Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function

Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition

The Prevention and Control of HIV/AIDS, TB and Vector-borne Diseases in Informal Settlements: Challenges, Opportunities and Insights

Today’s urban settings are redefining the field of public health. The complex dynamics of cities, with their concentration of the poorest and most vulnerable (even within the developed world) pose an urgent challenge to the health community. While retaining fidelity to the core principles of disease prevention and control, major adjustments are needed in the systems and approaches to effectively reach those with the greatest health risks (and the least resilience) within today’s urban environment. This is particularly relevant to infectious disease prevention and control. Controlling and preventing HIV/AIDS, tuberculosis and vector-borne diseases like malaria are among the key global health priorities, particularly in poor urban settings. The challenge in slums and informal settlements is not in identifying which interventions work, but rather in ensuring that informal settlers: (1) are captured in health statistics that define disease epidemiology and (2) are provided opportunities equal to the rest of the population to access proven interventions. Growing international attention to the plight of slum dwellers and informal settlers, embodied by Goal 7 Target 11 of the Millennium Development Goals, and the considerable resources being mobilized by the Global Fund to fight AIDS, TB and malaria, among others, provide an unprecedented potential opportunity for countries to seriously address the structural and intermediate determinants of poor health in these settings. Viewed within the framework of the “social determinants of disease” model, preventing and controlling HIV/AIDS, TB and vector-borne diseases requires broad and integrated interventions that address the underlying causes of inequity that result in poorer health and worse health outcomes for the urban poor. We examine insights into effective approaches to disease control and prevention within poor urban settings under a comprehensive social development agenda

Understanding atrioventricular septal defect: Anatomoechocardiographic correlation

<p>Abstract</p> <p>Objective</p> <p>Correlate the anatomic features of atrioventricular septal defect with echocardiographic images.</p> <p>Materials and methods</p> <p>Sixty specimen hearts were studied by sequential segmental analysis. Echocardiograms were performed on 34 patients. Specimen hearts with findings equivalent to those of echocardiographic images were selected in order to establish an anatomo-echocardiographic correlation.</p> <p>Results</p> <p>Thirty-three specimen hearts were in situs solitus, 19 showed dextroisomerism, 6 were in situs inversus and 2 levoisomerism. Fifty-eight had a common atrioventricular valve and 2 had two atrioventricular valves. Rastelli types were determined in 21 hearts. Nine were type A, 2 intermediate between A and B, 1 mixed between A and B, 4 type B and 5 type C. Associated anomalies included pulmonary stenosis, pulmonary atresia atrial septal defect, patent ductus arteriosus and anomalous connection of pulmonary veins. Echocardiograms revealed dextroisomerism in 12 patients, situs solitus in 11, levoisomerism in 7 and situs inversus in 4. Thirty-one patients had common atrioventricular valves and three two atrioventricular valves. Rastelli types were established in all cases with common atrioventricular valves; 17 had type A canal defects, 10 type B, 3 intermediate between A and B, 1 mixed between A and B and 3 type C. Associated anomalies included regurgitation of the atrioventricular valve, pulmonary stenosis, anomalous connection of pulmonary veins, pulmonary hypertension and pulmonary atresia.</p> <p>Conclusion</p> <p>Anatomo-echocardiographic correlation demonstrated a high degree of diagnostic precision with echocardiography.</p

The Drosophila Mitochondrial Translation Elongation Factor G1 Contains a Nuclear Localization Signal and Inhibits Growth and DPP Signaling

Mutations in the human mitochondrial elongation factor G1 (EF-G1) are recessive lethal and cause death shortly after birth. We have isolated mutations in iconoclast (ico), which encodes the highly conserved Drosophila orthologue of EF-G1. We find that EF-G1 is essential during fly development, but its function is not required in every tissue. In contrast to null mutations, missense mutations exhibit stronger, possibly neomorphic phenotypes that lead to premature death during embryogenesis. Our experiments show that EF-G1 contains a secondary C-terminal nuclear localization signal. Expression of missense mutant forms of EF-G1 can accumulate in the nucleus and cause growth and patterning defects and animal lethality. We find that transgenes that encode mutant human EF-G1 proteins can rescue ico mutants, indicating that the underlying problem of the human disease is not just the loss of enzymatic activity. Our results are consistent with a model where EF-G1 acts as a retrograde signal from mitochondria to the nucleus to slow down cell proliferation if mitochondrial energy output is low

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Compartmentation of Redox Metabolism in Malaria Parasites

Malaria, caused by the apicomplexan parasite Plasmodium, still represents a major threat to human health and welfare and leads to about one million human deaths annually. Plasmodium is a rapidly multiplying unicellular organism undergoing a complex developmental cycle in man and mosquito – a life style that requires rapid adaptation to various environments. In order to deal with high fluxes of reactive oxygen species and maintain redox regulatory processes and pathogenicity, Plasmodium depends upon an adequate redox balance. By systematically studying the subcellular localization of the major antioxidant and redox regulatory proteins, we obtained the first complete map of redox compartmentation in Plasmodium falciparum. We demonstrate the targeting of two plasmodial peroxiredoxins and a putative glyoxalase system to the apicoplast, a non-photosynthetic plastid. We furthermore obtained a complete picture of the compartmentation of thioredoxin- and glutaredoxin-like proteins. Notably, for the two major antioxidant redox-enzymes – glutathione reductase and thioredoxin reductase – Plasmodium makes use of alternative-translation-initiation (ATI) to achieve differential targeting. Dual localization of proteins effected by ATI is likely to occur also in other Apicomplexa and might open new avenues for therapeutic intervention

Pneumonia and in-hospital mortality in the context of neurogenic oropharyngeal dysphagia (NOD) in stroke and a new NOD step-wise concept

The aim of our work was to develop a step-wise concept for investigating neurogenic oropharyngeal dysphagia (NOD) that could be used by both trained nursing staff as well as swallowing therapists and physicians to identify patients with NOD at an early stage and so enable an appropriate therapy to be started. To achieve this objective, we assessed uniform terminology and standard operating procedures (SOP) in a new NOD step-wise concept. In-house stroke mortality rates and rates of pneumonia were measured over time (2003–2009) in order to show improvements in quality of care. In addition, outcome measures in a stroke-unit monitoring system were studied after neurorehabilitation (day 90) assessing quality of life (QL) and patient feedback. An investigation that was carried out in the context of internal and external quality assurance stroke projects revealed a significant correlation between the NOD step-wise concept and low rates of pneumonia and in-house mortality. The quality of life measures show a delta value that can contribute to “post-stroke” depression. The NOD step-wise concept (NSC) should, on the one hand, be capable of being routinely used in clinical care and, on the other, being able to fulfil the requirements of being scientifically based for investigating different stages of swallowing disorders. The value of our NSC relates to the effective management of clinical resources and the provision of adequate diagnostic and therapeutic options for different grades of dysphagia. We anticipate that our concept will provide substantial support to physicians, as well as swallowing therapists, in clinical settings and rehabilitation facilities, thereby promoting better guidance and understanding of neurogenic dysphagia as a concept in acute and rehabilitation care, especially stroke-unit settings

Effect of lifestyle intervention for people with diabetes or prediabetes in real-world primary care: propensity score analysis

<p>Abstract</p> <p>Background</p> <p>Many lifestyle interventions for patients with prediabetes or type 2 diabetes mellitus (T2DM) have been investigated in randomised clinical trial settings. However, the translation of these programmes into primary care seems challenging and the prevalence of T2DM is increasing. Therefore, there is an urgent need for lifestyle programmes, developed and shown to be effective in real-world primary care. We evaluated a lifestyle programme, commissioned by the Dutch government, for patients with prediabetes or type 2 diabetes in primary care.</p> <p>Methods</p> <p>We performed a retrospective comparative medical records analysis using propensity score matching. Patients with prediabetes or T2DM were selected from ten primary healthcare centres. Patients who received the lifestyle intervention (n = 186) were compared with a matched group of patients who received usual care (n = 2632). Data were extracted from the electronic primary care records. Propensity score matching was used to control for confounding by indication. Outcome measures were exercise level, BMI, HbA1c, fasting glucose, systolic and diastolic blood pressure, total cholesterol, HDL and LDL cholesterol and triglycerides and the follow-up period was one year.</p> <p>Results</p> <p>There was no significant difference at follow-up in any outcome measure between either group. The reduction at one year follow-up of HbA1c and fasting glucose was positive in the intervention group compared with controls, although not statistically significant (-0.12%, <it>P </it>= 0.07 and -0.17 mmol/l, <it>P </it>= 0.08 respectively).</p> <p>Conclusions</p> <p>The effects of the lifestyle programme in real-world primary care for patients with prediabetes or T2DM were small and not statistically significant. The attention of governments for lifestyle interventions is important, but from the available literature and the results of this study, it must be concluded that improving lifestyle in real-world primary care is still challenging.</p

Saccadic Eye Movements Minimize the Consequences of Motor Noise

The durations and trajectories of our saccadic eye movements are remarkably stereotyped. We have no voluntary control over these properties but they are determined by the movement amplitude and, to a smaller extent, also by the movement direction and initial eye orientation. Here we show that the stereotyped durations and trajectories are optimal for minimizing the variability in saccade endpoints that is caused by motor noise. The optimal duration can be understood from the nature of the motor noise, which is a combination of signal-dependent noise favoring long durations, and constant noise, which prefers short durations. The different durations of horizontal vs. vertical and of centripetal vs. centrifugal saccades, and the somewhat surprising properties of saccades in oblique directions are also accurately predicted by the principle of minimizing movement variability. The simple and sensible principle of minimizing the consequences of motor noise thus explains the full stereotypy of saccadic eye movements. This suggests that saccades are so stereotyped because that is the best strategy to minimize movement errors for an open-loop motor system