Influence of cobalt ions on collagen gel formation and their interaction with osteoblasts

Metals on metal implants have long been used in arthroplasties because of their robustness and low dislocation rate. Several relatively low-corrosion metals have been used in arthroplasty, including 316L stainless steel, titanium, and cobalt–chromium–molybdenum alloy. Debris from these implants, however, has been found to cause inflammatory responses leading to unexpected failure rates approaching 10% 7 years surgery. Safety assessment of these materials traditionally relies on the use of simple two-dimensional assays, where cells are grown on the surface of the material over a relatively short time frame. It is now well-known that the composition and stiffness of the extracellular matrix (ECM) have a critical effect on cell function. In this work, we have evaluated how cobalt ions influence the assembly of type I collagen, the principle component of the ECM in bone. We found that cobalt had a significant effect on collagen matrix formation, and its presence results in local variations in collagen density. This increase in heterogeneity causes an increase in localized mechanical properties but a decrease in the bulk stiffness of the material. Moreover, when collagen matrices contained cobalt ions, there was a significant change in how the cells interacted with the collagen matrix. Fluorescence images and biological assays showed a decrease in cell proliferation and viability with an increase in cobalt concentration. We present evidence that the cobalt ion complex interacts with the hydroxyl group present in the carboxylic terminal of the collagen fibril, preventing crucial stabilizing bonds within collagen formation. This demonstrates that the currently accepted toxicity assays are poor predictors of the longer-term biological performance of a material

A systematic review investigating the behaviour change strategies in interventions to prevent misuse of anabolic steroids.

We examined intervention effectiveness of strategies to prevent image- and performance-enhancing drug use. Comprehensive searches identified 14 interventions that met review inclusion criteria. Interventions were predominantly educational and delivered within school sport settings, but targeted a wide range of mediating factors. Identification of effective components was limited across studies by brief or imprecise descriptions of intervention content, lack of behavioural outcome measures and short-term follow-up times. However, studies with components in addition to information provision may be more promising. Interventions outside of sport settings are required to reflect the transition of this form of substance use to the general population

Sharing a household with children and risk of COVID-19: a study of over 300 000 adults living in healthcare worker households in Scotland

Objective: Children are relatively protected from COVID-19, due to a range of potential mechanisms. We investigated if contact with children also affords adults a degree of protection from COVID-19. Design: Cohort study based on linked administrative data. Setting: Scotland. Study population: All National Health Service Scotland healthcare workers and their household contacts as of March 2020. Main exposure: Number of young children (0–11 years) living in the participant’s household. Main outcomes: COVID-19 requiring hospitalisation, and any COVID-19 (any positive test for SARS-CoV-2) in adults aged ≥18 years between 1 March and 12 October 2020. Results: 241 266, 41 198, 23 783 and 3850 adults shared a household with 0, 1, 2 and 3 or more young children, respectively. Over the study period, the risk of COVID-19 requiring hospitalisation was reduced progressively with increasing numbers of household children—fully adjusted HR (aHR) 0.93 per child (95% CI 0.79 to 1.10). The risk of any COVID-19 was similarly reduced, with the association being statistically significant (aHR per child 0.93; 95% CI 0.88 to 0.98). After schools reopened to all children in August 2020, no association was seen between exposure to young children and risk of any COVID-19 (aHR per child 1.03; 95% CI 0.92 to 1.14). Conclusion: Between March and October 2020, living with young children was associated with an attenuated risk of any COVID-19 and COVID-19 requiring hospitalisation among adults living in healthcare worker households. There was no evidence that living with young children increased adults’ risk of COVID-19, including during the period after schools reopened

Effects of Fasting on Isolated Murine Skeletal Muscle Contractile Function During Acute Hypoxia

Stored muscle carbohydrate supply and energetic efficiency constrain muscle functional capacity during exercise and are influenced by common physiological variables (e.g. age, diet, and physical activity level). Whether these constraints affect overall functional capacity or the timing of muscle energetic failure during acute hypoxia is not known. We interrogated skeletal muscle contractile properties in two anatomically distinct rodent hindlimb muscles that have well characterized differences in energetic efficiency (locomotory- extensor digitorum longus (EDL) and postural- soleus muscles) following a 24 hour fasting period that resulted in substantially reduced muscle carbohydrate supply. 180 mins of acute hypoxia resulted in complete energetic failure in all muscles tested, indicated by: loss of force production, substantial reductions in total adenosine nucleotide pool intermediates, and increased adenosine nucleotide degradation product-inosine monophosphate (IMP). These changes occurred in the absence of apparent myofiber structural damage assessed histologically by both transverse section and whole mount. Fasting and the associated reduction of the available intracellular carbohydrate pool (~50% decrease in skeletal muscle) did not significantly alter the timing to muscle functional impairment or affect the overall force/work capacities of either muscle type. Fasting resulted in greater passive tension development in both muscle types, which may have implications for the design of pre-clinical studies involving optimal timing of reperfusion or administration of precision therapeutics

Factors influencing the commissioning and implementation of health and social care interventions for people with dementia: commissioner and stakeholder perspectives

BackgroundDespite several interventions demonstrating benefit to people living with dementia and their caregivers, few have been translated and implemented in routine clinical practice. There is limited evidence of the barriers and facilitators for commissioning and implementing health and social care interventions for people living with dementia. The aim of the current study was to explore the barriers and facilitators to commissioning and implementing health and social care interventions for people with dementia, using a dementia friendly exercise and physical activity-based intervention (PrAISED [Promoting Activity, Stability and Independence in Early Dementia and Mild Cognitive Impairment]) as a case study.MethodsQualitative semi-structured interviews were conducted with stakeholders from a range of backgrounds including individuals from health and social care, local government, the voluntary and community sector, universities, and research centres in England. The Consolidated Framework for Intervention Research (CFIR) was used to guide the design and analysis.ResultsFourteen participants took part, including commissioning managers, service managers, partnership managers, charity representatives, commercial research specialists, academics/researchers, and healthcare professionals. Data were represented in 33 constructs across the five CFIR domains. Participants identified a need for greater support for people diagnosed with dementia and their caregivers immediately post dementia diagnosis. Key barriers included cost/financing, the culture of commissioning, and available resources. Key facilitators included the adaptability of the intervention, cosmopolitanism/partnerships and connections, external policy and incentives, and the use of already existing (and untapped) workforces.ConclusionSeveral barriers and facilitators for commissioning and implementing health and social care interventions for people with dementia were identified which need to be addressed. Recommended actions to facilitate the commissioning and implementation of dementia friendly services are: 1) map out local needs, 2) evidence the intervention including effectiveness and cost-effectiveness, 3) create/utilise networks with stakeholders, and 4) plan required resources

Edith Steins Beitrag zu heutigen Debatten über die personale Identität

Cilj je rada osvijetliti i vrednovati doprinos E. Stein raspravama o personalnom identitetu. U radu se polazi od teze da odgovor na pitanje o personalnom identitetu ovisi o shvaćanju osobe i njezinom razvoju do osobnosti, pri čemu kod E. Stein ključnu ulogu ima koncepcija ljudskog sebstva. U tu svrhu s osloncem u filozofskom djelu E. Stein najprije će se pokazati koje značenje za pitanje personalnog identiteta ima njezin pokušaj misliti sveze između ja, duše i tijela u odnosu na sebstvo. To pretpostavlja bistrenje pojmova “ja”, “jezgra osobe”, “duša” i višeznačnog izraza “sebstvo”. Potom će se pokazati na koji je način Steinovoj uspjelo povezivanjem filozofije svijesti i klasične filozofije bitka naći pristup “pravom sebstvu”, tj. na koji način prevladavanje “suprotnosti ja-života i bitka” predstavlja pristup “pravom sebstvu” čovjeka. To nam omogućuje pokazati u čemu je aktualni i originalni doprinos njezine teorije sebstva, kako u odnosu na klasična rješenja tog problema, tako i u odnosu na aktualne rasprave o personalnom identitetu i pitanju sebstva kako se ono postavlja u neuroznanostima.Ziel der vorliegenden Arbeit liegt im Versuch, Edith Steins Beitrag zur aktuellen Diskussion über die personale Identität zu erhellen und zu würdigen. Dabei gehen wir von der These aus, dass die Antwort auf die Frage nach der personalen Identität von der Theorie der Person und ihrer Entwicklung zur Personalität abhängt, wobei Steins Konzeption des menschlichen Selbst eine Schlüsselrolle zukommt. In Anlehnung an Steins philosophische Werke soll gezeigt werden, welche Bedeutung Steins Versuch, “Ich”, “Seele” und “Leib” im Hinblick auf das “Selbst” zusammenzudenken, für die Frage der personalen Identität hat. Das setzt die Klärung der Begriffe “Ich”, “Kern der Person”, “Seele” und des mehrdeutigen Ausdrucks vom “Selbst” voraus. Danach soll gezeigt werden, dass es Edith Stein durch die Verbindung moderner Bewusstseinsphilosophie mit klassischer Seinsmetaphysik gelungen ist, den Zugang zum “wahren Selbst” des Menschen zu finden, bzw. auf welche Weise die Überwindung “des Gegensatzes von Ich-leben und Sein” den Zugang zum “wahren Selbst” des Menschen darstellt. Auf dieser Grundlage versucht die Autorin auf folgende Frage zu antworten: Worin liegt die Aktualität von Steins Theorie vom Selbst sowohl im Hinblick auf die klassische Lösungsvariante dieses Problems, als auch im Hinblick auf die aktuelle Diskussion zur personalen Identität und der Frage nach dem Selbst, wie sie in den Neurowissenschaften gestellt wird

Smaller classes promote equitable student participation in STEM

Under embargo until: 2020-07-24As science, technology, engineering, and mathematics (STEM) classrooms in higher education transition from lecturing to active learning, the frequency of student interactions in class increases. Previous research documents a gender bias in participation, with women participating less than would be expected on the basis of their numeric proportions. In the present study, we asked which attributes of the learning environment contribute to decreased female participation: the abundance of in-class interactions, the diversity of interactions, the proportion of women in class, the instructor's gender, the class size, and whether the course targeted lower division (first and second year) or upper division (third or fourth year) students. We calculated likelihood ratios of female participation from over 5300 student–instructor interactions observed across multiple institutions. We falsified several alternative hypotheses and demonstrate that increasing class size has the largest negative effect. We also found that when the instructors used a diverse range of teaching strategies, the women were more likely to participate after small-group discussions.acceptedVersio

HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease

Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods

Alcohol-related brain damage in humans

Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann’s area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic) subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics