Hypothalamic paraventricular nucleus neurons regulate medullary catecholamine cell responses to restraint stress

Both physical and psychological stressors recruit catecholamine cells (CA) located in the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In the case of physical stressors, this effect is initiated by signals that first access the central nervous system at or below the level of the medulla. For psychological stressors, however, CA cell recruitment depends on higher structures within the neuraxis. Indeed, we have recently provided evidence of a pivotal role for the medial amygdala (MeA) in this regard, although such a role must involve a relay, as MeA neurons do not project directly to the medulla. However, some of the MeA neurons that respond to psychological stress have been found to project to the hypothalamic paraventricular nucleus (PVN), a structure that provides significant input to the medulla. To determine whether the PVN might regulate medullary CA cell responses to psychological stress, animals were prepared with unilateral injections of the neurotoxin ibotenic acid into the PVN (Experiment 1), or with unilateral injections of the retrograde tracer wheat germ agglutinin-gold (WGA-Au) into the CA cell columns of the VLM or NTS (Experiment 2). Seven days later, animals were subjected to a psychological stressor (restraint; 15 minutes), and their brains were subsequently processed for Fos plus appropriate cytoplasmic markers (Experiment 1), or Fos plus WGA-Au (Experiment 2). PVN lesions significantly suppressed the stress-related induction of Fos in both VLM and NTS CA cells, whereas tracer deposits in the VLM or NTS retrogradely labeled substantial numbers of PVN cells that were also Fos-positive after stress. Considered in concert with previous results, these data suggest that the activation of medullary CA cells in response to psychological stress may involve a critical input from the PVN. (C) 2004 Wiley-Liss, Inc.

Investigation of the coping antecedents to positive outcomes and distress in multiple sclerosis (MS)

This study examined relations between stress and coping predictors and distress and positive outcomes in multiple sclerosis (MS). A total of 502 people with MS completed a questionnaire at Time 1 and, 3 months later, Time 2 (n= 404). Predictors included Time 1 illness (duration, number of symptoms, course), number of problems, appraisal and coping (acceptance, problem solving, emotional release, avoidance, personal health control, energy conservation). Dependent variables were Time 2 distress (anxiety, depression) and positive outcomes (life satisfaction, positive affect, benefits). Results indicated that as hypothesised, personal health control, emotional release and physical assistance were related to the positive outcomes, whereas avoidance was related to distress, and acceptance was associated with the positive outcomes and distress. Findings highlight the differential relations between coping strategies and positive and negative outcomes and the role of appraisal and coping in regulating distress and promoting positive psychological states while managing a chronic illness.

Thalamic paraventricular nucleus lesions facilitate central amygdala neuronal responses to acute psychological stress

The thalamic paraventricular nucleus (PVT) is activated by stress and projects to forebrain structures directly implicated in processing stress-related information. Accordingly, it seems likely the PVT plays an important role in modulating stress responses. We examined effects of excitotoxic PVT lesions on forebrain Fos expression patterns normally elicited by an acute psychological stressor. PVT lesions significantly increased stress-induced Fos in a key stress-processing region, the central amygdala.

Attributions, cognitions, and coping styles:teleworkers' reactions to work-related problems

Based on the attributional reformulation of learned helplessness theory (Abramson, Seligman, & Teasdale, 1978) and Lazarus and Launier's (1978) primary-secondary appraisal theory of stress, the present study sought to examine teleworkers' reactions to their work-related problems. The role of attributions about the sources, and cognitions about the consesquences, of these problems in promoting positive adaptation was addressed. In particular, it was predicted that teleworkers who made optimistic attributions and cognitions would be more likely to employ problem-focused coping strategies and, as a result, report more positive psychological and job-related outcomes. Based on a survey sample of 192 teleworkers, the results indicated that a tendency to engage in self-blame was related to the use of emotion-focused coping strategies. In turn, there was evidence linking emotion-focused coping strategies to negative outcomes and problem-focused coping strategies to positive outcomes. The results are discussed in relation to attributional approaches to stress which highlight the importance of cognitions about the consequences of negative events. Finally, implications for the training of teleworkers are presented.

The role of inflammation in vascular function and pregnancy outcome in the pregnant stroke prone spontaneously hypertensive rat

During pregnancy, the maternal cardiovascular system undergoes major adaptation. One of these changes is a 40-50 % increase in circulating blood volume which requires a systemic remodelling of the vasculature in order to regulate maternal blood pressure and maximise blood supply to the developing placenta and fetus. These changes are broadly conserved between humans and rats making them an appropriate pre-clinical model in which to study the underlying mechanisms of pregnancy-dependent cardiovascular remodelling. Whilst women are normally protected against cardiovascular disease; pregnancy marks a period of time where women are susceptible to cardiovascular complications. Cardiovascular disease is the leading cause of maternal mortality in the United Kingdom; in particular hypertensive conditions are among the most common complications of pregnancy. One of the main underlying pathologies of these pregnancy complications is thought to be a failure of the maternal cardiovascular system to adapt. The remodelling of the uterine arteries, which directly supply the maternal-fetal interface, is paramount to a healthy pregnancy. Failure of the uterine arteries to remodel sufficiently can result in a number of obstetric complications such as preeclampsia, fetal growth restriction and spontaneous pregnancy loss. At present, it is poorly understood whether this deficient vascular response is due to a predisposition from existing maternal cardiovascular risk factors, the physiological changes that occur during pregnancy or a combination of both. Previous work in our group employed the stroke prone spontaneously hypertensive rat (SHRSP) as a model to investigate pregnancy-dependent remodelling of the uterine arteries. The SHRSP develops hypertension from 6 weeks of age and can be contrasted with the control strain, the Wistar Kyoto (WKY) rat. The phenotype of the SHRSP is therefore reflective of the clinical situation of maternal chronic hypertension during pregnancy. We showed that the SHRSP exhibited a deficient uterine artery remodelling response with respect to both structure and function accompanied by a reduction in litter size relative to the WKY at gestational day (GD) 18. A previous intervention study using nifedipine in the SHRSP achieved successful blood pressure reduction from 6 weeks of age and throughout pregnancy; however uterine artery remodelling and litter size at GD18 was not improved. We concluded that the abnormal uterine artery remodelling present in the SHRSP was independent of chronic hypertension. From these findings, we hypothesised that the SHRSP could be a novel model of spontaneously deficient uterine artery remodelling in response to pregnancy which was underpinned by other as yet unidentified cardiovascular risk factors. In Chapter 1 of this thesis, I have characterised the maternal, placental and fetal phenotype in pregnant (GD18) SHRSP and WKY. The pregnant SHRSP exhibit features of left ventricular hypertrophy in response to pregnancy and altered expression of maternal plasma biomarkers which have been previously associated with hypertension in human pregnancy. I developed a protocol for accurate dissection of the rat uteroplacental unit using qPCR probes specific for each layer. This allowed me to make an accurate and specific statement about gene expression in the SHRSP GD18 placenta; where oxidative stress related gene markers were increased in the vascular compartments. The majority of SHRSP placenta presented at GD18 with a blackened ring which encircled the tissue. Further investigation of the placenta using western blot for caspase 3 cleavage determined that this was likely due to increased cell death in the SHRSP placenta. The SHRSP also presented with a loss of one particular placental cell type at GD18: the glycogen cells. These cells could have been the target of cell death in the SHRSP placenta or were utilised early in pregnancy as a source of energy due to the deficient uterine artery blood supply. Blastocyst implantation was not altered but resorption rate was increased between SHRSP and WKY; indicating that the reduction in litter size in the SHRSP was primarily due to late (>GD14) pregnancy loss. Fetal growth was not restricted in SHRSP which led to the conclusion that SHRSP sacrifice part of their litter to deliver a smaller number of healthier pups. Activation of the immune system is a common pathway that has been implicated in the development of both hypertension and adverse pregnancy outcome. In Chapter 2, I proposed that this may be a mechanism of interest in SHRSP pregnancy and measured the pro-inflammatory cytokine, TNFα, as a marker of inflammation in pregnant SHRSP and WKY and in the placentas from these animals. TNFα was up-regulated in maternal plasma and urine from the GD18 SHRSP. In addition, TNFα release was increased from the GD18 SHRSP placenta as was the expression of the pro-inflammatory TNFα receptor 1 (Tnfr1). In order to investigate whether this excess TNFα was detrimental to SHRSP pregnancy, a vehicle-controlled intervention study using etanercept (a monoclonal antibody which works as a TNFα antagonist) was carried out. Etanercept treatment at GD0, 6, 12 and 18 resulted in an improvement in pregnancy outcome in the SHRSP with an increased litter size and reduced resorption rate. Furthermore, there was an improved uterine artery function in GD18 SHRSP treated with etanercept which was associated with an improved uterine artery blood flow over the course of gestation. In Chapter 3, I sought to identify the source of this detrimental excess of TNFα by designing a panel for maternal leukocytes in the blood and placenta at GD18. A population of CD3- CD161+ cells, which are defined as rat natural killer (NK) cells, were increased in number in the SHRSP. Intracellular flow cytometry also identified this cell type as a source of excess TNFα in blood and placenta from pregnant SHRSP. I then went on to evaluate the effects of etanercept treatment on these CD3- CD161+ cells and showed that etanercept reduced the expression of CD161 and the cytotoxic molecule, granzyme B, in the NK cells. Thus, etanercept limits the cytotoxicity and potential damaging effect of these NK cells in the SHRSP placenta. Analysing the urinary peptidome has clinical potential to identify novel pathways involved with disease and/or to develop biomarker panels to aid and stratify diagnosis. In Chapter 4, I utilised the SHRSP as a pre-clinical model to identify novel urinary peptides associated with hypertensive pregnancy. Firstly, a characterisation study was carried out in the kidney of the WKY and SHRSP. Urine samples from WKY and SHRSP taken at pre-pregnancy, mid-pregnancy (GD12) and late pregnancy (GD18) were used in the peptidomic screen. In order to capture peptides which were markers of hypertensive pregnancy from the urinary peptidomic data, I focussed on those that were only changed in a strain dependent manner at GD12 and 18 and not pre-pregnancy. Peptide fragments from the uromodulin protein were identified from this analysis to be increased in pregnant SHRSP relative to pregnant WKY. This increase in uromodulin was validated at the SHRSP kidney level using qPCR. Uromodulin has previously been identified to be a candidate molecule involved in systemic arterial hypertension but not in hypertensive pregnancy thus is a promising target for further study. In summary, we have characterised the SHRSP as the first model of maternal chronic hypertension during pregnancy and identified that inflammation mediated by TNFα and NK cells plays a key role in the pathology. The evidence presented in this thesis establishes the SHRSP as a pre-clinical model for pregnancy research and can be continued into clinical studies in pregnant women with chronic hypertension which remains an area of unmet research need.

Factores asociados al estrés del cuidador primario de niños con autismo: Sobrecarga, psicopatología y estado de salud

The objective of this study was to evaluate if caregivers were overloaded when their children were diagnosed with autism disorder, how it may influence their mental and physical health. 40 caregivers have been participating in this study, mainly mothers. The parameters studied include sociodemographic factors, caregivers burden overload (Zarit Scale, adapted to the Spanish language), Psychopathology (SCL-90) and health status (SF-60). The results indicate that caregivers were overloaded, and in a worse state of mental and physical health compared to the general population. A strong positive correlation was observed between overwhelmed carers and the evaluated health and pathopsicological parameters. These results are in accordance with previous findings that were published by other groups, supporting the idea that specific health programs are needed for caregivers of children with chronic diseases.

The relationships of stress, health and wellbeing among workers

The precise relationship between the positive psychological state of work (i.e. engagement ) and the negative psychological state (i.e. burnout) has recently received research attention. Some view these as opposite states on the same similar continuum, while others take the position that they represent different biobehavioral spheres. This study expands our knowledge of the phenomenta engagement and burnout by analyzing their separate and joint manifestations. Using a sample of 2094 nurses, respondents were analyzed to determine the configuration of antecedents leading to separate and joint states of engagement and burnout, the configuration of engagement and burnout leading to mental, physical and organizational outcomes, and the relationship between engagement, bornout, and risk of metabolic syndrome. The study found that while both work engagement and burnout are highly correlated to health and organizational outcomes, the relative statistical power of burnout has a greater direct effect on health. It is important for workers and managers to adress the sources of burnout before addressing the positive psychological aspects of worker engagement.

Stressing schizotypy: The modulating role of stress-relieving behaviours and intellectual capacity on functional hemispheric asymmetry.

Relative cognitive impairments are common along the schizophrenia spectrum reflecting potential psychopathological markers. Yet stress, a vulnerability marker in schizophrenia (including its spectrum), is likewise related to cognitive impairments. We investigated whether one such cognitive marker (attenuated functional hemispheric asymmetry) during stressful life periods might be linked to individuals' schizotypal features or rather to individuals' stress-related experiences and behaviours. A total of 58 students performed a left hemisphere dominant (lateralised lexical decisions) and right hemisphere dominant (sex decisions on composite faces) task. In order to account for individual differences in stress sensitivity we separated participants into groups of high or low cognitive reserve according to their average current marks. In addition, participants filled in questionnaires on schizotypy (short O-LIFE), perceived stress, stress response, and a newly adapted questionnaire that enquired about potential stress compensation behaviour (elevated substance use). The most important finding was that enhanced substance use and cognitive disorganisation contributed to a right and left hemisphere shift in language dominance, respectively. We discuss that (i) former reports on right hemisphere shifts in language dominance with positive schizotypy might be explained by an associated higher substance use and (ii) cognitive disorganisation relates to unstable cognitive functioning that depend on individuals' life circumstances, contributing to published reports on inconsistent laterality-schizotypy relationships.

Psychological transformations in kidney transplantation: A prospective qualitative study

The aim of this IRB-approved study was to prospectively analyze psychological transformations in ESRD patients before and after transplantation (KT). Semi-structured interviews were conducted in 30 patients (mean age = 53±10) after their inclusion on the waiting-list (Gr. A). Follow-up interviews were performed 6 months later in 15 patients still awaiting KT (Gr. B6), and in 15 patients 6 months (Gr. C6) and 12 months (Gr. C12) after KT. Qualitative analysis was performed. Gr: A:All patients underlined loss of freedom, 87% devoted much energy to maintain normality, 57% modified medical directives. All reported emotional fragility related to dialysis and loss of quality of life (QOL), negative (43%) or suicidal thoughts (20%). Professional stigma was underlined (26%). Gr: B6:40% reported no change, 60% mentioned increase of illness intrusiveness, 46% dialysis side-effects, 40% communication problems, 33% tension with medical staff and waiting list handling. Fear of emotional breakdown (40%), couple problems (47%) and worsened professional difficulties (20%) were reported. Gr: C6:All patients mentioned improved QOL and freedom recovery (87%). All expressed concerns about possible acute rejection, 73% were anxious about laboratory results, 93% experienced dependence to immunosuppressants, 47% reported difficulties in handling medication, 21% feared to forget them, 47% were concerned about side-effects, 67% had resumed work but medical constraints led to professional tension (40%). Gr: C12:All mentioned recovered QOL. Medical controls were accepted as a routine (87%) and adherence to medication was mandatory (100%). All mentioned the limited long-term graft survival and 47% were anxious about possible return to dialysis, especially younger patients (27%). Positive identity and existential changes were reported (60%). This prospective qualitative study identifies psychological modifications in the course of KT. It provides a basis to adequately address concerns, but it shows also that KT is clearly associated with positive psychological transformations.

Le stress du soignant ou comment se soigner soi-même [Stress in health care workers]

La littérature scientifique confirme que les soignants ont besoin de soutien. Par-delà la surchage clinique et administrative, le stress lié à la signifiance des facteurs contextuels est une source de détresse importante. La reconnaissance et la gestion de ce stress peuvent soutenir le clinicien de manière durable. L'article discute les éléments clés de ces stresseurs, notamment le rôle des émotions du soignant, la reconnaissance des limites, la confusion concernant l'empathie, l'influence du développement et de la trajectoire de vie sur l'identité professionnelle ainsi que le conflit que représente le fait d'être un soignant qui a besoin d'aide. A growing body of evidence indicates that health care professionals are in need of support. Beside heavy clinical patient volume or administrative duties, stress related to the significance of contextual factors is an important source of clinician's distress. Identification of and working through such stress can be a durable source of support. This article discusses key elements of these stressors, namely, the role of emotions of the clinician, awareness of limits, confusion about empathy, the influence of development and life trajectory on professional identity and the conflicting roles of the health care provider being in need of support http://titan.medhyg.ch/mh/formation/article.php3?sid=32934

Experience and endocrine stress responses in neonatal and pediatric critical care nurses and physicians.

OBJECTIVE: Critical care is a working environment with frequent exposure to stressful events. High levels of psychological stress have been associated with increased prevalence of burnout. Psychological distress acts as a potent trigger of cortisol secretions. We attempted to objectify endocrine stress reactivity. DESIGN: Observational cohort study during two 12-day periods in successive years. SETTING: A tertiary multidisciplinary neonatal and pediatric intensive care unit (33 beds). SUBJECTS: One hundred and twelve nurses and 27 physicians (94% accrual rate). INTERVENTIONS AND MEASUREMENTS: Cortisol determined from salivary samples collected every 2 hrs and after stressful events. Participants recorded the subjective perception of stress with every sample. Endocrine reactions were defined as transient surges in cortisol of >50% and 2.5 nmol/L over the baseline. MAIN RESULTS: During 7,145 working hours, we observed 474 (12.5%) endocrine reactions from 3,781 samples. The mean cortisol increase amounted to 10.6 nmol/L (219%). The mean occurrence rate of endocrine reactions per subject and sample was 0.159 (range, 0-0.43). Although the mean raw cortisol levels were lower in experienced team members (>3 yrs of intensive care vs. <3 yrs, 4.1 vs. 4.95 nmol/L, p < .001), professional experience failed to attenuate the frequency and magnitude of endocrine reactions, except for the subgroup of nurses and physicians with >8 yrs of intensive care experience. A high proportion (71.3%) of endocrine reactions occurred without conscious perception of stress. Unawareness of stress was higher in intensive care nurses (75.1%) than in intermediate care nurses (51.8%, p < .01). CONCLUSIONS: Stress-related cortisol surges occur frequently in neonatal and pediatric critical care staff. Cortisol increases are independent of subjective stress perception. Professional experience does not abate the endocrine stress reactivity.

Symptoms of chronic stress at work in NGO workers

Working in a NGO often involves providing life saving resources (food, medicine, equipment, water, etc) to needy populations around the globe. Such duty requires highly dedicated employees and humanitarian workers are said to face a hign degree of pressure in their daily work. Despite the evidence of taxing work demands, and a high potential for stress related problems, very few studies on occupational chronic stress have specifically looked at NGO workers. Assuming that "field stress" can relay to workers at headquarters, we carried out an exploratory study about occupational health among employees of a NGO's headquarters. We sent a questionnaire to all employees (N=130) of a NGO headquarters located in Switzerland. We used the TST questionnaire (French version of the Langner's questionnaire on psychiatric symptoms) to identify cases with potential mental health problems. We also included in the questionnaire some items about motivation, acknowledgment, work-life balance, job demand, and autonomy. A total of 75 employees answered our questionnaire (57% response rate). 44% of our sample were men (n=33) and 56% were women (n=42). The mean age was of 40 years (SD=7.6). 56% were working at the headquarters of the NGO in questions as of 2 years or less. Not surprisingly, a majority of respondents reported to be highly motivated (74%) and the meaning of work was important for 80% of them. However, 35% indicated having problems in conciliating their private and professional life. Most frequent reported symptoms included feeling "weak all over" (81%), having "trouble getting asleep often" (35%), "clogging in nose" (35%), feeling "nervous often" (33%), and "memory not all right" (33%). The score for psychiatric symptoms was high in 8 (11%) employees whose health might therefore be at risk. In comparison, other sudies showed that this proportion was 9% for French teachers and 16% for sales personnel1. Results show that symptoms of mental health problems do occur among NGO workers. Some of these symptoms are known to be linked to occupational stress. Chronic stress manifests itself first in non-specific symptoms (e.g. fatigue) and later in specific pathologies. This could explain the relatively low proportion of cases with a high score in Langner's scale than was expected. Therefore, we hypothesize a healthy worker effect. The fact that our sample is 40 years old in average, and that the turnover is quite high can also support this hypothesis. Further research is needed in order to better understand occupational stress in this specific population. An upcoming study will investigate the role of organizational factors associated with health complaints. Therefore, a longitudinal survey including quantitative and qualitative methods is appropriate.

Työn fyysinen ja psyykkinen kuormittavuus vanhustenhoidossa - seurantatutkimus ergonomisen kehittämistyön tuloksista

Tutkimuksen tarkoituksena oli analysoida vanhusten ympärivuorokautisen hoidon yksiköissä työskentelevien työntekijöiden työn fyysistä ja psyykkistä kuormittavuutta ja työhön liittyviä fyysisiä riskejä. Lisäksi haluttiin selvittää, millaisia vaikutuksia fyysisen kuormittavuuden vähentämistä tavoitelleella ergonomisella kehittämisinterventiolla saadaan aikaan. Tutkimuksessa hyödynnettiin Turun kaupungin vanhuspalveluissa vuosina 2010–2012 toteutuneessa ergonomisessa kehittämisinterventiossa (47 työyksikköä) kertynyttä ja vuosien 2010 ja 2012 Kunta10-kyselyn (120 työyksikköä) tuottamaa tietoa. Intervention ydin oli Työterveyslaitoksen Fyysisten riskien hallintamalli hoitoalalla -mallin käyttööotto. Käytetyt mittarit olivat seuraavat: Työn kuormitus- ja työtyytyväisyyskysely työntekijöille, asiakkaiden toimintakykyä mittaava RAVATM -indeksi, fyysistä kuormitusta ja työn riskejä mittava Care ThermometerTM-menetelmä, potilassiirtojen turvallisuusjohtamisen (PHOQS) arviointi sekä esimies- ja ergonomiavastaavien kysely. Lisäksi käytössä olivat Kunta10-kyselyn tulokset valittujen muuttujien osalta kaikista tutkimukseen osallistuvista kaupungeista sekä ympärivuorokautisen hoidon asiakkaita ja hoitohenkilöstöä kuvaavia tilastoja. Työ vanhusten ympärivuorokautisessa hoidossa on fyysisesti ja psyykkisesti kuormittavaa. Interventiotoimenpiteistä huolimatta koettu fyysinen ja psyykkinen kuormittavuus kasvoivat, tosin fyysinen psyykkistä vähemmän. Kuormittavuus vaihteli toimintamuodoittain ja ammattiryhmittäin. Fyysisesti kuormittavimmaksi työ koettiin pitkäaikaissairaanhoidossa, psyykkinen kuormitus kasvoi eniten tehostetussa palveluasumisessa. Vanhainkodit sijoittuivat näiden väliin. Lähihoitajat kokivat työnsä fyysisesti kuormittavimmaksi, kun taas sairaanhoitajien työ oli psyykkisesti lähihoitajien työtä kuormittavampaa. Ergonomiakoulutus vähensi eniten koettua fyysistä kuormittavuutta. Kehityskeskustelut ja aiempaa paremmaksi arvioitu työkyky vähensivät mutta tyytymättömyys työhön lisäsi koettua fyysistä ja psyykkistä kuormittavuutta. Työntekijöiden ikä, RAVATM -indeksi, Care ThermometerTM -mittaukset ja PHOQS-pisteet eivät olleet tilastollisesti merkitsevästi yhteydessä kuormittavuuden muutoksiin. Työn kuormittavuuden vähentäminen ja turvallisen työskentelyn edistäminen vaativat pitkäkestoista toimintaa ja hyvää johtamista erityisesti lähiesimiehiltä. Fyysisten riskien hallintamallin käyttöönotto ja ergonomiavastaavien toiminnan vakiinnuttaminen tukevat tavoitteiden saavuttamista.

Effect of psychological stress on the L-arginine-nitric oxide pathway and semen quality

It has been reported that mental stress causes abnormality of spermiogram parameters. We investigated the effect of psychological stress on the L-arginine-nitric oxide (NO) pathway. Semen samples were collected from 29 healthy fourth semester medical students just before (stress) and 3 months after (non-stress) the final examinations. Psychological stress was measured by the State Anxiety Inventory questionnaire. After standard semen analysis, arginase activity and NO concentration were measured spectrophotometrically in the seminal plasma. Measurements were made in duplicate. During the stress period, sperm concentration (41.28 ± 3.70 vs 77.62 ± 7.13 x 10(6)/mL), rapid progressive motility of spermatozoa (8.79 ± 1.66 vs 20.86 ± 1.63%) and seminal plasma arginase activity (0.12 ± 0.01 vs 0.22 ± 0.01 U/mL) were significantly lower than in the non-stress situation, whereas seminal plasma NO (17.28 ± 0.56 vs 10.02 ± 0.49 µmol/L) was higher compared to the non-stress period (P < 0.001 for all). During stress there was a negative correlation between NO concentration and sperm concentration, the percentage of rapid progressive motility and arginase activity (r = -0.622, P < 0.01; r = -0.425, P < 0.05 and r = -0.445, P < 0.05, respectively). These results indicate that psychological stress causes an increase of NO level and a decrease of arginase activity in the L-arginine-NO pathway. Furthermore, poor sperm quality may be due to excessive production of NO under psychological stress. In the light of these results, we suggest that the arginine-NO pathway, together with arginase and NO synthase, are involved in semen quality under stress conditions.

Genome wide search for genetic determinants of habitual alcohol, tobacco and coffee use, obesity-related traits, response to mental and physical stress and hemodynamic traits

Les habitudes de consommation de substances psychoactives, le stress, l’obésité et les traits cardiovasculaires associés seraient en partie reliés aux mêmes facteurs génétiques. Afin d’explorer cette hypothèse, nous avons effectué, chez 119 familles multi-générationnelles québécoises de la région du Saguenay-Lac-St-Jean, des études d’association et de liaison pangénomiques pour les composantes génétiques : de la consommation usuelle d’alcool, de tabac et de café, de la réponse au stress physique et psychologique, des traits anthropométriques reliés à l’obésité, ainsi que des mesures du rythme cardiaque (RC) et de la pression artérielle (PA). 58000 SNPs et 437 marqueurs microsatellites ont été utilisés et l’annotation fonctionnelle des gènes candidats identifiés a ensuite été réalisée. Nous avons détecté des corrélations phénotypiques significatives entre les substances psychoactives, le stress, l’obésité et les traits hémodynamiques. Par exemple, les consommateurs d’alcool et de tabac ont montré un RC significativement diminué en réponse au stress psychologique. De plus, les consommateurs de tabac avaient des PA plus basses que les non-consommateurs. Aussi, les hypertendus présentaient des RC et PA systoliques accrus en réponse au stress psychologique et un indice de masse corporelle (IMC) élevé, comparativement aux normotendus. D’autre part, l’utilisation de tabac augmenterait les taux corporels d’épinéphrine, et des niveaux élevés d’épinéphrine ont été associés à des IMC diminués. Ainsi, en accord avec les corrélations inter-phénotypiques, nous avons identifié plusieurs gènes associés/liés à la consommation de substances psychoactives, à la réponse au stress physique et psychologique, aux traits reliés à l’obésité et aux traits hémodynamiques incluant CAMK4, CNTN4, DLG2, DAG1, FHIT, GRID2, ITPR2, NOVA1, NRG3 et PRKCE. Ces gènes codent pour des protéines constituant un réseau d’interactions, impliquées dans la plasticité synaptique, et hautement exprimées dans le cerveau et ses tissus associés. De plus, l’analyse des sentiers de signalisation pour les gènes identifiés (P = 0,03) a révélé une induction de mécanismes de Potentialisation à Long Terme. Les variations des traits étudiés seraient en grande partie liées au sexe et au statut d’hypertension. Pour la consommation de tabac, nous avons noté que le degré et le sens des corrélations avec l’obésité, les traits hémodynamiques et le stress sont spécifiques au sexe et à la pression artérielle. Par exemple, si des variations ont été détectées entre les hommes fumeurs et non-fumeurs (anciens et jamais), aucune différence n’a été observée chez les femmes. Nous avons aussi identifié de nombreux traits reliés à l’obésité dont la corrélation avec la consommation de tabac apparaît essentiellement plus liée à des facteurs génétiques qu’au fait de fumer en lui-même. Pour le sexe et l’hypertension, des différences dans l’héritabilité de nombreux traits ont également été observées. En effet, des analyses génétiques sur des sous-groupes spécifiques ont révélé des gènes additionnels partageant des fonctions synaptiques : CAMK4, CNTN5, DNM3, KCNAB1 (spécifique à l’hypertension), CNTN4, DNM3, FHIT, ITPR1 and NRXN3 (spécifique au sexe). Ces gènes codent pour des protéines interagissant avec les protéines de gènes détectés dans l’analyse générale. De plus, pour les gènes des sous-groupes, les résultats des analyses des sentiers de signalisation et des profils d’expression des gènes ont montré des caractéristiques similaires à celles de l’analyse générale. La convergence substantielle entre les déterminants génétiques des substances psychoactives, du stress, de l’obésité et des traits hémodynamiques soutiennent la notion selon laquelle les variations génétiques des voies de plasticité synaptique constitueraient une interface commune avec les différences génétiques liées au sexe et à l’hypertension. Nous pensons, également, que la plasticité synaptique interviendrait dans de nombreux phénotypes complexes influencés par le mode de vie. En définitive, ces résultats indiquent que des approches basées sur des sous-groupes et des réseaux amélioreraient la compréhension de la nature polygénique des phénotypes complexes, et des processus moléculaires communs qui les définissent.