The mitochondrial RNA granule modulates manganese-dependent cell toxicity.

Prolonged manganese exposure causes manganism, a neurodegenerative movement disorder. The identity of adaptive and nonadaptive cellular processes targeted by manganese remains mostly unexplored. Here we study mechanisms engaged by manganese in genetic cellular models known to increase susceptibility to manganese exposure, the plasma membrane manganese efflux transporter SLC30A10 and the mitochondrial Parkinson's gene PARK2. We found that SLC30A10 and PARK2 mutations as well as manganese exposure compromised the mitochondrial RNA granule composition and function, resulting in disruption of mitochondrial transcript processing. These RNA granule defects led to impaired assembly and function of the mitochondrial respiratory chain. Notably, cells that survived a cytotoxic manganese challenge had impaired RNA granule function, thus suggesting that this granule phenotype was adaptive. CRISPR gene editing of subunits of the mitochondrial RNA granule, FASTKD2 or DHX30, as well as pharmacological inhibition of mitochondrial transcription-translation, were protective rather than deleterious for survival of cells acutely exposed to manganese. Similarly, adult Drosophila mutants with defects in the mitochondrial RNA granule component scully were safeguarded from manganese-induced mortality. We conclude that impairment of the mitochondrial RNA granule function is a protective mechanism for acute manganese toxicity.

Development and psychometric properties of the Attitudes Toward Intellectual Disability Questionnaire - Short Form.

BACKGROUND: Understanding public attitudes towards people with intellectual disability (ID) can help orient activities to promote the social inclusion of this group. The ATTitudes toward Intellectual Disability (ATTID) questionnaire is a validated 67-item tool used to assess attitudes towards people with ID from a multidimensional perspective. It is based on a five-factor model tapping into cognitive, emotional and behavioural components of attitudes. In order to facilitate international research, the goal of this study was to develop a short version that would retain the long form's psychometric properties. METHODS: Analyses were conducted on a sample of 1608 respondents who completed the full-length ATTID. A four-step test refinement procedure was used to reduce the number of items. The first two steps involved a Cronbach's alpha analysis. Items retained were then reviewed to assess face validity. Correlations between factors were calculated, and a factor analysis was performed to compare the original and short forms. RESULTS: The number of items in the ATTID was reduced from 67 to 35. The short form maintained good overall reliability. The correlational pattern between factors in both the long and short form is generally the same. The factor analysis of the short form showed a similar five-factor structure with some loss of variance. CONCLUSIONS: We recommend the short form be used when administration time is an issue, particularly in a research context. Replication studies with new samples are needed to further assess the psychometric properties of the ATTID-Short Form.

Attitudes of health care professionals toward people with intellectual disability: a comparison with the general population.

BACKGROUND: Few studies have examined attitudes that may promote the social inclusion of persons with an intellectual disability (ID) among health care providers (HCPs). Yet these attitudes could impact the accessibility and quality of services provided to this population, as well as the general attitudes of HCPs. The objectives of this study were to (1) examine HCPs' pro-inclusion attitudes toward people with ID, (2) compare these to the general population's attitudes and (3) examine how HCPs' attitudes vary as a function of their socio-demographic characteristics. METHOD: The Attitudes Toward Intellectual Disability Questionnaire was administered to 367 HCPs and a representative sample of the Québec population (N = 1605). RESULTS: Results indicated that at least half of HCPs displayed positive attitudes, that is, attitudes that are compatible with notions of social inclusion and equal rights, toward individuals with ID. Positive attitudes were less frequently observed for the Interaction and the Sensitivity or tenderness factors measured by the Attitudes Toward Intellectual Disability Questionnaire. In comparison with the general population, HCPs exhibited more positive attitudes on the Knowledge of causes and Sensitivity or tenderness factors and less positive attitudes on the Interaction factor. HCPs who regarded themselves as more knowledgeable about ID and those who reported higher quality contacts or interactions with persons with ID expressed attitudes that were more favourable toward social inclusion. CONCLUSIONS: In addition to providing general knowledge about ID and the specific health care needs of individuals with ID, training programmes should also promote interactions with this population. Further studies are needed to document HCPs' pro-inclusion attitudes toward people with ID and to assess the impact of interventions on these attitudes.

The safety and efficacy of early-initiation exercise training after acute venous thromboembolism: a randomized clinical trial.

BACKGROUND: Exercise training after myocardial infarction is the standard of care within a cardiac rehabilitation setting. However, there is scant evidence regarding the safety and efficacy of early exercise training following a venous thromboembolism (VTE). METHODS: Eligible consenting participants were randomly allocated, on an individual basis, to either a 3-month exercise and behavioral weight loss intervention group or a control group. The primary clinical outcomes were change in health behavior (body weight and physical activity) and objectively measured fitness (Vo2peak ). RESULTS: From 2013 to 2014, 239 patients presented to a community-based specialty clinic after an acute VTE; 43 (18%) of these met the eligibility criteria for inclusion in the study. Of these, 19 (44%) consented to participate (nine in the intervention group; 10 in the control group). There were no adverse events in either group over a 3-month period. The mean difference in body weight between the intervention and control groups was - 4.6 kg (95% confidence interval [CI] - 11.4 to 2.2) in favor of the intervention. The mean difference in duration of physical activity from baseline to 3 months between the intervention and control groups was 133 min (95% CI 7-248) in favor of the intervention. There was a significant change in fitness over a 3-month period for the intervention group (baseline Vo2peak , 26.1 ± 5.4 mL O2 kg(-1)  min(-1) ; postintervention Vo2peak , 29.8 ± 5.4 mL O2 kg(-1)  min(-1) ). CONCLUSION: Early initiation of exercise training resulted in improvements in physical activity and fitness, and did not result in adverse events while individuals were receiving therapeutic anticoagulation. These are the first data on initiation of an exercise training and behavioral weight loss program in the early post-VTE setting.

Norms of the Attitudes Toward Intellectual Disability Questionnaire.

BACKGROUND: The Attitudes Toward Intellectual Disability Questionnaire (ATTID) has demonstrated good psychometric qualities for measuring the attitudes of different groups of adults in the general population toward intellectual disability (ID). A significant advantage of the ATTID is that it addresses the concept of attitudes using a three-dimensional model (affective, cognitive and behavioural). To our knowledge, there are no normative data published regarding attitudes toward ID on general population-based samples. METHODS: The sample of 1605 men and women was stratified to be representative of the general adult population of Quebec. The ATTID was administered by phone interview through an independent survey firm. RESULTS: Normative data are presented as percentile scores associated with the raw score of the ATTID by gender and age categories. Analysis of the variance yielded significant differences in attitude by gender and age. The directions and the strength of these associations vary according to each of the five factors used to define attitudes. CONCLUSION: These norms will provide an essential tool to compare different groups and assess the effectiveness of various public campaigns to encourage more positive attitudes towards persons with ID. These norms would also allow international comparisons.

The role of personality in aggressive behaviour among individuals with intellectual disabilities.

BACKGROUND: Aggressive behaviour is associated with certain personality traits in both the general population and among individuals with mental health problems, but little attention has been paid to the relationship between aggressive behaviour and personality among individuals with intellectual disabilities (ID). The aim of this study was to circumscribe personality profiles associated with aggressive behaviour among individuals with ID. METHOD: In this cross-sectional study of 296 adults with mild or moderate ID, information on mental health, personality and aggressive behaviour was gathered through structured interviews with the ID participants and their case manager, and a review of client files. RESULTS: The results of the Reiss Profile were submitted to hierarchical cluster analysis method. Subsequently, the distribution of aggressive behaviour, sociodemographic characteristics and clinical characteristics across personality profiles was analysed. The analyses yielded seven distinct personality profiles in relation to patterns of aggressive behaviour: Pacifists, Socials, Confidents, Altruists, Conformists, Emotionals and Asocials. CONCLUSION: The identification of distinct personality profiles sheds light on the risk factors for aggressive behaviour, and suggests new approaches to improving diagnostic and intervention strategies.

Intellectual disability and co-occurring mental health and physical disorders in aggressive behaviour.

BACKGROUND: Mental and physical health problems are more prevalent among individuals with an intellectual disability (ID) than in the general population. Studies suggest that there may be significant associations between these co-occurring disorders and aggressive behaviour, but few studies have taken into account multiple mental and physical problems, as well as their level of severity. OBJECTIVES: The main goal of this study was to identify the associations between different types of aggressive behaviour and various types of physical and mental health problems. METHODS: These associations were explored through a cross-sectional study of 296 adult men and women with mild or moderate ID living in the community and receiving ID services. Information was gathered through interviews with ID participants, case managers and file review. RESULTS: The results show that individuals with ID who have more mental and physical health problems have higher odds of displaying aggressive behaviour than those with fewer and less severe physical health problems. DISCUSSION: These results can help guide future prevention and intervention strategies for persons with ID who display aggressive behaviour or who are at risk of become aggressive.

Public attitudes towards intellectual disability: a multidimensional perspective.

BACKGROUND: Public attitudes towards persons with intellectual disabilities (IDs) have a significant effect on potential community integration. A better understanding of these can help target service provision and public awareness programmes. OBJECTIVE: The objective of the present study is threefold: (1) describe public attitudes towards persons with ID along affective, cognitive and behavioural dimensions; (2) compare and contrast attitudes according to sex, age, education and income, as well as frequency and quality of contacts with persons with ID; and (3) ascertain whether the level of functioning has an effect on attitudes. METHODS: The Attitudes Toward Intellectual Disability Questionnaire (ATTID) was administered by phone to 1605 randomly selected adult men and women, stratified by region in the province of Québec, Canada. The ATTID uses a multidimensional perspective of attitudes that reflect affective, cognitive and behavioural dimensions. RESULTS: The results showed that public attitudes were generally positive regarding all three attitudinal dimensions. Public attitudes towards persons with ID are presented in terms of the five factors measured through the ATTID: (1) discomfort; (2) sensibility or tenderness; (3) knowledge of causes; (4) knowledge of capacity and rights; and (5) interaction. Attitude factor scores vary as a function of participant characteristics (sex, age, education and income) and the degree of knowledge about ID, the number of persons with ID known to the participants, as well as the frequency and quality of their contacts with these persons. Men had greater negative attitudes than women as regards the discomfort factor, while women had more negative attitudes regarding the knowledge of capacity and rights factor. More positive attitudes were revealed among younger and more educated participants. Attitudes were generally not associated with income. Public attitudes tended to be more negative towards people with lower functioning ID. CONCLUSION: These results yield useful information to target public awareness and education.

Validation of the attitudes toward intellectual disability: ATTID questionnaire.

BACKGROUND: Individuals with an intellectual disability (ID) continue to experience major obstacles towards social, educational and vocational integration. Negative attitudes toward persons with ID has remained relevant over time and has led to discrimination and stigma. OBJECTIVE: The present study describes the development of a new questionnaire for tapping into the general population's attitudes toward individuals with ID and addresses its psychometric properties. METHODS: Adopting a multidimensional perspective, the Attitudes Toward Intellectual Disability Questionnaire (ATTID) was developed from a series of previously validated instruments and principles from the Montreal Declaration on Intellectual Disability (2004). The ATTID was administered by phone to 1605 randomly selected adult men and women, stratified by region in the Province of Quebec, Canada. RESULTS: The ATTID yielded a five-factor structure overlapping the tri-partite model of attitudes. The cognitive component was represented by two factors: knowledge of capacity and rights and knowledge of causes of ID. The affective component tapped into two factors: discomfort and sensitivity/compassion. Finally, the behavioural component emerged as a single factor. The ATTID had good internal consistency with Cronbach's alpha coefficients ranging from 0.59 to 0.89 for the five factors and of 0.92 for the overall questionnaire. Test-retest reliability yielded correlations from 0.62 to 0.83 for the five factors. CONCLUSION: The ATTID can be used to measure attitudes among different populations and allows comparisons over time within the same population as a function of various intervention strategies for de-stigmatising ID.

Evolving systems of care: Individuals found not criminally responsible on account of mental disorder in custody of civil and forensic psychiatric services.

Following psychiatric deinstitutionalization and changes in involuntary civil commitment laws, many individuals with severe mental disorders have been receiving mental health services through the back door, that is, the criminal justice system. Significant changes to the section of Criminal Code of Canada dealing with individuals with mental disorders have led to significant annual increases in the number of individuals declared Not criminally responsible on account of mental disorder (NCRMD), many of whom are directed to civil psychiatric settings. The goal of the present study was to describe the psychosociocriminological and risk characteristics of individuals found NCRMD remanded to civil psychiatric hospitals (CPH) compared to a forensic psychiatric hospital (FPH). This study was conducted between October 2004 and August 2006 in the sole FPH of the province of Québec and two large CPH in the Montréal metropolitan area. The final sample for the current study consisted of 96 men: 60 from the FPH and 36 from the two CPH. Results indicate that individuals in both settings have similar psychosociocriminal profiles, including PCL-R scores, but that individuals in CPH have higher scores in the Risk subscale of the HCR-20 than do their counterparts in the FPH. This difference is due to a higher score on two items: exposure to destabilizing factors and noncompliance with remediation attempts. Results are discussed in terms of the need for civil psychiatric settings to implement risk assessment and management programs into their services, and the need for further research into forensic mental health services.

Profiles and correlates of aggressive behaviour among adults with intellectual disabilities.

BACKGROUND: Despite the heterogeneity in aggressive behaviours observed among individuals with intellectual disabilities (ID), little attention has been paid to the identification of typologies of aggression among individuals with mild or moderate ID and their associated factors. OBJECTIVE: The goal of the present study was to identify profiles of aggressive behaviour and their psychosocial correlates. METHOD: In this cross-sectional study of 296 adults with mild or moderate ID, information was gathered through interviews with the ID participants, their case manager and a significant other. Client files were also reviewed. RESULTS: Multiple correspondence analysis followed by hierarchical cluster analysis generated six distinct profiles of aggressive behaviour in this sample. The 'violent' group clearly stood out as lacking social and vocational involvement, having more severe mental health problems, high levels of impulsivity and antisocial tendencies compared with all other groups. DISCUSSION: The identification of distinct profiles of aggressive behaviour offers new possibilities for studying risk factors and eventually targeting specific risk prevention strategies.

Molecular analysis of sleep: wake cycles in Drosophila.

Sleep is controlled by two major regulatory systems: a circadian system that drives it with a 24-hour periodicity and a home-ostatic system that ensures that adequate amounts of sleep are obtained. We are using the fruit fly Drosophila melanogaster to understand both types of regulation. With respect to circadian control, we have identified molecular mechanisms that are critical for the generation of a clock. Our recent efforts have focused on the analysis of posttranslational mechanisms, specifically the action of different phosphatases that control the phosphorylation and thereby the stability and/or nuclear localization of circadian clock proteins period (PER) and timeless (TIM). Resetting the clock in response to light is also mediated through posttranslational events that target TIM for degradation by the proteasome pathway; a recently identified ubiquitin ligase, jet lag (JET), is required for this response. Our understanding of the homeostatic control of sleep is in its early stages. We have found that mushroom bodies, which are a site of synaptic plasticity in the fly brain, are important for the regulation of sleep. In addition, through analysis of genes expressed under different behavioral states, we have identified some that are up-regulated during sleep deprivation. Thus, the Drosophila model allows the use of cellular and molecular approaches that should ultimately lead to a better understanding of sleep biology.

Prevalence and types of aggressive behaviour among adults with intellectual disabilities.

BACKGROUND: Aggressive behaviours represent major obstacles to the integration into society of individuals with intellectual disability (ID) and pose significant management issues for carers. METHODS: The present study assessed the prevalence and severity of five types of aggressive behaviours in 3165 adult men and women with ID receiving services from three rehabilitation agencies in Québec by surveying their carers using the Modified Overt Aggressive Scale. RESULTS: The 12-month prevalence of aggressive behaviour was 51.8%: 24% property damage, 37.6% verbal, 24.4% self-oriented and 24.4% physical aggression, and 9.8% sexually aggressive behaviour, most of which being mild in severity. Only 4.9% of individuals displayed aggressive behaviour leading to injury of the victim. Few gender differences were observed. CONCLUSIONS: The capacity to document and assess the types as well as the severity of aggressive behaviour is thus critical, not only to better understand the correlates of various types of behaviours but also to orient intervention programmes whether they be prevention, assessment, monitoring or management of aggressive behaviour.

Concomitant loss of dynorphin, NARP, and orexin in narcolepsy.

BACKGROUND: Narcolepsy with cataplexy is associated with a loss of orexin/hypocretin. It is speculated that an autoimmune process kills the orexin-producing neurons, but these cells may survive yet fail to produce orexin. OBJECTIVE: To examine whether other markers of the orexin neurons are lost in narcolepsy with cataplexy. METHODS: We used immunohistochemistry and in situ hybridization to examine the expression of orexin, neuronal activity-regulated pentraxin (NARP), and prodynorphin in hypothalami from five control and two narcoleptic individuals. RESULTS: In the control hypothalami, at least 80% of the orexin-producing neurons also contained prodynorphin mRNA and NARP. In the patients with narcolepsy, the number of cells producing these markers was reduced to about 5 to 10% of normal. CONCLUSIONS: Narcolepsy with cataplexy is likely caused by a loss of the orexin-producing neurons. In addition, loss of dynorphin and neuronal activity-regulated pentraxin may contribute to the symptoms of narcolepsy.

Deletion of presynaptic adenosine A1 receptors impairs the recovery of synaptic transmission after hypoxia.

Adenosine protects neurons during hypoxia by inhibiting excitatory synaptic transmission and preventing NMDA receptor activation. Using an adeno-associated viral (AAV) vector containing Cre recombinase, we have focally deleted adenosine A(1) receptors in specific hippocampal regions of adult mice. Recently, we found that deletion of A(1) receptors in the CA1 area blocks the postsynaptic responses to adenosine in CA1 pyramidal neurons, and deletion of A(1) receptors in CA3 neurons abolishes the presynaptic effects of adenosine on the Schaffer collateral input [J Neurosci 23 (2003) 5762]. In the current study, we used this technique to delete A(1) receptors focally from CA3 neurons to investigate whether presynaptic A(1) receptors protect synaptic transmission from hypoxia. We studied the effects of prolonged (1 h) hypoxia on the evoked field excitatory postsynaptic potentials (fEPSPs) in the CA1 region using in vitro slices. Focal deletion of the presynaptic A(1) receptors on the Schaffer collateral input slowed the depression of the fEPSPs in response to hypoxia and impaired the recovery of the fEPSPs after hypoxia. Delayed responses to hypoxia linearly correlated with impaired recovery. These findings provide direct evidence that the neuroprotective role of adenosine during hypoxia depends on the rapid inhibition of synaptic transmission by the activation of presynaptic A(1) receptors.

Genetic and nutritional effects on swine excreta.

The objective of this study was to investigate genetic and nutritional effects on swine excreta. Two studies were used. Study I was a 3 x 2 x 2 factorial design with three genetic groups, two diets, and two sexes. Genetic groups were a maternal line (WL), paternal line (BL) and their F1 progeny. Corn-soybean meal diets with either 18 or 14% CP, differing only by substitution of soybean meal for corn, were used in both studies. Study II was a 2 x 2 factorial design with two genetic groups and two diets. High testosterone (D2) and low testosterone (D1) Duroc lines were used. Solid and liquid wastes were collected for 3 d. A total of 108 pens in Study I and 50 pens in Study II were sampled twice. Total excreta were measured and samples collected for chemical analysis of N, NH3N, P, Ca, Cu, K, Zn, and Fe. Measures were adjusted for pig weight and feed disappearance. Maternal-line pigs excreted significantly less P, Ca, Cu, Zn, and Fe than F1 or BL pigs and numerically smaller quantities of all nutrients than BL pigs. In study II, differences were found between lines ofthe same breed. Line D2 pigs had greater output of P, Ca, and Cu (P< 0.05) than D1 pigs and numerically larger quantities of all other nutrients except NH3N and Fe. Pigs fed 14% CP excreted less N, NH3N, and K (P < 0.01) in both studies and excreted significantly less P in Study I. Pigs on a 14% CP diet excreted numerically smaller amounts of all nutrients in both studies except Ca in Study II. In Study I, gilts excreted smaller (P < 0.05) amounts of all nutrients than barrows. Genetic, nutritional, and gender differences influenced waste output.

Coitarche and care: does experience of the 'looked after' system affect timing of a woman's sexual debut?

Women with an early coitarche may be less connected to home than those with a later coitarche and are more at risk of sexually transmitted infections (STIs). Children in care or the 'looked after' system feel less connected. We investigated whether women ever in care (WEIC) differed from women never in care (WNIC) in terms of coitarche and STIs using self-reported data from women attending Genitourinary Medicine clinics. Of the 336 women participating 17 women had experienced care, of whom 13 (76.5%) had coitarche below 16 years of age; of these five (38.5%) had used a condom at coitarche and three (60%) with genital infections had gonorrhoea, chlamydial infection or pelvic inflammatory disease. This compared with 112 (35.1%), 70 (62.5%) and 29 (40.8%), respectively for WNIC. WEIC are more likely to have early coitarche; if this is below 16 years subsequent genital infections are more likely to be fertility-threatening.

Atropine acts in the ventral striatum to reduce raclopride-induced catalepsy.

While muscarinic receptor antagonists are used to reduce motor side effects associated with the use of antipsychotic drugs, their site of action remains unclear. The study investigated the site of action of the non-selective muscarinic receptor antagonist atropine on catalepsy induced by the selective dopamine D2 receptor antagonist, raclopride. Initially, catalepsy and striatal muscarinic receptor occupancy was assessed 2 h following subcutaneous injection of raclopride and either atropine or vehicle. Catalepsy was significantly reduced by doses of atropine that occupied more than 69% of muscarinic receptors. Next, atropine was injected bilaterally into the ventral striatum, which produced a significant reduction in catalepsy, while injections into the dorsal striatum and substantia nigra had no effect. The site of atropine's action was localised to a discrete area of the ventral striatum through the use of quantitative autoradiographic techniques. These findings provide further evidence for the importance of the ventral striatum in the expression of behaviours.

Changes in muscle tone are regulated by D1 and D2 dopamine receptors in the ventral striatum and D1 receptors in the substantia nigra.

Muscle rigidity associated with antipsychotic drug treatment is believed to result from reduced striatal dopamine neurotransmission. In the current study the regulatory roles of dopamine D1 and D2 receptor subfamilies in the dorsal (DSTR) and ventral striatum (VSTR) and substantia nigra (SN) were investigated on muscle tone, assessed as increases in tonic electromyographic (EMG) activity. Rats were injected with the irreversible D1/D2 antagonist N-ethoxycarbonyl-2-ethoxy, -1,2-dihydroquinoline (EEDQ), the reversible D1 antagonist SCH23390, or D2 antagonist sulpiride. Increased EMG activity was observed following injection of EEDQ and SCH23390 into the SN or VSTR, and sulpiride into the VSTR. Mapping, using quantitative autoradiographic analysis of dopamine receptor occupancy after striatal injections, showed D1 and D2 receptors in discrete ventral sites were associated with EMG increases. Overall the results support roles for dopamine D1 and D2 receptors in the ventral striatum, and D1 receptors in the substantia nigra, in the regulation of muscle tone.