Easter Bush Pathology Department, University of Edinburgh. Animal husbandry was performed by Centre for Integrative Physiology bio-research restructure technical staff, University of Edinburgh. Assistance with intravenous injections was provided by Ian Coldicott (University of Sheffield) and Hannah Shorrock (University of Edinburgh). Human blood cDNA was a gift to GH from Kathy Evans, University of Edinburgh. Imaging was performed at the IMPACT imaging facility, University of Edinburgh, with technical assistance from Anisha Kubasik-Thayil. The authors would also like to thank Lyndsay Murray for technical discussions relating to qRT-PCR analysis. This work was supported by funding from the SMA Trust and the Anatomical Society (via grants to THG); the Euan MacDonald Centre for Motor Neurone Disease Research (via grants to THG and SHP); the Wellcome Trust (via grants to EJNG and THG); Muscular Dystrophy UK (via grants to THG and CGB); a Elphinstone Scholarship from the University of Aberdeen (to SHP); and The French Muscular Dystrophy Association (via grants to CM and JC).Peer reviewedPublisher PD

Framingham score and work-related variables for predicting cardiovascular disease in the working population

Background: The Framingham score is commonly used to estimate the risk of cardiovascular disease (CVD). This study investigated whether work-related variables improve Framingham score predictions of sickness absence due to CVD. Methods: Eleven occupational health survey variables (descent, marital status, education, work type, work pace, cognitive demands, supervisor support, co-worker support, commitment to work, intrinsic work motivation and distress) and the Framingham Point Score (FPS) were combined into a multi-variable logistic regression model for CVD sickness absence during 1-year follow-up of 19 707 survey participants. The Net Reclassification Index (NRI) was used to investigate the added value of work-related variables to the FPS risk classification. Discrimination between participants with and without CVD sickness absence during follow-up was investigated by the area under the receiver operating characteristic curve (AUC). Results: A total of 129 (0.7%) occupational health survey participants had CVD sickness absence during 1-year follow-up. Manual work and high cognitive demands, but not the other work-related variables contributed to the FPS predictions of CVD sickness absence. However, work type and cognitive demands did not improve the FPS classification for risk of CVD sickness absence [NRI = 2.3%; 95% confidence interval (CI) -2.7 to 9.5%; P = 0.629]. The FPS discriminated well between participants with and without CVD sickness absence (AUC = 0.759; 95% CI 0.724-0.794). Conclusion: Work-related variables did not improve predictions of CVD sickness absence by the FPS. The non-laboratory Framingham score can be used to identify health survey participants at risk of CVD sickness absence

Adaptive mutation using statistics mechanism for genetic algorithms

Copyright @ 2004 Springer-Verla

On the statistical mechanics of prion diseases

We simulate a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., Mad Cow disease) with concommitant prion protein misfolding and aggregation. Our simulations lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self averaging. We model `species barriers' to prion infection and assess a related treatment protocol.Comment: 5 Pages, 3 eps figures (submitted to Physical Review Letters

Cinnamides Target Leishmania amazonensis Arginase Selectively

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3-17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors

CIP2A expression is increased in prostate cancer

Abstract Background The CIP2A protein is a recently characterized oncoprotein which inhibits protein phosphatase 2A activity. Expression of CIP2A has been detected in several carcinomas, but its expression and significance in prostate cancer has not been examined so far. Methods Expression of the CIP2A protein was studied using immunohistochemistry in prostate cancer (n = 59) and in benign prostatic hyperplasia (n = 20) specimens. The CIP2A staining scores were compared with several clinicopathological parameters. Results Expression of CIP2A was increased in prostate cancer epithelium as compared with the benign hyperplastic epithelium (p Conclusions Expression of the CIP2A protein is increased in prostate cancer specimens and its expression is associated with poorly differentiated and high-risk tumors.</p

Perspectives on Chemical Oceanography in the 21st century: Participants of the COME ABOARD Meeting examine aspects of the field in the context of 40 years of DISCO

The questions that chemical oceanographers prioritize over the coming decades, and the methods we use to address these questions, will define our field's contribution to 21st century science. In recognition of this, the U.S. National Science Foundation and National Oceanic and Atmospheric Administration galvanized a community effort (the Chemical Oceanography MEeting: A BOttom-up Approach to Research Directions, or COME ABOARD) to synthesize bottom-up perspectives on selected areas of research in Chemical Oceanography. Representing only a small subset of the community, COME ABOARD participants did not attempt to identify targeted research directions for the field. Instead, we focused on how best to foster diverse research in Chemical Oceanography, placing emphasis on the following themes: strengthening our core chemical skillset; expanding our tools through collaboration with chemists, engineers, and computer scientists; considering new roles for large programs; enhancing interface research through interdisciplinary collaboration; and expanding ocean literacy by engaging with the public. For each theme, COME ABOARD participants reflected on the present state of Chemical Oceanography, where the community hopes to go and why, and actionable pathways to get there. A unifying concept among the discussions was that dissimilar funding structures and metrics of success may be required to accommodate the various levels of readiness and stages of knowledge development found throughout our community. In addition to the science, participants of the concurrent Dissertations Symposium in Chemical Oceanography (DISCO) XXV, a meeting of recent and forthcoming Ph.D. graduates in Chemical Oceanography, provided perspectives on how our field could show leadership in addressing long-standing diversity and early-career challenges that are pervasive throughout science. Here we summarize the COME ABOARD Meeting discussions, providing a synthesis of reflections and perspectives on the field

Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data

OBJECTIVE: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. DESIGN: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. DATA SOURCES: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. RESULTS: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). CONCLUSIONS: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002780

Neuroprotective effects of the multitarget agent AVCRI104P3 in brain of middle-aged mice

Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia

An unusual clinical presentation resembling superior vena cava syndrome post heart surgery

BACKGROUND: An unusual sequence of post operative events heralded by hemodynamic deterioration followed by dyspnea and rapidly progressive dilatation of superficial neck and facial veins, resembling a superior vena cava syndrome, two days post surgical resection of filamentous aortic valve masses, closure of a patent foramen ovale, and performance of a modified Maze procedure for atrial fibrillation in a patient that presented with transient neurologic findings is presented. CASE PRESENTATION: Although both clinical findings and hemodynamic derangements completely resolved following tricuspid valve repair aimed to correct the new onset severe tricuspid regurgitation noted post operatively; a clear mechanism was not readily obvious and diagnostic testing data somewhat conflictive. We present a careful retrospective examination of all clinical data and review possible clinical entities that could have been implicated in this particular case and recognize that transesophageal echocardiographic findings were most useful in identifying the best course of action. CONCLUSION: After reviewing all clinical data and despite the inconclusive nature of test results; the retrospective examination of transesophageal echocardiographic findings proved to be most useful in identifying the best course of action. We postulate that in our case, resolution of the suspected pulmonary embolism with anticoagulation and reestablishment of a normal right ventricular geometry with tricuspid valve repair worked in unison in restoring normal hemodynamics and resolving both dyspnea and venous dilatation