Nicotinamide phosphoribosyltransferase as a target in inflammation- related disorders.

NAD(+) biosynthesis through nicotinamide phosphoribosyltransferase (NAMPT) holds potential as a target for the treatment of inflammatory disorders due to NAD(+)'s role in immune cell signaling and metabolism. In addition to its activity as an enzyme, NAMPT is also secreted in the extracellular space where it acts as a pro-inflammatory and proangiogenic cytokine. NAMPT inhibition with FK866 has anti-inflammatory activity in different models of immune disorders and it prevents ischemia-reperfusion-induced heart damage by dampening the production of neutrophil chemoattractants. NAMPT blockade with a neutralizing antibody has beneficial effects in an acute lung injury model. Last, but not least, the anticancer activity of NAMPT inhibitors may also reflect, at least in part, their ability to modify the cancer microenvironment through their anti-inflammatory properties. Overall, NAMPT inhibition holds potential for the treatment of inflammation-related disorders and the development of effective and safe NAMPT inhibitors remains an area of strong interest in pharmaceutical research.

L'entretien motivationnel, une nouvelle "panacée" dans la prise en charge de patients toxicodépendants ? Une revue de littérature [Motivational interviewing, the new "panacea" for treatment of substance use disorders ? A review of literature]

Cet article aborde l'entretien motivationnel (EM), considéré comme un style thérapeutique centré sur le client et directif, visant à développer la motivation au changement par l'exploration et la résolution de l'ambivalence (Miller, W.R., Rollnick, S., 2002. Motivational interviewing: preparing people for change. The Guilford Press, New York, p. 25). Après une brève présentation théorique de ce style thérapeutique, nous présentons un survol des principaux résultats empiriques relatifs à la question de son efficacité dans la prise en charge des troubles liés à l'utilisation de substances psychoactives. Malgré un corpus important de travaux qui mettent en évidence les effets de l'EM, la question des « ingrédients actifs » reste encore relativement peu explorée. Quelques hypothèses permettant de mieux comprendre le succès de l'EM sont évoquées.

Associations between mood, anxiety or substance use disorders and inflammatory markers after adjustment for multiple covariates in a population-based study.

Inflammation is one possible mechanism underlying the associations between mental disorders and cardiovascular diseases (CVD). However, studies on mental disorders and inflammation have yielded inconsistent results and the majority did not adjust for potential confounding factors. We examined the associations of several pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and high sensitive C-reactive protein (hsCRP) with lifetime and current mood, anxiety and substance use disorders (SUD), while adjusting for multiple covariates. The sample included 3719 subjects, randomly selected from the general population, who underwent thorough somatic and psychiatric evaluations. Psychiatric diagnoses were made with a semi-structured interview. Major depressive disorder was subtyped into "atypical", "melancholic", "combined atypical-melancholic" and "unspecified". Associations between inflammatory markers and psychiatric diagnoses were assessed using multiple linear and logistic regression models. Lifetime bipolar disorders and atypical depression were associated with increased levels of hsCRP, but not after multivariate adjustment. After multivariate adjustment, SUD remained associated with increased hsCRP levels in men (β = 0.13 (95% CI: 0.03,0.23)) but not in women. After multivariate adjustment, lifetime combined and unspecified depression were associated with decreased levels of IL-6 (β = -0.27 (-0.51,-0.02); β = -0.19 (-0.34,-0.05), respectively) and TNF-α (β = -0.16 (-0.30,-0.01); β = -0.10 (-0.19,-0.02), respectively), whereas current combined and unspecified depression were associated with decreased levels of hsCRP (β = -0.20 (-0.39,-0.02); β = -0.12 (-0.24,-0.01), respectively). Our data suggest that the significant associations between increased hsCRP levels and mood disorders are mainly attributable to the effects of comorbid disorders, medication as well as behavioral and physical CVRFs.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Challenging the "inoffensiveness" of regular cannabis use by its associations with other current risky substance use--a census of 20-year-old Swiss men.

3,537 men enrolling in 2007 for mandatory army recruitment procedures were assessed for the co-occurrence of risky licit substance use among risky cannabis users. Risky cannabis use was defined as at least twice weekly; risky alcohol use as 6+ drinks more than once/monthly, or more than 20 drinks per week; and risky tobacco use as daily smoking. Ninety-five percent of all risky cannabis users reported other risky use. They began using cannabis earlier than did non-risky users, but age of onset was unrelated to other risky substance use. A pressing public health issue among cannabis users stems from risky licit substance use warranting preventive efforts within this age group.

Prevalence of substance use in a Swiss psychiatric hospital: interview reports and urine screening.

BACKGROUND: Co-morbid substance misuse is common in psychiatric disorders, has potentially severe adverse consequences and may be frequently undetected. AIMS: To measure the prevalence of substance use among patients admitted to a Swiss psychiatric hospital and to examine the potential utility of routine urine drug screening in this setting. METHOD: 266 inpatients were included. 238 patients completed the interview and 240 underwent a urine drug screening. RESULTS: Lifetime prevalence of substance use among psychiatric patients was very high for alcohol (98%; 95% CI: 96-100), benzodiazepines (86%; 95% CI: 82-91) and cannabis (53%; 95% CI: 47-60), but also for "hard drugs" like cocaine (25% ; 95% CI: 19-30) or opiates (20%; 95% CI: 15-25). Regular current use of alcohol (32%; 95% CI: 26-38) or cannabis (17%; 95% CI: 12-22) was the most frequent. Substance use was associated with male sex, younger age, unmarried status and nicotine smoking. Urine screening confirms reports from patients on recent use, and remained positive for cannabis during hospitalisation, but not for cocaine nor for opiates. CONCLUSION: Substance use is frequent among psychiatric patients. Systematic interviewing of patients about their substance use remains essential, and is usually confirmed by urine screening. Urine screening can be useful to provide specific answers about recent use.

Subtypes of adolescents with substance use disorders and psychiatric comorbidity using cluster and discriminant analysis of MMPI-A profiles

The main aim of this study was to replicate and extend previous results on subtypes of adolescents with substance use disorders (SUD), according to their Minnesota Multiphasic Personality Inventory for adolescents (MMPI-A) profiles. Sixty patients with SUD and psychiatric comorbidity (41.7% male, mean age = 15.9 years old) completed the MMPI-A, the Teen Addiction Severity Index (T-ASI), the Child Behaviour Checklist (CBCL), and were interviewed in order to determine DSMIV diagnoses and level of substance use. Mean MMPI-A personality profile showed moderate peaks in Psychopathic Deviate, Depression and Hysteria scales. Hierarchical cluster analysis revealed four profiles (acting-out, 35% of the sample; disorganized-conflictive, 15%; normative-impulsive, 15%; and deceptive-concealed, 35%). External correlates were found between cluster 1, CBCL externalizing symptoms at a clinical level and conduct disorders, and between cluster 2 and mixed CBCL internalized/externalized symptoms at a clinical level. Discriminant analysis showed that Depression, Psychopathic Deviate and Psychasthenia MMPI-A scales correctly classified 90% of the patients into the clusters obtained.

Disease profiles of detainees in the Canton of Vaud in Switzerland: gender and age differences in substance abuse, mental health and chronic health conditions.

BACKGROUND: Literature on the disease profile of prisoners that differentiates by age and gender remains sparse. This study aimed to describe the health of correctional inmates in terms of substance abuse problems and mental and somatic health conditions, and compare it by gender and age. METHODS: This study examined cross-sectional data from the Canton of Vaud in Switzerland on the health conditions of detainees who were in prison on January 1, 2011 or entered prison in 2011. Health conditions validated by physician examination were reported using the International Classification of Diseases (ICD) version 10. The analyses were descriptive by groups of prisoners: the entire sample (All), Men, Older adults and Women. RESULTS: A total of 1,664 individuals were included in the analysis. Men comprised 91.5 % of the sample and had a mean age of 33 years. The other 8.5 % were women and had an average age of 39. Older adults (i.e., age 50 and older) represented 7 % of the total sample. Overall, 80 % of inmates were non-Swiss citizens, but the proportion of Swiss prisoners was higher among the older adults (51 %) and women (29 %). Overall, 41 % of inmates self-reported substance abuse problems. Of those, 27 % were being treated by psychiatrists for behavioral disorders related to substance abuse. Chronic infectious diseases were found in 9 % of the prison population. In addition, 27 % of detainees suffered from serious mental health conditions. Gender and age had an influence on the disease profile of this sample: compared to the entire prison population, the older inmates were less likely to misuse illegal drugs and to suffer from communicable infections but exhibited more problems with alcohol and a higher burden of chronic health conditions. Female prisoners were more disposed to mental health problems (including drug abuse) and infectious diseases. In terms of chronic diseases, women suffered from the same conditions as men, but the diseases were more prevalent in women. CONCLUSION: It is important to understand the different disease profiles of prisoners by gender and age, as it helps identify the needs of different groups and tailor age-and gender-specific interventions.

Screening of mental health and substance users in frequent users of a general Swiss emergency department.

BACKGROUND: The objectives of this study were to determine the proportions of psychiatric and substance use disorders suffered by emergency departments' (EDs') frequent users compared to the mainstream ED population, to evaluate how effectively these disorders were diagnosed in both groups of patients by ED physicians, and to determine if these disorders were predictive of a frequent use of ED services. METHODS: This study is a cross-sectional study with concurrent and retrospective data collection. Between November 2009 and June 2010, patients' mental health and substance use disorders were identified prospectively in face-to-face research interviews using a screening questionnaire (i.e. researcher screening). These data were compared to the data obtained from a retrospective medical chart review performed in August 2011, searching for mental health and substance use disorders diagnosed by ED physicians and recorded in the patients' ED medical files (i.e. ED physician diagnosis). The sample consisted of 399 eligible adult patients (≥18 years old) admitted to the urban, general ED of a University Hospital. Among them, 389 patients completed the researcher screening. Two hundred and twenty frequent users defined by >4 ED visits in the previous twelve months were included and compared to 169 patients with ≤4 ED visits in the same period (control group). RESULTS: Researcher screening showed that ED frequent users were more likely than members of the control group to have an anxiety, depressive disorder, post-traumatic stress disorder (PTSD), or suffer from alcohol, illicit drug abuse/addiction. Reviewing the ED physician diagnosis, we found that the proportions of mental health and substance use disorders diagnosed by ED physicians were low both among ED frequent users and in the control group. Using multiple logistic regression analyses to predict frequent ED use, we found that ED patients who screened positive for psychiatric disorders only and those who screened positive for both psychiatric and substance use disorders were more likely to be ED frequent users compared to ED patients with no disorder. CONCLUSIONS: This study found high proportions of screened mental health and/or substance use disorders in ED frequent users, but it showed low rates of detection of such disorders in day-to-day ED activities which can be a cause for concern. Active screening for these disorders in this population, followed by an intervention and/or a referral for treatment by a case-management team may constitute a relevant intervention for integration into a general ED setting.

Subtypes of adolescents with substance use disorders and psychiatric comorbidity using cluster and discriminant analysis of MMPI-A profiles

The main aim of this study was to replicate and extend previous results on subtypes of adolescents with substance use disorders (SUD), according to their Minnesota Multiphasic Personality Inventory for adolescents (MMPI-A) profiles. Sixty patients with SUD and psychiatric comorbidity (41.7% male, mean age = 15.9 years old) completed the MMPI-A, the Teen Addiction Severity Index (T-ASI), the Child Behaviour Checklist (CBCL), and were interviewed in order to determine DSMIV diagnoses and level of substance use. Mean MMPI-A personality profile showed moderate peaks in Psychopathic Deviate, Depression and Hysteria scales. Hierarchical cluster analysis revealed four profiles (acting-out, 35% of the sample; disorganized-conflictive, 15%; normative-impulsive, 15%; and deceptive-concealed, 35%). External correlates were found between cluster 1, CBCL externalizing symptoms at a clinical level and conduct disorders, and between cluster 2 and mixed CBCL internalized/externalized symptoms at a clinical level. Discriminant analysis showed that Depression, Psychopathic Deviate and Psychasthenia MMPI-A scales correctly classified 90% of the patients into the clusters obtained.

Disease profiles of detainees in the Canton of Vaud in Switzerland: gender and age differences in substance abuse, mental health and chronic health conditions.

BACKGROUND: Literature on the disease profile of prisoners that differentiates by age and gender remains sparse. This study aimed to describe the health of correctional inmates in terms of substance abuse problems and mental and somatic health conditions, and compare it by gender and age. METHODS: This study examined cross-sectional data from the Canton of Vaud in Switzerland on the health conditions of detainees who were in prison on January 1, 2011 or entered prison in 2011. Health conditions validated by physician examination were reported using the International Classification of Diseases (ICD) version 10. The analyses were descriptive by groups of prisoners: the entire sample (All), Men, Older adults and Women. RESULTS: A total of 1,664 individuals were included in the analysis. Men comprised 91.5 % of the sample and had a mean age of 33 years. The other 8.5 % were women and had an average age of 39. Older adults (i.e., age 50 and older) represented 7 % of the total sample. Overall, 80 % of inmates were non-Swiss citizens, but the proportion of Swiss prisoners was higher among the older adults (51 %) and women (29 %). Overall, 41 % of inmates self-reported substance abuse problems. Of those, 27 % were being treated by psychiatrists for behavioral disorders related to substance abuse. Chronic infectious diseases were found in 9 % of the prison population. In addition, 27 % of detainees suffered from serious mental health conditions. Gender and age had an influence on the disease profile of this sample: compared to the entire prison population, the older inmates were less likely to misuse illegal drugs and to suffer from communicable infections but exhibited more problems with alcohol and a higher burden of chronic health conditions. Female prisoners were more disposed to mental health problems (including drug abuse) and infectious diseases. In terms of chronic diseases, women suffered from the same conditions as men, but the diseases were more prevalent in women. CONCLUSION: It is important to understand the different disease profiles of prisoners by gender and age, as it helps identify the needs of different groups and tailor age-and gender-specific interventions.

Anxiety-Related Disorders in Primary-Junior Grades (K-3): Teacher Perceptions and Knowledge

This study used a descriptive case study design to analyze teachers’ experiences of anxiety-related conditions and emotions in the primary-junior grades (K-3). The study sought to examine (a) educators’ perceptions of anxiety conditions and how such interpretations influence their teaching practice; (b) teachers’ knowledge of the diagnostic processes, symptomology, and emotions related to anxiety disorders; (c) primary teachers’ knowledge of and experience with emotional regulation strategies and therapeutic approaches for anxiety; and (d) additional strategies and knowledge that should be available to help students. The study adopted Bronfenbrenner’s (1986) Ecological Model to frame participants’ experiences and perspectives, as well as the impact of several factors (e.g., school, home) and individuals (e.g. teachers, parents, students) on students’ anxiety and the participants’ perspectives. Through in-person interviews, participants shared their experiences with and knowledge about students in their teaching practice who had experienced anxiety-related conditions and emotions. Four major themes emerged from the data: symptoms and situational contexts; knowledge of strategies and interventions; understanding and perspectives of students; anxious emotional responses; and challenges. The study contributes to the literature by providing the real-life perspectives and experiences of primary-junior teachers (K-3) related to students experiencing anxiety. The study provides further information for educators, administrators, and research regarding any additional support and knowledge that should be implemented to further assist educators and students in regards to anxiety.