Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone.

The virulence factor mycolactone is responsible for the immunosuppression and tissue necrosis that characterise Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans. In this study, we confirm that Sec61, the protein-conducting channel that coordinates entry of secretory proteins into the endoplasmic reticulum, is a primary target of mycolactone, and characterise the nature of its inhibitory effect. We conclude that mycolactone constrains the ribosome-nascent chain-Sec61 complex, consistent with its broad-ranging perturbation of the co-translational translocation of classical secretory proteins. In contrast, the effect of mycolactone on the post-translational, ribosome-independent translocation of short secretory proteins through the Sec61 complex is dependent on both signal sequence hydrophobicity and the translocation competence of the mature domain. Changes to protease sensitivity strongly suggest that mycolactone acts by inducing a conformational change in the pore-forming Sec61α subunit. These findings establish that mycolactone inhibits Sec61-mediated protein translocation and highlight differences between the co- and post-translational routes that the Sec61 complex mediates. We propose that mycolactone also provides a useful tool for further delineating the molecular mechanisms of Sec61-dependent protein translocation

Mobility and other predictors of hospitalization for urinary tract infection: a retrospective cohort study

Abstract Background Many hospitalizations for residents of skilled nursing facilities are potentially avoidable. Factors that could prevent hospitalization for urinary tract infection (UTI) were investigated, with focus on patient mobility. Methods A retrospective cohort study was conducted using 2003–2004 data from the Centers for Medicare and Medicaid Services. The study included 408,192 residents of 4267 skilled nursing facilities in California, Florida, Michigan, New York, and Texas. The patients were followed over time, from admission to the skilled nursing facility to discharge or, for those who were not discharged, for 1 year. Cox proportional hazards regression was conducted with hospitalization for UTI as the outcome. Results The ability to walk was associated with a 69% lower rate of hospitalization for UTI. Maintaining or improving walking ability over time reduced the risk of hospitalization for UTI by 39% to 76% for patients with various conditions. For residents with severe mobility problems, such as being in a wheelchair or having a missing limb, maintaining or improving mobility (in bed or when transferring) reduced the risk of hospitalization for UTI by 38% to 80%. Other potentially modifiable predictors included a physician visit at the time of admission to the skilled nursing facility (Hazard Ratio (HR), 0.68), use of an indwelling urinary catheter (HR, 2.78), infection with Clostridium difficile or an antibiotic-resistant microorganism (HR, 1.20), and use of 10 or more medications (HR, 1.31). Patient characteristics associated with hospitalization for UTI were advancing age, being Hispanic or African-American, and having diabetes mellitus, renal failure, Parkinson's disease, dementia, or stroke. Conclusion Maintaining or improving mobility (walking, transferring between positions, or moving in bed) was associated with a lower risk of hospitalization for UTI. A physician visit at the time of admission to the skilled nursing facility also reduced the risk of hospitalization for UTI.http://deepblue.lib.umich.edu/bitstream/2027.42/112369/1/12877_2008_Article_125.pd

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5?SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.© 2022. The Author(s)

Exploring synergies between human rights and public health ethics: A whole greater than the sum of its parts

<p>Abstract</p> <p>Background</p> <p>The fields of human rights and public health ethics are each concerned with promoting health and elucidating norms for action. To date, however, little has been written about the contribution that these two justificatory frameworks can make together. This article explores how a combined approach may make a more comprehensive contribution to resolving normative health issues and to advancing a normative framework for global health action than either approach made alone. We explore this synergy by first providing overviews of public health ethics and of international human rights law relevant to health and, second, by articulating complementarities between human rights and public health ethics.</p> <p>Discussion</p> <p>We argue that public health ethics can contribute to human rights by: (a) reinforcing the normative claims of international human rights law, (b) strengthening advocacy for human rights, and (c) bridging the divide between public health practitioners and human rights advocates in certain contemporary health domains. We then discuss how human rights can contribute to public health ethics by contributing to discourses on the determinants of health through: (a) definitions of the right to health and the notion of the indivisibility of rights, (b) emphasis on the duties of states to progressively realize the health of citizens, and (c) recognition of the protection of human rights as itself a determinant of health. We also discuss the role that human rights can play for the emergent field of public health ethics by refocusing attention on the health and illness on marginalized individuals and populations.</p> <p>Summary</p> <p>Actors within the fields of public health, ethics and human rights can gain analytic tools by embracing the untapped potential for collaboration inherent in such a combined approach.</p

Why caretakers bypass Primary Health Care facilities for child care - a case from rural Tanzania

<p>Abstract</p> <p>Background</p> <p>Research on health care utilization in low income countries suggests that patients frequently bypass PHC facilities in favour of higher-level hospitals - despite substantial additional time and financial costs. There are limited number of studies focusing on user's experiences at such facilities and reasons for bypassing them. This study aimed to identify factors associated with bypassing PHC facilities among caretakers seeking care for their underfive children and to explore experiences at such facilities among those who utilize them.</p> <p>Methods</p> <p>The study employed a mixed-method approach consisting of an interviewer administered questionnaires and in-depth interviews among selected care-takers seeking care for their underfive children at Korogwe and Muheza district hospitals in north-eastern Tanzania.</p> <p>Results</p> <p>The questionnaire survey included 560 caretakers. Of these 30 in-depth interviews were conducted. Fifty nine percent (206/348) of caretakers had not utilized their nearer PHC facilities during the index child's sickness episode. The reasons given for bypassing PHC facilities were lack of possibilities for diagnostic facilities (42.2%), lack of drugs (15.5%), closed health facility (10.2%), poor services (9.7%) and lack of skilled health workers (3.4%). In a regression model, the frequency of bypassing a PHC facility for child care increased significantly with decreasing travel time to the district hospital, shorter duration of symptoms and low disease severity.</p> <p>Findings from the in-depth interviews revealed how the lack of quality services at PHC facilities caused delays in accessing appropriate care and how the experiences of inadequate care caused users to lose trust in them.</p> <p>Conclusion</p> <p>The observation that people are willing to travel long distances to get better quality services calls for health policies that prioritize quality of care before quantity. In a situation with limited resources, utilizing available resources to improve quality of care at available facilities could be more appropriate for improving access to health care than increasing the number of facilities. This would also improve equity in health care access since the poor who can not afford travelling costs will then get access to quality services at their nearer PHC facilities.</p

The pathogenic mechanism of the Mycobacterium ulcerans virulence factor, mycolactone, depends on blockade of protein translocation into the ER.

Infection with Mycobacterium ulcerans is characterised by tissue necrosis and immunosuppression due to mycolactone, the necessary and sufficient virulence factor for Buruli ulcer disease pathology. Many of its effects are known to involve down-regulation of specific proteins implicated in important cellular processes, such as immune responses and cell adhesion. We have previously shown mycolactone completely blocks the production of LPS-dependent proinflammatory mediators post-transcriptionally. Using polysome profiling we now demonstrate conclusively that mycolactone does not prevent translation of TNF, IL-6 and Cox-2 mRNAs in macrophages. Instead, it inhibits the production of these, along with nearly all other (induced and constitutive) proteins that transit through the ER. This is due to a blockade of protein translocation and subsequent degradation of aberrantly located protein. Several lines of evidence support this transformative explanation of mycolactone function. First, cellular TNF and Cox-2 can be once more detected if the action of the 26S proteasome is inhibited concurrently. Second, restored protein is found in the cytosol, indicating an inability to translocate. Third, in vitro translation assays show mycolactone prevents the translocation of TNF and other proteins into the ER. This is specific as the insertion of tail-anchored proteins into the ER is unaffected showing that the ER remains structurally intact. Fourth, metabolic labelling reveals a near-complete loss of glycosylated and secreted proteins from treated cells, whereas cytosolic proteins are unaffected. Notably, the profound lack of glycosylated and secreted protein production is apparent in a range of different disease-relevant cell types. These studies provide a new mechanism underlying mycolactone's observed pathological activities both in vitro and in vivo. Mycolactone-dependent inhibition of protein translocation into the ER not only explains the deficit of innate cytokines, but also the loss of membrane receptors, adhesion molecules and T-cell cytokines that drive the aetiology of Buruli ulcer

Factors associated with the health and nutritional status of children under 5 years of age in Afghanistan: family behaviour related to women and past experience of war-related hardships

<p>Abstract</p> <p>Background</p> <p>The present study was performed to assess, beyond socio-economic factors, independent associations between the health and nutritional status of children under 5 years old and (1) family behavioural factors related to women with regard to child care and (2) war-related experience by the household of hardships in Afghanistan.</p> <p>Methods</p> <p>The subjects were all children born during the previous 5 years from 1400 households in Kabul Province, Afghanistan and were selected by multistage sampling in March 2006. Height and weight measurements of the children and culturally sensitive interviews with their mothers were conducted by household visits. Child mortality, morbidity and nutritional status were evaluated. Four areas were assessed as variables for family behavioural factors related to women: education of mothers, child marriage of the mothers, maternal autonomy in obtaining healthcare for children and preference for a female physician. Hardships experienced by the family were examined by determining their satisfaction of basic material needs and by any experience of being forced to leave a preferred residence.</p> <p>Results</p> <p>A total of 2474 children from 1327 households completed the examinations and interviews; among them, 101 children were deceased by the time of the interview visits. Diarrhoea (32.5%) and acute respiratory infection (41.0%) were common child health problems and both emaciation (12.4%) and linear growth retardation (39.9%) were prevalent. Regardless of the influence of economic, demographic, family behavioural or hardships experience factors, a lack of maternal autonomy (79.1%) was associated with the occurrence of acute respiratory infection (odds-ratio = 1.72; 95% confidence interval = 1.23, 2.40), and linear growth retardation of children (odds-ratio = 1.38; 95% confidence interval = 1.01, 1.90); a lack of education of the mother (71.7%) and child marriage of the mothers (18.3%) were associated with diarrhoea (odds-ratio = 1.84; 95% confidence interval = 1.40, 2.41; odds-ratio = 1.46; 95% confidence interval = 1.08, 1.96, respectively); a shortage of basic material needs (59.1%) was associated with diarrhoea (odds-ratio = 1.35; 95% confidence interval = 1.08, 1.68); and migration inside the country (52.9%) was associated with underweight children (odds-ratio = 2.48; 95% confidence interval = 1.13, 5.44).</p> <p>Conclusion</p> <p>A lack of education of the mothers, child marriage, lack of maternal autonomy, shortage of basic material needs and internal displacement showed independent and significant negative associations with child health and nutritional variables in this country that has experienced a long period of conflict.</p

Social cohesion through football: a quasi-experimental mixed methods design to evaluate a complex health promotion program

Social isolation and disengagement fragments local communities. Evidence indicates that refugee families are highly vulnerable to social isolation in their countries of resettlement. Research to identify approaches to best address this is needed. Football United is a program that aims to foster social inclusion and cohesion in areas with high refugee settlement in New South Wales, Australia, through skills and leadership development, mentoring, and the creation of links with local community and corporate leaders and organisations. The Social Cohesion through Football study’s broad goal is to examine the implementation of a complex health promotion program, and to analyse the processes involved in program implementation. The study will consider program impact on individual health and wellbeing, social inclusion and cohesion, as well as analyse how the program by necessity interacts and adapts to context during implementation, a concept we refer to as plasticity. The proposed study will be the first prospective cohort impact study to our knowledge to assess the impact of a comprehensive integrated program using football as a vehicle for fostering social inclusion and cohesion in communities with high refugee settlement

A school-based physical activity program to improve health and fitness in children aged 6–13 years ("Kinder-Sportstudie KISS"): study design of a randomized controlled trial [ISRCTN15360785]

BACKGROUND: Childhood obesity is the result of a long lasting imbalance between energy intake and energy expenditure. A major contributing factor is physical inactivity which is closely linked to bone health, cardiovascular disease risk, fitness and psychological factors. The school seems to provide an excellent setting to enhance levels of physical activity (PA). However, there is insufficient data from previous school-based intervention trials on how to enhance overall PA. It is also unknown whether an intervention aimed at increasing PA is effective in improving the children's health. The purpose of this paper is to outline the design of a school-based randomized, controlled trial (RCT) aiming to increase overall PA and to improve fitness and health in 6- to 13-year-old children. METHODS/DESIGN: 15 schools were randomized to the intervention (n = 9) or the control (n = 6) group, stratified by geographic region (urban vs. rural) and by age (1(st )and 5(th )grade). Participation was given for all children in the intervention group since in this group the intervention was part of the normal school curriculum. The intervention during one academic year consisted of: 1. two additional physical education classes per week given by trained physical education teachers adding up to a total of five PA classes per week, 2. short PA breaks (2–5 min each) during academic lessons, 3. PA home work, and 4. adaptation of recreational areas around the school. All children underwent anthropometric measurements, blood pressure assessment, fitness testing, measurement of PA and they filled out questionnaires. At least 70% of all children agreed to blood sampling and measurements of body composition and bone mineral measurements by dual energy x-ray absorptiometry. The primary endpoints of the study after one year were an increase in total PA by accelerometry, an increase in aerobic fitness measured by the 20 m shuttle run, a decrease in percent body fat derived from skinfold measurements and an increase in quality of life as assessed by the child health questionnaire in the intervention group compared to the control group. Secondary outcomes were overall fitness, differences in body composition including body fat distribution, cardiovascular risk factors, psychosocial health, bone mineral content and density of femur, lumbar spine and total body and food intake. DISCUSSION: Our preliminary data suggest that the children were representative of Swiss children with respect to sex, socio-demographic status, and body mass index. Short-term results can be expected by the beginning of 2007. We hypothesized that our intervention will lead to an increase in PA, fitness and overall health. Based on our data, we aim to provide important information regarding the influence of such an intervention on these outcome measures in school-aged children and to provide nationwide guidelines to improve PA in children

Therapeutic strategies to slow chronic kidney disease progression

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve kidney function not only by lowering blood pressure but also by their antiproteinuric, antifibrotic, and anti-inflammatory properties. Intensified blood pressure control, probably aiming for a target blood pressure below the 75th percentile, may exert additional renoprotective effects. Other factors contributing in a multifactorial manner to renal disease progression include dyslipidemia, anemia, and disorders of mineral metabolism. Measures to preserve renal function should therefore also comprise the maintenance of hemoglobin, serum lipid, and calcium-phosphorus ion product levels in the normal range