Influence of ischemic core muscle fibers on surface depolarization potentials in superfused cardiac tissue preparations: a simulation study

Thin-walled cardiac tissue samples superfused with oxygenated solutions are widely used in experimental studies. However, due to decreased oxygen supply and insufficient wash out of waste products in the inner layers of such preparations, electrophysiological functions could be compromised. Although the cascade of events triggered by cutting off perfusion is well known, it remains unclear as to which degree electrophysiological function in viable surface layers is affected by pathological processes occurring in adjacent tissue. Using a 3D numerical bidomain model, we aim to quantify the impact of superfusion-induced heterogeneities occurring in the depth of the tissue on impulse propagation in superficial layers. Simulations demonstrated that both the pattern of activation as well as the distribution of extracellular potentials close to the surface remain essentially unchanged. This was true also for the electrophysiological properties of cells in the surface layer, where most relevant depolarization parameters varied by less than 5.5 %. The main observed effect on the surface was related to action potential duration that shortened noticeably by 53 % as hypoxia deteriorated. Despite the known limitations of such experimental methods, we conclude that superfusion is adequate for studying impulse propagation and depolarization whereas repolarization studies should consider the influence of pathological processes taking place at the core of tissue sample

On the genetic involvement of apoptosis-related genes in Crohn's disease as revealed by an extended association screen using 245 markers: no evidence for new predisposing factors

Crohn's disease (CD) presents as an inflammatory barrier disease with characteristic destructive processes in the intestinal wall. Although the pathomechanisms of CD are still not exactly understood, there is evidence that, in addition to e.g. bacterial colonisation, genetic predisposition contributes to the development of CD. In order to search for predisposing genetic factors we scrutinised 245 microsatellite markers in a population-based linkage mapping study. These microsatellites cover gene loci the encoded protein of which take part in the regulation of apoptosis and (innate) immune processes. Respective loci contribute to the activation/suppression of apoptosis, are involved in signal transduction and cell cycle regulators or they belong to the tumor necrosis factor superfamily, caspase related genes or the BCL2 family. Furthermore, several cytokines as well as chemokines were included. The approach is based on three steps: analyzing pooled DNAs of patients and controls, verification of significantly differing microsatellite markers by genotyping individual DNA samples and, finally, additional reinvestigation of the respective gene in the region covered by the associated microsatellite by analysing single-nucleotide polymorphisms (SNPs). Using this step-wise process we were unable to demonstrate evidence for genetic predisposition of the chosen apoptosis- and immunity-related genes with respect to susceptibility for CD

Interpersonal functioning deficits in association with DSM-IV personality disorder dimensions

PURPOSE: According to DSM, interpersonal functioning deficits are a main criterion for the general definition of personality disorders (PDs), but some PD diagnoses do not appear to be related to impaired interpersonal functioning. Social deficits have rarely been studied in all PD dimensions to date. METHODS: We analyzed 511 adults aged 20-41 years from the general population of the canton of Zurich, Switzerland, using data from the Epidemiology Survey of the Zurich Programme for Sustainable Development of Mental Health Services (ZInEP). PD dimensions were measured with a questionnaire and indicators of interpersonal functioning with a semi-structured interview. Associations were analyzed with generalized linear models. RESULTS: All PD dimensions were significantly associated with various indicators of interpersonal functioning deficits, such as distress and conflicts in friendships and partnership, feeling lonely, few close friends, and reduced social support. Schizotypal and borderline PD were relatively strongly associated with distress in friendships when compared with other PD dimensions. Furthermore, both dimensions were significantly related to all indicators of interpersonal functioning deficits. CONCLUSIONS: Subjects scoring high on any PD dimension reported considerable deficits in interpersonal functioning as characterized by a solitary lifestyle, conflictual and distressful social relations, and lack of social support. All DSM-IV PDs are associated with poor interpersonal functioning, but there is some evidence that schizotypal and borderline symptomatology affects deficits in social interactions even more profoundly and pervasively than other PD dimensions

Impact of the AHI1 Gene on the Vulnerability to Schizophrenia: A Case-Control Association Study

BackgroundThe Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany.Methodology/Principal Findings29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (280 patients with psychotic disorders; 348 controls) and Germany (247 patients with schizophrenic disorders; 360 controls). Allelic, genotypic and haplotype frequencies were compared between cases and controls in both samples separately, as well as in the combined sample. The effect of genotype on several psychopathological measures (BPRS, KGV, PANSS) assessed in a Spanish subsample was also evaluated. We found several significant associations in the Spanish sample. Particularly, rs7750586 and rs911507, both located upstream of the AHI1 coding region, were found to be associated with schizophrenia in the analysis of genotypic (p = 0.0033, and 0.031, respectively) and allelic frequencies (p = 0.001 in both cases). Moreover, several other risk and protective haplotypes were detected (0.006<p<0.036). Joint analysis also supported the association of rs7750586 and rs911507 with the risk for schizophrenia. The analysis of clinical measures also revealed an effect on symptom severity (minimum P value = 0.0037).Conclusions/SignificanceOur data support, in agreement with previous reports, an effect of AHI1 variation on the susceptibility to schizophrenia in central and southern European populations

Design of a multicentered randomized controlled trial on the clinical and cost effectiveness of schema therapy for personality disorders

<p>Abstract</p> <p>Background</p> <p>Despite international guidelines describing psychotherapy as first choice for people with personality disorders (PDs), well-designed research on the effectiveness and cost-effectiveness of psychotherapy for PD is scarce. Schema therapy (ST) is a specific form of psychological treatment that proved to be effective for borderline PD. Randomized controlled studies on the effectiveness of ST for other PDs are lacking. Another not yet tested new specialized treatment is Clarification Oriented Psychotherapy (COP). The aim of this project is to perform an effectiveness study as well as an economic evaluation study (cost effectiveness as well as cost-utility) comparing ST versus COP versus treatment as usual (TAU). In this study, we focus on avoidant, dependent, obsessive-compulsive, paranoid, histrionic and narcissistic PD.</p> <p>Methods/Design</p> <p>In a multicentered randomized controlled trial, ST, and COP as an extra experimental condition, are compared to TAU. Minimal 300 patients are recruited in 12 mental health institutes throughout the Netherlands, and receive an extensive screening prior to enrolment in the study. When eligible, they are randomly assigned to one of the intervention groups. An economic evaluation and a qualitative research study on patient and therapist perspectives on ST are embedded in this trial. Outcome assessments (both for clinical effectiveness and economic evaluation) take place at 6,12,18,24 and 36 months after start of treatment. Primary outcome is recovery from PD; secondary measures include general psychopathological complaints, social functioning and quality of life. Data for the cost-effectiveness and cost-utility analyses are collected by using a retrospective cost interview. Information on patient and therapist perspectives is gathered using in-depth interviews and focus groups, and focuses on possible helpful and impeding aspects of ST.</p> <p>Discussion</p> <p>This trial is the first to compare ST and COP head-to-head with TAU for people with a cluster C, paranoid, histrionic and/or narcissistic PD. By combining clinical effectiveness data with an economic evaluation and with direct information from primary stakeholders, this trial offers a complete and thorough view on ST as a contribution to the improvement of treatment for this PD patient group.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=566">NTR566</a></p

Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease.

BACKGROUND: Crohn's Disease (CD) is a chronic relapsing disorder characterized by granulomatous inflammation of the gastrointestinal tract. Although its pathogenesis is complex, we have recently shown that CD patients have a systemic defect in macrophage function, which results in the defective clearance of bacteria from inflammatory sites. METHODOLOGY/PRINCIPAL FINDINGS: Here we have identified a number of additional macrophage defects in CD following diacylglycerol (DAG) homolog phorbol-12-myristate-13-acetate (PMA) activation. We provide evidence for decreased DNA fragmentation, reduced mitochondrial membrane depolarization, impaired reactive oxygen species production, diminished cytochrome c release and increased IL-6 production compared to healthy subjects after PMA exposure. The observed macrophage defects in CD were stimulus-specific, as normal responses were observed following p53 activation and endoplasmic reticulum stress. CONCLUSION: These findings add to a growing body of evidence highlighting disordered macrophage function in CD and, given their pivotal role in orchestrating inflammatory responses, defective apoptosis could potentially contribute to the pathogenesis of CD

Occupational functioning and work impairment in association with personality disorder trait-scores

PURPOSE: According to the DSM, functional impairment is a main criterion for the general definition of personality disorders (PDs), but research suggests that some PDs might not be related to impaired functioning. Occupational functioning has rarely been examined in all ten DSM PDs. METHODS: We analysed 511 adults aged 20-41 years from the general population of the canton of Zurich, Switzerland, using data from the Epidemiology Survey of the Zurich Programme for Sustainable Development of Mental Health Services. All PDs were assessed with dimensional trait-scores and associations with indicators of occupational functioning were analysed with generalised linear models. RESULTS: Each PD revealed at least a weak association with some form of occupational impairment. Most PDs, especially from cluster A and B, were significantly related to occupational dysfunction, in particular low education level, conflicts in the workplace, dismissal or demotion, and unemployment. In contrast, obsessive-compulsive PD was mostly unrelated to occupational functioning. A total personality pathology dose-response relationship was observed for low education level, conflicts in the workplace, dismissal or demotion, and unemployment. CONCLUSIONS: Impairment in occupational functioning is an important aspect particularly of cluster A and B PDs. Assuming that functional impairment is a predictor of illness severity, we advocate that clinicians should carefully explore indicators of occupational functioning in the diagnosis, prognosis, and treatment of PDs. The findings discussed herein have implications for general treatment, interventions in the work environment, or re-integration of patients into the labour force

Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.

BACKGROUND: Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults. METHODS: We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity). FINDINGS: Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0·01 kg/m2 per decade; 95% credible interval -0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m2 per decade (0·69-1·35, PP>0·9999) in central Latin America and an increase of 0·95 kg/m2 per decade (0·64-1·25, PP>0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m2 per decade (-0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m2 per decade (0·50-1·06, PP>0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4-1·2) in 1975 to 5·6% (4·8-6·5) in 2016 in girls, and from 0·9% (0·5-1·3) in 1975 to 7·8% (6·7-9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0-12·9) in 1975 to 8·4% (6·8-10·1) in 2016 in girls and from 14·8% (10·4-19·5) in 1975 to 12·4% (10·3-14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7-29·6) among girls and 30·7% (23·5-38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese. INTERPRETATION: The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults. FUNDING: Wellcome Trust, AstraZeneca Young Health Programme

Elite squash players nutrition knowledge and influencing factors

Background There is a reported mismatch between macronutrient consumption and contemporary macronutrient guidelines in elite standard squash players. Suboptimal dietary practices could be due to a lack of nutrition knowledge among players. Subsequently, the purpose of this study was to assess the sports nutrition knowledge of elite squash players through the Nutrition for Sport Knowledge Questionnaire (NSKQ) and provide an indication of whether players require nutrition support to increase their nutrition knowledge. Methods This cross-sectional study assessed the nutrition knowledge of 77 elite squash players via the NSKQ over the period of June 2020 to August 2020. Results Players conveyed average nutrition knowledge with a mean NSKQ score of 48.78 ± 10.06 (56.07% ± 11.56%). There were no significant differences in NSKQ score between male and female players (p = .532). There was found to be a weak positive association between world ranking and NSKQ score (r = .208) and age and NSKQ score (r = .281). Players who had a relevant undergraduate degree (e.g. BSc Sport & Exercise Science) had significantly greater NSKQ score than players with no relevant qualifications (p = .022). Players who consulted a sports nutritionist to obtain their main source of nutrition information were shown to have significantly greater knowledge than those who acquired knowledge from a sports scientist (p = .01) or the internet / social media (p = .007). Conclusions Players should consult with a sports nutritionist to increase their sport nutrition knowledge. Future research should quantify the effectiveness of a nutritional education intervention at increasing nutrition knowledge in players

Potential cellular and biochemical mechanisms of exercise and physical activity on the ageing process

Exercise in young adults has been consistently shown to improve various aspects of physiological and psychological health but we are now realising the potential benefits of exercise with advancing age. Specifically, exercise improves cardiovascular, musculoskeletal, and metabolic health through reductions in oxidative stress, chronic low-grade inflammation and modulating cellular processes within a variety of tissues. In this this chapter we will discuss the effects of acute and chronic exercise on these processes and conditions in an ageing population, and how physical activity affects our vasculature, skeletal muscle function, our immune system, and cardiometabolic risk in older adults