Regulation of Opioid Receptor Trafficking and Morphine Tolerance by Receptor Oligomerization

AbstractThe utility of morphine for the treatment of chronic pain is hindered by the development of tolerance to the analgesic effects of the drug. Morphine is unique among opiates in its ability to activate the mu opioid receptor (MOR) without promoting its desensitization and endocytosis. Here we demonstrate that [D-Ala2-MePhe4-Gly5-ol] enkephalin (DAMGO) can facilitate the ability of morphine to stimulate MOR endocytosis. As a consequence, rats treated chronically with both drugs show reduced analgesic tolerance compared to rats treated with morphine alone. These results demonstrate that endocytosis of the MOR can reduce the development of tolerance, and hence suggest an approach for the development of opiate analogs with enhanced efficacy for the treatment of chronic pain

A KING’S COLLEGE LONDON UNDERGRADUATE PSYCHIATRY SOCIETY EVENT TO CHALLENGE THE STIGMA ATTACHED TO PSYCHOLOGICAL PROBLEMS IN HEALTHCARE PROFESSIONALS AND STUDENTS

Background: There are higher levels of psychological distress in healthcare professionals and students compared to the general population. Yet, despite the availability of effective treatment, many in this group continue to suffer in silence. Fear of exposure to stigmatization has been identified to be a major barrier to accessing and using mental health services. King’s College London Undergraduate Psychiatry Society (KCL PsychSoc) organized an event entitled, \u27What does bipolar disorder even mean? Psychological distress: How can we challenge the stigma?\u27. Healthcare professionals who themselves recovered from psychological problems and a mental health advocate with first-hand experience of psychological distress were invited to deliver talks followed by an interactive question and answer session. Design: We conducted a single-arm pre-post comparison study. People who attended the KCL Psych Soc event were recruited to participate. Validated stigma scales on knowledge (Mental Health Knowledge Schedule (MAKS), attitudes (Community Attitudes towards the Mentally Ill) and behavior (Reported and Intended Behavior Scale (RIBS)) were administered on participants before and immediately after exposure to the event. Results: 44/44 of the participants recruited completed the study (100% response rate). There were statistically significant changes in the respondents’ scores for all 3 stigma scales (p value MAKS <0.0001, p value CAMI<0.0001, p value RIBS=0.0011). Discussion: As far as the authors are aware, this is the first study to date of an anti-stigma intervention comprised of healthcare professionals with first-hand experience of psychological distress. The KCL PsychSoc event was associated with statistically significant changes in the respondents\u27 scores in all three of the stigma scales. More robust research in this area is needed before scaling up similar anti-stigma initiatives

Downregulation of MicroRNA-9 in iPSC-Derived Neurons of FTD/ALS Patients with TDP-43 Mutations

Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts

Can excitatory neuromodulation change distorted perception of one's appearance?

Body dysmorphic disorder (BDD) is marked by preoccupation with misperceived appearance flaws. Previous functional magnetic resonance imaging (fMRI) studies have found reduced neural activity and connectivity of visual areas specialized for global/holistic visual processing in BDD [[1], [2], [3]], suggesting that aberrant dorsal visual system functioning might contribute to distorted perception. In this proof-of-concept study we tested if intermittent theta-burst stimulation (iTBS), a form of excitatory repetitive transcranial magnetic stimulation (rTMS), would enhance dorsal visual system utilization as quantified through dynamic effective connectivity (DEC) modeling [4]. This is a single-session study with the application of iTBS and an fMRI scan immediately afterwards (within 15 min after the stimulation). We hypothesized that those undergoing active iTBS would show enhanced connectivity in dorsal visual areas responsible for global/holistic visual processing compared with sham

Variability in COVID-19 in-hospital mortality rates between national health service trusts and regions in England: A national observational study for the Getting It Right First Time Programme

Background A key first step in optimising COVID-19 patient outcomes during future case-surges is to learn from the experience within individual hospitals during the early stages of the pandemic. The aim of this study was to investigate the extent of variation in COVID-19 outcomes between National Health Service (NHS) hospital trusts and regions in England using data from March–July 2020. Methods This was a retrospective observational study using the Hospital Episode Statistics administrative dataset. Patients aged ≥ 18 years who had a diagnosis of COVID-19 during a hospital stay in England that was completed between March 1st and July 31st, 2020 were included. In-hospital mortality was the primary outcome of interest. In secondary analysis, critical care admission, length of stay and mortality within 30 days of discharge were also investigated. Multilevel logistic regression was used to adjust for covariates. Findings There were 86,356 patients with a confirmed diagnosis of COVID-19 included in the study, of whom 22,944 (26.6%) died in hospital with COVID-19 as the primary cause of death. After adjusting for covariates, the extent of the variation in-hospital mortality rates between hospital trusts and regions was relatively modest. Trusts with the largest baseline number of beds and a greater proportion of patients admitted to critical care had the lowest in-hospital mortality rates. Interpretation There is little evidence of clustering of deaths within hospital trusts. There may be opportunities to learn from the experience of individual trusts to help prepare hospitals for future case-surges

The cruel optimism of mobility : aspiration, belonging, and the “good life” among transnational Chinese migrants in Tokyo

Over the past thirty years, moving overseas has been a positively valued aspiration in China. On both a government level, and within popular discourse, migration has been propagated as a means to be better citizens, and a better nation, resonating with families’ desire for a better life. However, there are consequences for those who move, in terms of belonging and how they imagine their life projects. This article extends the established scholarship on mobility out of China by comparing the rhetorical construction of mobility with the experiences of Chinese migrants in Japan. Based on ethnographic fieldwork among educationally channeled Chinese migrants in Tokyo, I show how the imaginaries that shape migrant projects are constituted by conflicting aspirations and desires. The mismatch between daily experiences and discursively informed perceptions of what constitutes a “good life” and “success,” in many senses resemble what Lauren Berlant has called “cruel optimism.” Educationally channeled migration out of China is posited as a desirable object-idea that is “cruel” because the “cluster of promises” that constitute its “optimism” cannot be reconciled with the mobile lifeworlds of many Chinese transnational migrants. Due to the impossibility of simultaneously achieving the promises of success, pleasing one’s family, and attaining a sense of cosmopolitanism, many migrants resign themselves to the instabilities of mobile life. Their experiences are suggestive of the consequences of a world that increasingly celebrates mobility, with implications for how “being at home in the world” is imagined today

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Bullying escolar: um fenômeno multifacetado

School bullying can involve children in different ways, making them play different roles, among them, victims, bullies and bully-victims. The aim of this study was to describe how bullying occurs in high social vulnerability schools of Florianópolis metropolitan area and the roles played by students in this phenomenon. Overall, 409 children and adolescents from the 3rd to 5th grades and of two public elementary schools aged 8-16 years (X = 11.14) participated in this study. As a tool, the Olweus Questionnaire adapted to the Brazilian population was used. For data analysis, descriptive statistics and inferential statistics were applied by the Mann Whitney and Kruskal Wallis tests. As for results, 29.8% of boys and 40.5% of girls reported being victims; 32.3% of boys and 24.6% of girls reported being bullies. Victims were the most willing to help a colleague who is suffering from bullying (X = 1.54; p> 0.001), even if they do not know the victims (X = 1.57; p> 0.004). Bullies are differentiated from the group that does not participate (X = 1.73) and the group of victims (X = 2.34), being those who felt less alone (x = 1.47; p> 0.001). It was concluded that the information obtained in this study is indispensable in the search for alternatives to reduce school bullying. The strengthening of relations between school and students and a better preparation of teachers and school staff are extremely necessary to try to minimize the effects of risk factors to which these children are exposed and consequently violence at school.O bullying escolar pode envolver crianças de diferentes maneiras, fazendo com que essas assumam papéis diferenciados. Dentre estes, têm-se vítimas, agressores e vítimas-agressoras. O objetivo deste estudo foi descrever como ocorre o bullying em escolas de alta vulnerabilidade social da Grande Florianópolis e os papéis assumidos pelos alunos nesse fenômeno. Quanto ao método, participaram 409 crianças e adolescentes do terceiro ao quinto ano e da quarta à sexta série do ensino fundamental, de duas escolas públicas municipais, com idades entre 8 e 16 anos (X=11,14). Como instrumento, utilizou-se o Questionário de Olweus adaptado à população brasileira. Para a análise dos dados, empregaram-se a estatística descritiva e estatística inferencial por meio dos testes Mann Whitney e Kruskal Wallis. Quanto aos resultados, 29,8% dos meninos e 40,5% das meninas relataram terem sido vítimas; já 32,3% dos meninos e 24,6% das meninas relataram terem sido agressores. As vítimas foram as que se mostraram mais dispostas a ajudar como podem um colega que esteja sofrendo agressão (X=1,54; p>0,001), mesmo que não o conheçam (X=1,57; p>0,004). Em contrapartida, os agressores se diferenciaram do grupo que não participa (X=1,73) e do grupo das vítimas (X=2,34), sendo aqueles que menos se sentiram sozinhos (X=1,47; p>0,001). Concluiu-se que as informações obtidas neste estudo são indispensáveis na busca de alternativas para redução do bullying escolar. O fortalecimento das relações entre escola e alunos, e um maior preparo dos professores e funcionários são extremamente necessários para tentar minimizar os efeitos dos fatores de risco a que essas crianças estão expostas e consequentemente a violência na escola.CAPES - Proc. nº 0815/14-4CIEC - Centro de Investigação em Estudos da Criança, IE, UMinho (UI 317 da FCT)Projeto Estratégico da FCT: UID/CED/00317/201