Biochemical and metabolic characterization of a G6PC2 inhibitor.

Three glucose-6-phosphatase catalytic subunits, that hydrolyze glucose-6-phosphate (G6P) to glucose and inorganic phosphate, have been identified, designated G6PC1-3, but only G6PC1 and G6PC2 have been implicated in the regulation of fasting blood glucose (FBG). Elevated FBG has been associated with multiple adverse clinical outcomes, including increased risk for type 2 diabetes and various cancers. Therefore, G6PC1 and G6PC2 inhibitors that lower FBG may be of prophylactic value for the prevention of multiple conditions. The studies described here characterize a G6PC2 inhibitor, designated VU0945627, previously identified as Compound 3. We show that VU0945627 preferentially inhibits human G6PC2 versus human G6PC1 but activates human G6PC3. VU0945627 is a mixed G6PC2 inhibitor, increasing the Km but reducing the Vmax for G6P hydrolysis. PyRx virtual docking to an AlphaFold2-derived G6PC2 structural model suggests VU0945627 binds two sites in human G6PC2. Mutation of residues in these sites reduces the inhibitory effect of VU0945627. VU0945627 does not inhibit mouse G6PC2 despite its 84% sequence identity with human G6PC2. Mutagenesis studies suggest this lack of inhibition of mouse G6PC2 is due, in part, to a change in residue 318 from histidine in human G6PC2 to proline in mouse G6PC2. Surprisingly, VU0945627 still inhibited glucose cycling in the mouse islet-derived ßTC-3 cell line. Studies using intact mouse liver microsomes and PyRx docking suggest that this observation can be explained by an ability of VU0945627 to also inhibit the G6P transporter SLC37A4. These data will inform future computational modeling studies designed to identify G6PC isoform-specific inhibitors.

G6PC1 and G6PC2 influence G6P flux but not HSD11B1 activity.

In the endoplasmic reticulum (ER) lumen, glucose-6-phosphatase catalytic subunit 1 and 2 (G6PC1; G6PC2) hydrolyze glucose-6-phosphate (G6P) to glucose and inorganic phosphate whereas hexose-6-phosphate dehydrogenase (H6PD) hydrolyzes G6P to 6-phosphogluconate (6PG) in a reaction that generates NADPH. 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1) utilizes this NADPH to convert inactive cortisone to cortisol. HSD11B1 inhibitors improve insulin sensitivity whereas G6PC inhibitors are predicted to lower fasting blood glucose (FBG). This study investigated whether G6PC1 and G6PC2 influence G6P flux through H6PD and vice versa. Using a novel transcriptional assay that utilizes separate fusion genes to quantitate glucocorticoid and glucose signaling, we show that overexpression of H6PD and HSD11B1 in the islet-derived 832/13 cell line activated glucocorticoid-stimulated fusion gene expression. Overexpression of HSD11B1 blunted glucose-stimulated fusion gene expression independently of altered G6P flux. While overexpression of G6PC1 and G6PC2 blunted glucose-stimulated fusion gene expression, it had minimal effect on glucocorticoid-stimulated fusion gene expression. In the liver-derived HepG2 cell line, overexpression of H6PD and HSD11B1 activated glucocorticoid-stimulated fusion gene expression but overexpression of G6PC1 and G6PC2 had no effect. In rodents, HSD11B1 converts 11-dehydrocorticosterone (11-DHC) to corticosterone. Studies in wild-type and G6pc2 knockout mice treated with 11-DHC for 5 weeks reveal metabolic changes unaffected by the absence of G6PC2. These data suggest that HSD11B1 activity is not significantly affected by the presence or absence of G6PC1 or G6PC2. As such, G6PC1 and G6PC2 inhibitors are predicted to have beneficial effects by reducing FBG without causing a deleterious increase in glucocorticoid signaling.

Strategies for Enhancing Resilience in Medical Students: a Group Concept Mapping Analysis.

OBJECTIVE: Research has consistently shown that medical students have greater rates of stress and mental-ill health in comparison with non-medical students. The objective of this study was to investigate the resilience strategies employed by medical students in an Irish medical school to inoculate themselves against the deleterious effects of stress on health and wellbeing. METHODS: Group concept mapping was utilized incorporating qualitative and quantitative methodologies. The stages undertaken by year 3 students at an Irish medical school involved brainstorming/idea generation, categorization, and rating of resilience strategies students employed to manage stress during medical school. The data was analyzed utilizing The Concept System® software through multidimensional scaling and hierarchical clustering. RESULTS: Categories of resilience strategies employed included "friends and family," "de-stress through exercise/sport," "extra-curricular non-medical activities," "self-enabled distraction," "organization," and "enhancing emotional and mental wellbeing." Students rated spending time with "friends and family" to be most effective when seeking to relieve stress, whereas students rated "de-stressing through exercise/sport" as being of greatest importance in relation to inclusion in a resilience-based intervention. Students recognized the value of incorporating strategies to enhance emotional and mental wellbeing into a resilience-promoting program. "Self-enabled distraction" rated poorly on both scales. CONCLUSIONS: Strategies rated by students to be important to incorporate in a stress reduction management program are accessible, are feasible, and can be implemented into the medical curriculum.

Violence within mental health services: how to enhance risk management.

This paper aims to present best practice in risk management within mental health services. Its purpose is to explore the prevalence of violence within mental health services, to examine the nature of risk, highlight lessons learned and guidance published on safer services, and to identify ways to enhance risk management in mental health care. We reflect on current health care practices in the UK, England and Wales, and Ireland and refer to research and practice from other jurisdictions internationally where it exists.

Evidence-based training of health professionals to inform families about disability.

OBJECTIVE: The development, delivery and evaluation of a training programme for medical and nursing professionals on best practice for informing families of their child's disability. DESIGN: A 2 h training course on 'Best practice guidelines for informing families of their child's disability' was designed based on the findings of a nationally representative study of parents and professionals. The classroom-based course comprised a presentation of the research and recommendations of the best practice guidelines; a DVD film of parent stories and professional advice; group discussion; and a half-hour input from a parent of two children with disabilities. An anonymous, pretraining and post-training questionnaire was administered to measure knowledge and confidence levels, using scales adapted from a study by Ferguson et al (2006). PARTICIPANTS: 235 participants, including medical students, nursing students, and junior hospital doctors (JHDs). OUTCOME MEASURES: Knowledge of best practice and confidence in communicating diagnosis of disability. RESULTS: Significant improvements in knowledge (time 1 mean (M)=14.31, SD=2.961; time 2 M=18.17, SD=3.068) and confidence (time 1 M=20.87, SD=5.333; time 2 M=12.43, SD=3.803) following training were found. In addition, a significant interaction between time and cohort (medical students, nurses and JHDs) was found for knowledge. Further examination suggested medical students' knowledge was developing to the extent that post-training, their scores were higher than nurses, but not significantly different to JHDs. CONCLUSIONS: The increase in reported levels of knowledge and confidence following training in best practice for informing families of their child's disability indicates the potential for providing communication skills training in this area.

Medical school attrition-beyond the statistics a ten year retrospective study.

BACKGROUND: Medical school attrition is important--securing a place in medical school is difficult and a high attrition rate can affect the academic reputation of a medical school and staff morale. More important, however, are the personal consequences of dropout for the student. The aims of our study were to examine factors associated with attrition over a ten-year period (2001-2011) and to study the personal effects of dropout on individual students. METHODS: The study included quantitative analysis of completed cohorts and qualitative analysis of ten-year data. Data were collected from individual student files, examination and admission records, exit interviews and staff interviews. Statistical analysis was carried out on five successive completed cohorts. Qualitative data from student files was transcribed and independently analysed by three authors. Data was coded and categorized and key themes were identified. RESULTS: Overall attrition rate was 5.7% (45/779) in 6 completed cohorts when students who transferred to other medical courses were excluded. Students from Kuwait and United Arab Emirates had the highest dropout rate (RR = 5.70, 95% Confidence Intervals 2.65 to 12.27;p < 0.0001) compared to Irish and EU students combined. North American students had a higher dropout rate than Irish and EU students; RR = 2.68 (1.09 to 6.58;p = 0.027) but this was not significant when transfers were excluded (RR = 1.32(0.38, 4.62);p = 0.75). Male students were more likely to dropout than females (RR 1.70, .93 to 3.11) but this was not significant (p = 0.079).Absenteeism was documented in 30% of students, academic difficulty in 55.7%, social isolation in 20%, and psychological morbidity in 40% (higher than other studies). Qualitative analysis revealed recurrent themes of isolation, failure, and despair. Student Welfare services were only accessed by one-third of dropout students. CONCLUSIONS: While dropout is often multifactorial, certain red flag signals may alert us to risk of dropout including non-EU origin, academic struggling, absenteeism, social isolation, depression and leave of absence. Psychological morbidity amongst dropout students is high and Student Welfare services should be actively promoted. Absenteeism should prompt early intervention. Behind every dropout statistic lies a personal story. All medical schools have a duty of care to support students who leave the medical programme.

A psychometric appraisal of the DREEM.

BACKGROUND: The quality of the Educational environment is a key determinant of a student centred curriculum. Evaluation of the educational environment is an important component of programme appraisal. In order to conduct such evaluation use of a comprehensive, valid and reliable instrument is essential. One of most widely used contemporary tools for evaluation of the learning environment is the Dundee Ready Education Environment Measure (DREEM). Apart from the initial psychometric evaluation of the DREEM, few published studies report its psychometric properties in detail. The aim of this study was to examine the psychometric quality of the DREEM measure in the context of medical education in Ireland and to explore the construct validity of the device. METHODS: 239 final year medical students were asked to complete the DREEM inventory. Anonymised responses were entered into a database. Data analysis was performed using PASW 18 and confirmatory factor analysis performed. RESULTS: Whilst the total DREEM score had an acceptable level of internal consistency (alpha 0.89), subscale analysis shows that two subscales had sub-optimal internal consistency. Multiple group confirmatory factor analysis (using Fleming's indices) shows an overall fit of 0.76, representing a weak but acceptable level of fit. 17 of the 50 items manifest fit indices less than 0.70. We sought the best fitting oblique solution to the 5-subscale structure, which showed large correlations, suggesting that the independence of the separate scales is open to question. CONCLUSIONS: There has perhaps been an inadequate focus on establishing and maintaining the psychometric credentials of the DREEM. The present study highlights two concerns. Firstly, the internal consistency of the 5 scales is quite variable and, in our sample, appears rather low. Secondly, the construct validity is not well supported. We suggest that users of the DREEM will provide basic psychometric appraisal of the device in future published reports.

The Medical Student Stress Profile: a tool for stress audit in medical training.

OBJECTIVES: It is well recognised that medical training can be extremely stressful and that high stress is a risk factor for a wide range of psychological and health-related consequences. The primary aims of this study were to introduce the Medical Student Stress Profile (MSSP) and to demonstrate its psychometric quality as a specific device for auditing medical student stress. Secondary aims were to establish the reliability, construct and criterion validity of this instrument and to explore the relationships between stress, coping, personality, motivation and emotional intelligence in medical students. METHODS: A battery of self-report measures including the MSSP was administered to a sample of 239 undergraduate and graduate-entry medical students. The battery included indices of stress, coping with and proneness to stress, as well as measures of emotional intelligence, motivation style, personality traits, educational environment perception and self-reported symptomatology. Psychometric evaluation of the MSSP was conducted along with a correlation analysis of stress concomitants. RESULTS: The MSSP revealed good psychometric properties and showed a substantial stress load in the participant sample. The pattern of correlations with concomitant measures conformed generally to expectations. Strong cohort effects were observed, which suggest the importance of future investigation into the role of the group in stress amelioration. Stress adversely affects ratings of the educational environment as measured by the Dundee Ready Education Environment Measure. CONCLUSIONS: The MSSP was specifically developed for the medical training context and may have utility for individual and group stress audits of medical students and as a device to inform remedial programmes in stress management in medical education.

Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a progressive, neuropsychiatric disorder, and limited reports indicate that risperidone might improve motor and psychiatric functioning for these patients. METHODS: In a retrospective, chart review study to evaluate the effectiveness of risperidone on motor, psychiatric, and cognitive functioning in HD, 17 patients taking risperidone in the course of clinical care and 12 patients not taking any antipsychotic medication were compared across a year. RESULTS: Patients taking risperidone demonstrated significantly improved psychiatric functioning and motor stabilization, whereas patients not taking risperidone were stable psychiatrically and worsened motorically. CONCLUSIONS: Although controlled clinical trials are clearly needed, these preliminary results support the use of risperidone in patients with HD in treating their psychiatric and possibly motor symptoms.