Defects in Mitochondrial ATP Synthesis in Dystrophin-Deficient Mdx Skeletal Muscles May Be Caused by Complex I Insufficiency

Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca2+ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn) we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrient-derivative substrate combination fed into the Kreb's cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca2+ load in comparison to controls, and 400 nM extramitochondrial Ca2+ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle

Demographic, criminal and psychiatric factors related to inmate suicide

A review of 19 studies suggests that it may be feasible to identify prisoners with suicide risk on the basis of demographic, psychiatric, and criminal characteristics. The present study aimed to identify combinations of characteristics that are capable of identifying potential suicide victims. Characteristics of 95 suicide victims in the Dutch prison system were compared with those of a random sample of 247 inmates in ten jails. Combinations of indicators for suicide risk were also tested for their capability of identifying 209 suicides in U.S. jails and 279 prison suicides in England and Wales. A combination of six characteristics (age 40+, homelessness, history of psychiatric care, history of drug abuse, one prior incarceration, violent offence) was capable of correctly classifying 82% of the Dutch suicide victims (82% specificity). Less powerful combinations correctly classified 53% of the U.S. suicides and 47% of the U.K. suicides. It is concluded that a set of demographic and criminal characteristics and indicators of psychiatric problems is useful for the identification of suicide risk in jails and prisons

A systematic review of prostate cancer heterogeneity: understanding the clonal ancestry of multifocal disease

Context Studies characterising genomic changes in prostate cancer (PCa) during natural progression have greatly increased our understanding of the disease. A better understanding of the evolutionary history of PCa would allow advances in diagnostics, prognostication, and novel therapies that together will improve patient outcomes. Objective To review the molecular heterogeneity of PCa and assess recent efforts to profile intratumoural heterogeneity and clonal evolution. Evidence acquisition We screened a total of 1313 abstracts from PubMed published between 2009 and 2020, of which we reviewed 84 full-text articles. We excluded 49, resulting in 35 studies for qualitative analysis. Evidence synthesis In studies of primary disease (16 studies, 4793 specimens), there is a lack of consensus regarding the monoclonal or polyclonal origin of primary PCa. There is no consistent mutation giving rise to primary PCa. Detailed clonal analysis of primary PCa has been limited by current techniques. By contrast, clonal relationships between PCa metastases and a potentiating clone have been consistently identified (19 studies, 732 specimens). Metastatic specimens demonstrate consistent truncal genomic aberrations that suggest monoclonal metastatic progenitors. Conclusions The relationship between the clonal dynamics of PCa and clinical outcomes needs further investigation. It is likely that this will provide a biological rationale for whether radical treatment of the primary tumour benefits patients with oligometastatic PCa. Future studies on the mutational burden in primary disease at single-cell resolution should permit the identification of clonal patterns underpinning the origin of lethal PCa. Patient summary Prostate cancers arise in different parts of the prostate because of DNA mutations that occur by chance at different times. These cancer cells and their origin can be tracked by DNA mapping. In this review we summarise the state of the art and outline what further science is needed to provide the missing answers

Common mental health disorders in adults with inflammatory skin conditions: nationwide population-based matched cohort studies in the UK

BACKGROUND: Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk. METHODS: We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma [eczema], psoriatic arthritis [psoriasis], Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index [BMI], smoking status, and, in eczema only, sleep quality [insomnia diagnoses, specific sleep problem medications] and high-dose oral glucocorticoids). RESULTS: We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR [95% CI]: eczema 1.14 [1.13-1.16], psoriasis 1.17 [1.15-1.19]) and depression (adjusted HR [95% CI]: eczema 1.11 [1.1-1.12], psoriasis 1.21 [1.19-1.22]). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry. CONCLUSIONS: Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management

Stress Effect on Ultrasonic Wave Propagation Through the Solid-Solid and Liquid-Solid Plane Interface

Ultrasonic wave propagation in prestressed materials has been studied extensively in the last 40 years. Most of this work was concentrated on the effect of stress on the velocities of different types of ultrasonic waves in homogeneous materials. Actually stresses affect not only wave velocities but also the boundary conditions at the interface. Many practical applications of ultrasonic stress characterization involve wave propagation through the interface between fluid and solid or two solids. In immersion measurements one needs to consider the effect of stress on wave propagation from fluid to solid. This leads to change in propagation direction and energy redistribution. Also additional modes could be excited leading to stress-induced birefringence. These are all important phenomena which require rigorous quantitative description since the stress effect in general is very small. Another important problem is ultrasonic characterization of residual stresses in composite materials [1]. It involves wave propagation through an interface between layers with different properties and stress levels

Severe Mental Illness Among Adults with Atopic Eczema or Psoriasis: Population-Based Matched Cohort Studies within UK Primary Care

BACKGROUND: Existing research exploring associations between atopic eczema (AE) or psoriasis, and severe mental illness (SMI – ie, schizophrenia, bipolar disorder, other psychoses) is limited, with longitudinal evidence particularly scarce. Therefore, temporal directions of associations are unclear. We aimed to investigate associations between AE or psoriasis and incident SMI among adults. METHODS: We conducted matched cohort studies using primary care electronic health records (January 1997 to January 2020) from the UK Clinical Practice Research Datalink GOLD. We identified two cohorts: 1) adults (≥ 18 years) with and without AE and 2) adults with and without psoriasis. We matched (on age, sex, general practice) adults with AE or psoriasis with up to five adults without. We used Cox regression, stratified by matched set, to estimate hazard ratios (HRs) comparing incident SMI among adults with and without AE or psoriasis. RESULTS: We identified 1,023,232 adults with AE and 4,908,059 without, and 363,210 with psoriasis and 1,801,875 without. After adjusting for matching variables (age, sex, general practice) and potential confounders (deprivation, calendar period) both AE and psoriasis were associated with at least a 17% increased hazard of SMI (AE: HR=1.17,95% CI=1.12– 1.22; psoriasis: HR=1.26,95% CI=1.18– 1.35). After additionally adjusting for potential mediators (comorbidity burden, harmful alcohol use, smoking status, body mass index, and, in AE only, sleep problems and high-dose glucocorticoids), associations with SMI did not persist for AE (HR=0.98,95% CI=0.93– 1.04), and were attenuated for psoriasis (HR=1.14,95% CI=1.05– 1.23). CONCLUSION: Our findings suggest adults with AE or psoriasis are at increased risk of SMI compared to matched comparators. After adjusting for potential mediators, associations with SMI did not persist for AE, and were attenuated for psoriasis, suggesting that the increased risk may be explained by mediating factors (eg, sleep problems). Our research highlights the importance of monitoring mental health in adults with AE or psoriasis

The Study of Rule-Governed Behavior and Derived Stimulus Relations: Bridging the Gap

The concept of rule-governed behavior or instructional control has been widely recognized for many decades within the behavior-analytic literature. It has also been argued that the human capacity to formulate and follow increasingly complex rules may undermine sensitivity to direct contingencies of reinforcement, and that excessive reliance upon rules may be an important variable in human psychological suffering. Although the concept of rules would appear to have been relatively useful within behavior analysis, it seems wise from time to time to reflect upon the utility of even well-established concepts within a scientific discipline. Doing so may be particularly important if it begins to emerge that the existing concept does not readily orient researchers toward potentially important variables associated with that very concept. The primary purpose of this article is to engage in this reflection. In particular, we will focus on the link that has been made between rule-governed behavior and derived relational responding, and consider the extent to which it might be useful to supplement talk of rules or instructions with terms that refer to the dynamics of derived relational responding

Feasibility and acceptability of a specialist clinical service for HIV-infected mineworkers in South Africa.

Occupational settings offer an ideal opportunity to provide preventive health services for HIV-infected workers. A specialized clinic was established in a mining hospital in the Free State, South Africa, with the primary aim of delivering preventive therapy such as isoniazid to those at high risk of tuberculosis (individuals with HIV infection or silicosis), and cotrimoxazole to those at highest risk for opportunistic infections. The clinic design has taken regard of the importance of minimizing stigma, protecting confidentiality, monitoring potential side effects, supporting adherence and identification of prophylaxis failure. The clinic opened in April 1999 and, by August 2001, 1773 patients had attended at least once; 1762 are HIV-infected and 11 have silicosis. Of those with HIV infection, most were asymptomatic at their first visit. The clinic has achieved high acceptability: 99% of persons who were actively recruited to the service agreed to attend. The number still attending after a median of 13 months from recruitment was 1,270 (72%) and only 48 (2.7%) have declined continued attendance. Most losses were due to termination of employment unrelated to a medical condition. The clinic has already been successfully replicated in two other regions of the mining health service in South Africa and provides a model for workplace HIV clinical services that could be used for implementation of further interventions such as antiretroviral therapy

30 days wild: development and evaluation of a large-scale nature engagement campaign to improve well-being

There is a need to increase people’s engagement with and connection to nature, both for human well-being and the conservation of nature itself. In order to suggest ways for people to engage with nature and create a wider social context to normalise nature engagement, The Wildlife Trusts developed a mass engagement campaign, 30 Days Wild. The campaign asked people to engage with nature every day for a month. 12,400 people signed up for 30 Days Wild via an online sign-up with an estimated 18,500 taking part overall, resulting in an estimated 300,000 engagements with nature by participants. Samples of those taking part were found to have sustained increases in happiness, health, connection to nature and pro-nature behaviours. With the improvement in health being predicted by the improvement in happiness, this relationship was mediated by the change in connection to nature