1,428 research outputs found

    The affinity and selectivity of α-adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-adrenoceptors

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    © 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. α1-adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and antipsychotics have been reported to have α1 affinity. This study examined 101 clinical drugs and laboratory compounds to build a comprehensive understanding of α1-adrenoceptor subtype affinity and selectivity. [3H]prazosin whole-cell binding was conducted in CHO cells stably expressing either the full-length human α1A, α1B, or α1D-adrenoceptor. As expected, doxazosin was a high-affinity nonselective α1-antagonist although other compounds (eg, cyclazosin, 3-MPPI, and ARC239) had higher affinities. Several highly α1A-selective antagonists were confirmed (SNAP5089 had over 1700-fold α1A selectivity). Despite all compounds demonstrating α1 affinity, only BMY7378 had α1D selectivity and no α1B-selective compounds were identified. Phenoxybenzamine (used in pheochromocytoma) and dibenamine had two-component-binding inhibition curves at all three receptors. Incubation with sodium thiosulfate abolished the high-affinity component suggesting this part is receptor mediated. Drugs used for hypertension and BPH had very similar α1A/α1B/α1D-adrenoceptor pharmacological profiles. Selective serotonin reuptake inhibitors (antidepressants) had poor α1-adrenoceptor affinity. Several tricyclic antidepressants (eg, amitriptyline) and antipsychotics (eg, chlorpromazine and risperidone) had high α1-adrenoceptor affinities, similar to, or higher than, α blockers prescribed for hypertension and BPH, whereas others had poor α1 affinity (eg, protriptyline, sulpiride, amisulpiride, and olanzapine). The addition of α blockers for the management of hypertension or BPH in people already taking tricyclic antidepressants and certain antipsychotics may not be beneficial. Awareness of the α-blocking potential of different antipsychotics may affect the choice of drug for those with delirium where additional hypotension (eg, in sepsis) may be detrimental

    AI Researchers, Video Games Are Your Friends!

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    If you are an artificial intelligence researcher, you should look to video games as ideal testbeds for the work you do. If you are a video game developer, you should look to AI for the technology that makes completely new types of games possible. This chapter lays out the case for both of these propositions. It asks the question "what can video games do for AI", and discusses how in particular general video game playing is the ideal testbed for artificial general intelligence research. It then asks the question "what can AI do for video games", and lays out a vision for what video games might look like if we had significantly more advanced AI at our disposal. The chapter is based on my keynote at IJCCI 2015, and is written in an attempt to be accessible to a broad audience.Comment: in Studies in Computational Intelligence Studies in Computational Intelligence, Volume 669 2017. Springe

    Intra-week spatial-temporal patterns of crime

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    Since its original publication, routine activity theory has proven most instructive for understanding temporal patterns in crime. The most prominent of the temporal crime patterns investigated is seasonality: crime (most often assault) increases during the summer months and decreases once routine activities are less often outside. Despite the rather widespread literature on the seasonality of crime, there is very little research investigating temporal patterns of crime at shorter time intervals such as within the week or even within the day. This paper contributes to this literature through a spatial-temporal analysis of crime patterns for different days of the week. It is found that temporal patterns are present for different days of the week (more crime on weekends, as would be expected) and there is a spatial component to that temporal change. Specifically, aside from robbery and sexual assault at the micro-spatial unit of analysis (street segments) the spatial patterns of crime changed. With regard to the spatial pattern changes, we found that assaults and theft from vehicle had their spatial patterns change in predictable ways on Saturdays: assaults increased in the bar district and theft from vehicles increased in the downtown and recreational car park areas

    How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

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    Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

    Mortality and causes of death among violent offenders and victims-a Swedish population based longitudinal study

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    <p>Abstract</p> <p>Background</p> <p>Most previous studies on mortality in violent offenders or victims are based on prison or hospital samples, while this study analyzed overall and cause specific mortality among violent offenders, victims, and individuals who were both offenders and victims in a general sample of 48,834 18-20 year-old men conscripted for military service in 1969/70 in Sweden.</p> <p>Methods</p> <p>Each person completed two non-anonymous questionnaires concerning family, psychological, and behavioral factors. The cohort was followed for 35 years through official registers regarding violent offenses, victimization, and mortality. The impact of violence, victimization, early risk factors and hospitalization for psychiatric diagnosis or alcohol and drug misuse during follow up on mortality was investigated using Cox proportional hazard regression analyses.</p> <p>Results</p> <p>Repeat violent offenses were associated with an eleven fold higher hazard of dying from a substance-related cause and nearly fourfold higher hazard of dying from suicide. These figures remained significantly elevated also in multivariate analyses, with a 3.03 and 2.39 hazard ratio (HR), respectively. Participants with experience of violence and inpatient care for substance abuse or psychiatric disorder had about a two to threefold higher risk of dying compared to participants with no substance use or psychiatric disorder.</p> <p>Conclusions</p> <p>Violent offending and being victimized are associated with excess mortality and a risk of dying from an alcohol or drug-related cause or suicide. Consequently, prevention of violent behavior might have an effect on overall mortality and suicide rates. Prevention of alcohol and drug use is also warranted.</p

    CYLD Enhances Severe Listeriosis by Impairing IL-6/STAT3-Dependent Fibrin Production

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    The facultative intracellular bacterium Listeria monocytogenes (Lm) may cause severe infection in humans and livestock. Control of acute listeriosis is primarily dependent on innate immune responses, which are strongly regulated by NF-kappa B, and tissue protective factors including fibrin. However, molecular pathways connecting NF-kappa B and fibrin production are poorly described. Here, we investigated whether the deubiquitinating enzyme CYLD, which is an inhibitor of NF-kappa B-dependent immune responses, regulated these protective host responses in murine listeriosis. Upon high dose systemic infection, all C57BL/6 Cyld(-/-) mice survived, whereas 100% of wildtype mice succumbed due to severe liver pathology with impaired pathogen control and hemorrhage within 6 days. Upon in vitro infection with Lm, CYLD reduced NF-kappa B-dependent production of reactive oxygen species, interleukin (IL)-6 secretion, and control of bacteria in macrophages. Furthermore, Western blot analyses showed that CYLD impaired STAT3-dependent fibrin production in cultivated hepatocytes. Immunoprecipitation experiments revealed that CYLD interacted with STAT3 in the cytoplasm and strongly reduced K63-ubiquitination of STAT3 in IL-6 stimulated hepatocytes. In addition, CYLD diminished IL-6-induced STAT3 activity by reducing nuclear accumulation of phosphorylated STAT3. In vivo, CYLD also reduced hepatic STAT3 K63-ubiquitination and activation, NF-kappa B activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis. In vivo neutralization of IL-6 by anti-IL-6 antibody, STAT3 by siRNA, and fibrin by warfarin treatment, respectively, demonstrated that IL-6-induced, STAT3-mediated fibrin production significantly contributed to protection in Cyld(-/-) mice. In addition, in vivo Cyld siRNA treatment increased STAT3 phosphorylation, fibrin production, pathogen control and survival of Lm-infected WT mice illustrating that therapeutic inhibition of CYLD augments the protective NF-kappa B/IL-6/STAT3 pathway and fibrin production

    Ritanserin as an adjunct to lithium and haloperidol for the treatment of medication-naive patients with acute mania: a double blind and placebo controlled trial

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    BACKGROUND: Bipolar disorder is a lifelong episodic condition characterized by mood swings between mania and depression. Several lines of evidence suggest that serotonin is likely to play a pivotal role in the pathophysiology of bipolar disorder. Ritanserin, a 5-HT(2 )receptor antagonist, has been reported to have antipsychotic activity. In this 6-week double blind, placebo controlled study involving moderate to severe manic patients, we assessed the effects of ritanserin plus haloperidol in combination with lithium. METHODS: 45 patients aged between 21–43 were eligible to participate as they met the DSM-IV criteria for a current manic episode, on the basis of a clinical interview by an academician psychiatrist. In addition, a score of at least 20 points on the Young Mania rating Scale was required representing moderate to severe mania. Patients were randomly allocated lithium (1–1.2 mEq/L) + haloperidol (10 mg/day)+ ritanserin (10 mg/day) (Group A) or lithium (1–1.2 mEq/L)+ haloperidol (10 mg/day) + placebo (Group B) for a 6-week, double-blind, placebo-controlled study. Patients were assessed by a third year psychiatry resident at baseline and 3, 7, 14, 21, 28 and 42 days after the medication started. All patients entered the hospital were not previously under any medication. The mean decrease in the Young Mania Rating Scale score from baseline was used as the main outcome measure of response of mania to treatment. The extrapyramidal symptoms were assessed using the Extrapyramidal Symptoms Rating Scale. Side effects were systematically recorded throughout the study and were assessed using a checklist. RESULTS: Young Mania Rating Scale total scores improved with ritanserin. The difference between the two protocols was significant as indicated by the effect of group and the between-subjects factor (F = 5.02, d.f. = 1, P = 0.03). The means Extrapyramidal Symptoms Rating Scale scores for the placebo group were higher than the ritanserin group and the difference was significant in day 42. The difference between the two groups in the frequency of side effects was not significant CONCLUSIONS: The efficacy of ritanserin to obtain a better improvement in patients with mania seems to support the 5-HT hypothesis of bipolar disorder

    No difference in stroke knowledge between Korean adherents to traditional and western medicine – the AGE study: an epidemiological study

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    BACKGROUND: Effective stroke intervention and risk reduction depend on the general public's awareness and knowledge of stroke. In Korea, where both traditional Oriental medicine and Western medicine are practiced, estimates of the general public's awareness and knowledge of stroke are poor. The present study sought to describe the inception cohort of the Ansan Geriatric Study (AGE study) and to determine baseline stroke awareness and preferred medical treatment for stroke in this Korean sample. METHODS: A total of 2,767 subjects selected randomly from the Ansan Geriatric Study in South Korea were questioned about stroke. Their answers were compared with their sociodemographic data and other variables. RESULTS: Only 44.8% of participants correctly identified stroke as a vascular disease in the human brain. Sudden numbness or weakness was the most frequently identified stroke warning sign (60.2%). Hypertension (66.7%) and mental stress (62.2%) were most frequently identified as stroke risk factors. The contributions of diabetes mellitus and cardiovascular disease to stroke were underestimated; they were identified as risk factors by 28.3% and 18.6% of participants, respectively. The predictors for poor knowledge of stroke warning signs and risk factors were similar irrespective of preference for Western or Oriental medical treatment, and included those with lower levels of education and inaccurate definition of stroke. Television and radio (40.3%) were the most frequent sources of stroke information for both groups. CONCLUSION: This study shows that knowledge of stroke is similar among Koreans with preferences for either Western or Oriental medical treatment and that misunderstandings about stroke are common among the Korean elderly. In order to prevent and manage stroke effectively, public health education regarding basic concepts of stroke is necessary. This should target those with a lower level of education and a misunderstanding of the definition of stroke
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