Laboratory research in rodents suggests that early exposure to methylphenidate (MPH) leads to altered sensitivity to the rewarding effects of stimulant drugs of abuse later in life and may have implications for drug-taking vulnerability. Netrin-1 is a family of guidance cue proteins that participates in the organization of neural circuits. During embryonic development through adulthood, both netrin-1 and its receptor DCC (deleted in colorectal cancer) are expressed in mesocorticolimbic dopamine (DA) brain regions. Studies conducted on dcc heterozygous rodents show a critical role for DCC expression in the development and function of the adult mesocorticolimbic DA system. Recently, variations in DCC expression, specifically in the ventral tegmental area (VTA), have been shown to be involved in adult stimulant-induced behavioral plasticity. Here we explored, 1) the effects of early adolescent MPH treatment on cocaine-reward in adulthood using conditioned place preference as a measure of drug-reward, and 2) whether early MPH treatment leads to alterations in DCC expression in mesocorticolimbic DA regions. Repeated exposure to MPH during early adolescence reduced sensitivity to the rewarding value of cocaine in adulthood. Remarkably this decrease in adult cocaine-reward was associated with a down-regulation of DCC expression in the VTA selectively. This is the first demonstration that developmental MPH treatment regulates netrin-1 DCC receptor expression in the adult brain and suggests that DCC regulation may be a mechanism by which exposure to stimulant drugs early in life induces enduring changes in sensitivity to their rewarding effects in adulthood. / La recherche chez les rongeurs suggère que l'administration de methylphenidate (MPH) durant le développement conduit à des réponses différentes aux effets de récompense des drogues stimulantes d'abus et peut aussi avoir des implications concernant la vulnérabilité d'abus de drogue plus tard dans la vie. Netrin-1 est une famille de protéines développementale fondamentale à l'organisation du system dopamine (DA) mésocorticolimbique. Durant le développement embryologique et pendant l'âge adulte, netrin-1 et son récepteur DCC, sont exprimés dans les régions mésocorticolimbiques. La recherche chez les souris avec des niveaux réduits de DCC suggèrent un rôle important de ces récepteurs durant le développement du cerveau et dans la plasticité du système DA mésocorticolimbique induite par les drogues stimulantes, particulièrement dans l'aire tegmentale ventrale (ATV). Durant cette étude, nous avons exploré 1) les effets de l'administration de MPH pendant l'enfance sur les effets de récompense de cocaïne durant l'âge adulte en utilisant un paradigme de préférence locative conditionnée, et 2) si les traitements MPH durant l'enfance mènent à des différences d'expression de DCC dans les régions DA mésocorticolimbiques. Nos résultats montrent que l'administration chronique de MPH pendant l'enfance réduit les réponses aux effets de récompenses de la cocaïne durant l'âge adulte. Remarquablement, cette diminution de réponse aux effets de récompense de cocaïne est associée à une réduction d'expression de DCC dans le ATV exclusivement. C'est la première étude qui montre que le traitement MPH durant le développement régularise l'expression de DCC dans le cerveau adulte et suggère un mécanisme par lequel l'administration de drogues stimulantes durant l'enfance pourrait entrainer de différentes réponses aux effets de récompenses durant l'âge adulte.

This study evaluates the prevalence and incidence rates of infection with Human immunodeficiency Virus (HIV), hepatitis B (HBV) and hepatitis C (HCV), in a cohort of drug users (DU) on methadone maintenance treatment in Geneva, Switzerland. Over 700 DU participated between 1988 and 1995; the follow-up rate was high. The prevalence rate at entry into treatment declined dramatically over time for all 3 viruses. Comparing DU born before 1961 to those born after 1970 the prevalence rate of HIV was 29. 1% versus 2.0%, of HBV 71.3% versus 2.2%, and of HCV 83.6% versus 17.9%. The incidence rates for HIV and HBV were low (0.6 and 2.1 per 100 person years of follow up). For HCV the rate was high (4.2) with a slightly higher rate among women. These data suggest that DU have changed HIV risk taking behaviour in response to HIV prevention campaigns. Current prevention efforts should focus on improvement of HCV prevention and maintaining safe behaviour.

Since type B adverse drug reactions tend to be rare and serious, they tend to be treated by tertiary-care specialists; and since they are commonly iatrogenic, the specialists should be concerned to document carefully not only the case per se but also the drug use history, leading to practice data of good research quality. The specialist should also be concerned to submit the data record to a central facility that would supply the probabilities, evidence-based, that a recent drug use by a patient caused the adverse event. Continual and systematic accumulation of these data records at the central facility--using the same logistic and organizational framework for each of different type B events--provides for both the numerator and denominator series for etiologic research. Since the targeted events are quite rare, the catchment population of the "registry" would have to be very large, international in scope, especially if the system is to provide for rapid resolution of crises arising from novel suspicions of type B effects with respect to newly marketed drugs.

The Newfoundland Department of Health administers several rubella vaccination programs for the prevention of congenital rubella syndrome (CRS). This study examined the effectiveness of these programs by reviewing rubella susceptibility in the population at risk for CRS, assessing the predictive value of a rubella vaccination record, and evaluating the effectiveness of the postnatal rubella vaccination program. / From 1989 to 1993, rubella susceptibility in women aged 15 to 44 averaged 4.6% overall, but was significantly higher in women aged 15 to 19 years, averaging 14%. The positive predictive value of a rubella vaccination record was 92% overall, but it differed by type of vaccine product and vaccine viral strain; 99% for any monovalent rubella vaccine, compared to 81% for recipients of HPV-77 DE-5 strain MR (measles rubella) or MMR (measles mumps rubella) vaccine. The postnatal rubella vaccination program failed to provide testing for 13% of pregnant women in the province in 1992, and 10% of susceptible women in 1992 were not subsequently vaccinated. / These results suggest that women of childbearing age in Newfoundland remain at risk of having children with CRS. The rubella vaccination record is not adequate proof of immunity for some of these women, and the postnatal vaccination program requires some improvement in order to prevent cases of CRS in the future.

The Brazilian Wilms' Tumor Study Group carried out a case-control study of Wilms' tumour (WT) to identify risk factors for the development of WT. Two controls per case, matched for sex, age (${ pm12}$ months), hospital and interviewer, were chosen. Controls were children admitted to hospital for conditions other than neoplasms. Pediatricians interviewed parents of 109 cases and 218 controls. / Increasing levels of parental education and family income were associated with the diagnosis of WT, probably the result of selecting a hospitalized control group. The positive association between high family income and WT was strongest among the cases diagnosed early, and absent among the cases diagnosed late. / Parental occupational exposure to pesticides or herbicides before the pregnancies of the subjects was identified as a risk factor, with a significant trend for increasing risk with increasing cumulative frequency of use. / Also identified as risk factors were maternal consumption during the pregnancy of coffee in excess of 2 cups/day and of dipyrone, an analgesic (both among the lowest income group), and of alcoholic beverages (among the most educated).

Objective. To investigate the independent association of changes in sexual and drug injection risk behaviour on Human Immunodeficiency Virus (HIV) seroconversion among Montreal injection drug users (IDUs). / Design. Subjects were selected from the St. Luc cohort, a prospective study that has recruited IDUs since September 1988. Eligible subjects must have enrolled in the cohort after December 31, 1991 and completed at least two follow-up visits. HIV serostatus testing was performed at baseline and semi-annually. Questionnaires on injection and sexual risk behaviour were administered at each visit. Cox regression with time-dependent covariates was used in the analysis. / Results. The risk of HIV infection appears to be dependent upon the consistency of risk behaviour practiced. Chronic IDUs, who made no attempt to change risk behaviour, were at high risk of HIV infection. Episodic IDUs, who attempted to practice low risk behaviour but experienced frequent relapse to high risk behaviour, were also at considerable risk of HIV infection. Episodic IDUs demonstrated a higher risk of HIV infection than chronic IDUs for certain behaviours. Stable IDUs, who had managed to maintain low risk behaviour, were at minimal risk of HIV infection. / Conclusion. Despite widespread reported behaviour change among Montreal IDUs, a substantial amount of high risk sexual and injection behaviour continues. Programs should be developed to address IDUs in each stage of change: IDUs who have no desire to change their behaviours, IDUs who require assistance maintaining behaviour changes and IDUs who have adopted low risk practises and are approaching long term maintenance of behaviour change.

The prognosis of Systemic Lupus Erythematosus (SLE) has improved markedly over recent decades, however, little research has focused on the improvement of SLE patient's quality of life. The main objective of this cross-sectional study was to evaluate the relationship between disease activity, cumulative damage and self-reported quality of life in 54 patients with SLE. / Disease activity was measured by the SLE Disease Activity Index (SLEDAI), Systemic Lupus Activity Measure (SLAM-2) and cumulative damage by the Systemic Lupus International Cooperating Clinics/ACR damage index (DI). Quality of life was assessed by the Medical Outcome Survey Short Form 36 (SF-36) and the Euroqol (EQ-5D) self-report questionnaires. Multiple linear regression was used to identify significant predictors of patients' self reported health status. Cumulative damage was found to be associated with physical function, physical health and social functioning (SF-36); disease activity was found to have a significant association with general health (SF-36) and a weaker association on overall health status as evaluated through the 'thermometer' rating scale of the EQ-5D. Patients' ratings of ability with usual activities was strongly related to overall physical health (SF-36) as well as the physical functioning and general health subscales of the SF-36. In addition, patients' ratings of anxiety and depression were strongly related to overall mental health status (SF-36). / In conclusion, physical health of SLE patients was associated with disease activity, disease damage, capacity for usual activity, and mobility.

The cause of seizures in epileptic patients is still poorly understood. Ongoing debates regarding the existence of a pre-seizure state initiating the seizure remain unresolved. Most of the work on this topic has focused on the identification of forerunners (prior to the seizure occurring) in the electroencephalogram, by using measures intended to isolate and distinguish recognizable patterns. New signal processing tools have been developed to allow for a more accurate characterization of the electroencephalogram, and therefore increase the potential to detect forerunners. This study presents both a statistical and an algorithmic evaluation of the predictive value of these measures. The evaluation was carried out on limited electroencephalogram segments of five temporal epilepsy patients whose EEG was recorded at 2000 Hz. The statistical analysis suggested several pathophysiological factors influencing the seizure prediction, and the algorithm implementation succeeded in detecting 71% of pre-seizure states at a mean time of 20.9 +/- 17.4 min prior to the seizure. / Les causes des crises d'épilepsie sont encore très mal comprises. L'existence d'un état préparatoire d'avant-crise occasionne de nombreux débats qui restent sans issue. La plupart des travaux sur ce sujet se concentrent sur la recherche de signes avant-coureur (avant la crise d'épilepsie) dans l'électroencéphalogramme. De nouveaux outils de traitement du signal permettent une meilleure description de l'électroencéphalogramme et ont, par conséquent, un plus fort potentiel pour la détection de signe avant-coureurs. Cette étude présente une évaluation statistique et algorithmique de ces mesures. L'évaluation se base sur un nombre de segments limité d'électroencéphalogramme échantillonné à 2000 Hz provenant de cinq patients avec épilepsie temporal. L'évaluation statistique a suggéré plusieurs facteurs pathophysiologique influençant la prédiction de crise d'épilepsie et l'algorithme a réussit à détecter 71% des états d'avant-crise à un temps moyen de 20.9 +/- 17.4 min avant la crise.

The negative symptoms of schizophrenia, characterized as a loss or reduction of normal functions, have drawn a lot of attention in recent years in the research community. Negative symptoms are a multidimensional domain and constitute an unmet therapeutic need. The present research project focused on the negative symptom of anhedonia, defined as the reduced capacity to gain pleasure. It has been suggested that anhedonia characterizes a subgroup of patients with schizophrenia and represents a vulnerability marker for the development of schizophrenia when measured in non-clinical individuals. Moreover, there is evidence that self-report anhedonia severity in schizophrenia is influenced by neurocognitive deficits. For instance, schizophrenia is characterized by significant memory problems and evidence suggests a potential link with negative symptoms. The major goals of this project were: 1) to explore the relationship between emotional memory and self-report anhedonia severity; and 2) to identify brain alterations associated with inter-individual variability in anhedonia severity in people with schizophrenia and in non-clinical individuals. In a first behavioral study, we used an emotional recognition task to test whether anhedonia was linked to memory performance for emotional face expressions. Results suggest that self-report anhedonia severity in schizophrenia is not directly influenced by emotional memory deficits. The neuroimaging studies first involved the design of a magnetic resonance imaging paradigm using complex emotional pictures. This paradigm allowed us to measure brain activity associated with the processing of hedonic information. We first found that elevat / Il y a un intérêt croissant chez les chercheurs pour l'étude plus approfondie des symptômes négatifs de la schizophrénie. Les symptômes négatifs, définis comme une perte ou une réduction du fonctionnement normal de l'individu, ont une nature multidimensionnelle et constituent un défi clinique, tant au niveau des traitements pharmacologiques que psychologiques. Ce projet de recherche de doctorat s'est concentré plus particulièrement sur le symptôme négatif de l'anhédonie, définie comme une réduction de la capacité à ressentir le plaisir. Des études antérieures suggèrent que l'anhédonie pourrait caractériser un sous-groupe distinct de patients schizophrènes. Certains chercheurs ont aussi démontré que ce symptôme peut représenter un marqueur de vulnérabilité pour le développement de la schizophrénie lorsque détecté dans une population non-clinique. Il y a finalement l'hypothèse que la sévérité de l'anhédonie dans la schizophrénie, telle que mesurée par des auto-questionnaires ou des entrevues cliniques, est modulée par des déficits neurocognitifs. Les buts principaux de ce projet de recherche étaient: 1) d'explorer la relation entre la mémoire émotionnelle et la sévérité de l'anhédonie auto-rapportée; et 2) d'identifier les altérations cérébrales associées à la variabilité inter-individuelle au niveau de la sévérité de l'anhédonie, et ce dans une population non-clinique ainsi que dans un groupe de patients schizophrènes. Dans une première étude comportementale, nous avons utilisé une tâche mnésique de reconnaissance émotionnelle afin de tester si l'anhédonie était liée, d'une part, à la performance$

A survey was planned to explore how estrogen receptor (ER) status of breast cancer was related to dietary and reproductive factors, in postmenopausal patients from Toronto. Unforeseeable circumstances created major delays and, even after enhancements of design, the number of subjects who could be included was seriously reduced. As statistical power had thus become undesirably low, emphasis is placed on the realities of epidemiologic research of this nature, i.e. how inevitable difficulties arise, have to be identified and, at the very least, mitigated. Despite small numbers, the odds of positive ER status were found to be low for patients with many pregnancies and high for those with one or two pregnancies, but intermediate for cases who had never been pregnant. This very strong association underlines the weaknesses of those with measured dietary intakes, which appear unlikely to be of major relative importance.