Lysosomal cholesterol accumulation sensitizes to acetaminophen hepatotoxicity by impairing mitophagy.

The role of lysosomes in acetaminophen (APAP) hepatotoxicity is poorly understood. Here, we investigated the impact of genetic and drug-induced lysosomal cholesterol (LC) accumulation in APAP hepatotoxicity. Acid sphingomyelinase (ASMase)(-/-) mice exhibit LC accumulation and higher mortality after APAP overdose compared to ASMase(+/+) littermates. ASMase(-/-) hepatocytes display lower threshold for APAP-induced cell death and defective fusion of mitochondria-containing autophagosomes with lysosomes, which decreased mitochondrial quality control. LC accumulation in ASMase(+/+) hepatocytes caused by U18666A reproduces the susceptibility of ASMase(-/-) hepatocytes to APAP and the impairment in the formation of mitochondria-containing autolysosomes. LC extraction by 25-hydroxycholesterol increased APAP-mediated mitophagy and protected ASMase(-/-) mice and hepatocytes against APAP hepatotoxicity, effects that were reversed by chloroquine to disrupt autophagy. The regulation of LC by U18666A or 25-hydroxycholesterol did not affect total cellular sphingomyelin content or its lysosomal distribution. Of relevance, amitriptyline-induced ASMase inhibition in human hepatocytes caused LC accumulation, impaired mitophagy and increased susceptibility to APAP. Similar results were observed upon glucocerebrosidase inhibition by conduritol β-epoxide, a cellular model of Gaucher disease. These findings indicate that LC accumulation determines susceptibility to APAP hepatotoxicity by modulating mitophagy, and imply that genetic or drug-mediated ASMase disruption sensitizes to APAP-induced liver injury

Variations in Pastors’ Perceptions of the Etiology of Depression By Race and Religious Affiliation

Depression is a major, preventable problem in the United States, yet relatively few individuals seek care in traditional mental health settings. Instead, many choose to confide in friends, family, or clergy. Thus, it is important to discover how clergy perceive the definition of and etiology of depression. The author conducted a survey with 204 Protestant pastors in California. Multinomial logistic regression revealed a statistically significant difference in how depression is perceived based on race. Caucasian American pastors more readily agreed with the statement that depression was a biological mood disorder, while African American pastors more readily agreed that depression was a moment of weakness when dealing with trials and tribulations. Also, mainline Protestants more frequently disagreed with statements about spiritual causes of depression than Pentecostals and non-denominational pastors. The findings suggest that racial and religious affiliational influences shape how pastors view, and ultimately intervene, in the area of depression

Decline in age at menarche among Spanish women born from 1925 to 1962

<p>Abstract</p> <p>Background</p> <p>While the timing of reproductive events varies across populations, a downward trend in age at menarche has nevertheless been reported in most of the developed world over the past century. Given the impact of change in age at menarche on health conditions, this study sought to examine secular trends in age at menarche among women living in Navarre (Northern Spain) who participated in a population-based breast cancer screening programme.</p> <p>Methods</p> <p>The study was based on 110545 women born from 1925 to 1962. Trends were tested using a linear regression model, in which year of birth was entered continuously as the predictor and age at menarche (years) as the response variable, using size of town and region of birth as covariates.</p> <p>Results</p> <p>Among women born in Navarre between 1925 and 1962, age at menarche declined steadily from an average of 13.72 years in the 1925-1929 birth-cohorts to 12.83 years in the 1958-1962 birth-cohorts. Controlling for size of town or city of birth, age at menarche declined by an average of 0.132 years every 5 years over the period 1925-1962. This decline was greater in women born in rural versus urban settings. Trends were also different among regions of birth.</p> <p>Conclusion</p> <p>We report a population-based study showing a downward trend in age of onset of menarche among Spanish women born in the period 1925-1962, something that is more pronounced among women born in rural settings and varies geographically.</p

A newer and broader definition of burnout: Validation of the "Burnout Clinical Subtype Questionnaire (BCSQ-36)"

<p>Abstract</p> <p>Background</p> <p>Burnout syndrome has been clinically characterised by a series of three subtypes: frenetic, underchallenged and worn-out, with reference to coping strategies for stress and frustration at work with different degrees of dedication. The aims of the study are to present an operating definition of these subtypes in order to assess their reliability and convergent validity with respect to a standard burnout criterion and to examine differences with regard to sex and the temporary nature of work contracts.</p> <p>Method</p> <p>An exploratory factor analysis was performed by the main component method on a range of items devised by experts. The sample was composed of 409 employees of the University of Zaragoza, Spain. The reliability of the scales was assessed with Cronbach's α, convergent validity in relation to the Maslach Burnout Inventory with Pearson's <it>r</it>, and differences with Student's t-test and the Mann-Whitney U test.</p> <p>Results</p> <p>The factorial validity and reliability of the scales were good. The subtypes presented relations of differing degrees with the criterion dimensions, which were greater when dedication to work was lower. The frenetic profile presented fewer relations with the criterion dimensions while the worn-out profile presented relations of the greatest magnitude. Sex was not influential in establishing differences. However, the temporary nature of work contracts was found to have an effect: temporary employees exhibited higher scores in the frenetic profile (<it>p </it>< 0.001), while permanent employees did so in the underchallenged (<it>p </it>= 0.018) and worn-out (<it>p </it>< 0.001) profiles.</p> <p>Conclusions</p> <p>The classical Maslach description of burnout does not include the frenetic profile; therefore, these patients are not recognised. The developed questionnaire may be a useful tool for the design and appraisal of specific preventive and treatment approaches based on the type of burnout experienced.</p

Communication methods and production techniques in fixed prosthesis fabrication: a UK based survey. Part 1: Communication methods

Statement of the problem The General Dental Council (GDC) states that members of the dental team have to 'communicate clearly and effectively with other team members and colleagues in the interest of patients'. A number of studies from different parts of the world have highlighted problems and confirmed the need for improved communication methods and production techniques between dentists and dental technicians.Aim The aim of this study was to identify the communication methods and production techniques used by dentists and dental technicians for the fabrication of fixed prostheses within the UK from the dental technicians' perspective. The current publication reports on the communication methods.Materials and methods Seven hundred and eighty-two online questionnaires were distributed to the Dental Laboratories Association membership and included a broad range of topics. Statistical analysis was undertaken to test the influence of various demographic variables.Results The number of completed responses totalled 248 (32% response rate). The laboratory prescription and the telephone were the main communication tools used. Statistical analysis of the results showed that a greater number of communication methods were used by large laboratories. Frequently missing items from the laboratory prescription were the shade and the date required. The majority of respondents (73%) stated that a single shade was selected in over half of cases. Sixty-eight percent replied that the dentist allowed sufficient laboratory time. Twenty-six percent of laboratories felt either rarely involved or not involved at all as part of the dental team.Conclusion This study suggests that there are continuing communication and teamwork issues between dentists and dental laboratories

Evaluating real-time internet therapy and online self-help for problematic alcohol consumers: a three-arm RCT protocol

<p>Abstract</p> <p>Background</p> <p>Only a minority of all alcohol- and drug abusers is receiving professional care. In an attempt to narrow this treatment gap, treatment facilities experiment with online healthcare. Therefore, it is important to test the (cost-)effectiveness of online health interventions in a randomized clinical trial.</p> <p>Methods</p> <p>This paper presents the protocol of a three-arm randomized clinical trial to test the (cost-) effectiveness of online treatment for problem drinkers. Self-help online, therapy online and a waiting list are tested against each other. Primary outcome is change in alcohol consumption. Secondary outcome measures include quality of life and working ability. Incremental cost-effectiveness ratios for self-help online alcohol and therapy online alcohol will be calculated. The predictive validity of participant characteristics on treatment adherence and outcome will be explored.</p> <p>Discussion</p> <p>To our best knowledge, this randomized clinical trial will be the first to test the effectiveness of therapy online against both self-help online and a waiting-list. It will provide evidence on (cost-) effectiveness of online treatment for problem drinkers and investigate outcome predictors.</p> <p>Trial registration</p> <p>This trial is registered in the Dutch Trialregister (Cochrane Collaboration) and traceable as NTR-TC1155.</p

Developing the Questionnaire

AbstractThis chapter outlines the essential topics for developing and testing a questionnaire for a discrete choice experiment survey. It addresses issues such as the description of the environmental good, pretesting of the survey, incentive compatibility, consequentiality or mitigation of hypothetical bias. For the latter, cheap talk scripts, opt-out reminders or an oath script are discussed. Moreover, the use of instructional choice sets, the identification of protest responses and strategic bidders are considered. Finally, issues related to the payment vehicle and the cost vector design are the subject of this section