Training in hypoxia fails to further enhance endurance performance and lactate clearance in well-trained men and impairs glucose metabolism during prolonged exercise.

The aim of this study was to investigate the synergistic effects of endurance training and hypoxia on endurance performance in normoxic and hypoxic conditions (approximately 3000 m above sea level) as well as on lactate and glucose metabolism during prolonged exercise. For this purpose, 14 well-trained cyclists performed 12 training sessions in conditions of normobaric hypoxia (HYP group, n = 7) or normoxia (NOR group, n = 7) over 4 weeks. Before and after training, lactate and glucose turnover rates were measured by infusion of exogenous lactate and stable isotope tracers. Endurance performance was assessed during incremental tests performed in normoxia and hypoxia and a 40 km time trial performed in normoxia. After training, performance was similarly and significantly improved in the NOR and HYP groups (training, P < 0.001) in normoxic conditions. No further effect of hypoxic training was found on markers of endurance performance in hypoxia (training x hypoxia interaction, n.s.). In addition, training and hypoxia had no significant effect on lactate turnover rate. In contrast, there was a significant interaction of training and hypoxia (P < 0.05) on glucose metabolism, as follows: plasma insulin and glucose concentrations were significantly increased; glucose metabolic clearance rate was decreased; and the insulin to glucagon ratio was increased after training in the HYP group. In conclusion, our results show that, compared with training in normoxia, training in hypoxia has no further effect on endurance performance in both normoxic and hypoxic conditions or on lactate metabolic clearance rate. Additionally, these findings suggest that training in hypoxia impairs blood glucose regulation in endurance-trained subjects during exercise.

Spatial relational learning and memory abilities do not differ between men and women in a real-world, open-field environment

This study assesses gender differences in spatial and non-spatial relational learning and memory in adult humans behaving freely in a real-world, open-field environment. In Experiment 1, we tested the use of proximal landmarks as conditional cues allowing subjects to predict the location of rewards hidden in one of two sets of three distinct locations. Subjects were tested in two different conditions: (1) when local visual cues marked the potentially-rewarded locations, and (2) when no local visual cues marked the potentially-rewarded locations. We found that only 17 of 20 adults (8 males, 9 females) used the proximal landmarks to predict the locations of the rewards. Although females exhibited higher exploratory behavior at the beginning of testing, males and females discriminated the potentially-rewarded locations similarly when local visual cues were present. Interestingly, when the spatial and local information conflicted in predicting the reward locations, males considered both spatial and local information, whereas females ignored the spatial information. However, in the absence of local visual cues females discriminated the potentially-rewarded locations as well as males. In Experiment 2, subjects (9 males, 9 females) were tested with three asymmetrically-arranged rewarded locations, which were marked by local cues on alternate trials. Again, females discriminated the rewarded locations as well as males in the presence or absence of local cues. In sum, although particular aspects of task performance might differ between genders, we found no evidence that women have poorer allocentric spatial relational learning and memory abilities than men in a real-world, open-field environment.

Postprandial thermogenesis at rest and during exercise in elderly men ingesting two levels of protein.

Seven elderly male subjects (69 +/- 3 yr, 67.8 +/- 9.2 kg, 24.5 +/- 3.6% body fat) lived for 12 consecutive weeks in a metabolic unit and maintained their weight with two different diets fed for 6 weeks each: Diet A, consisted of their habitual protein intake as determined on the outside by a dietary record (mean +/- SD, 1.12 +/- 0.22 g/kg d). Diet B was an isocaloric diet with reduced protein intake (70 mgN/kg d, i.e., 0.44 g protein/kg d) at the level of physiological protein requirement [7]. After 3 weeks on each diet, the thermogenic response to single meals A and B containing 38% of weight maintenance energy for each subject (731-994 kcal) was studied by indirect calorimetry under two situations: (1) at rest over a 4 hr period and (2) during graded exercise on a bicycle ergometer at four stepwise workloads (0,80, 200, and 300 kg/min). A postabsorptive control exercise was also performed in order to assess the net effect of the meal during exercise. Eating alone increased the energy expenditure by +0.18 +/- 0.07 kcal/min with meal A and +0.13 +/- 0.06 kcal/min with meal B. There was a positive correlation (r = 0.84, p less than 0.01) between the % energy derived from protein and the thermogenic response expressed as % of the energy content of test meal. Exercise failed to influence the thermogenic response to meals since the overall net increase in energy expenditure induced by the meals while exercising was not different from that obtained at rest: +0.22 +/- 0.17 kcal/min and +0.15 +/- 0.13 kcal/min with meal A and meal B, respectively. This study failed to show any interaction between exercise and postprandial thermogenesis in elderly individuals.

Association between nonmedical prescription drug use and health status among young swiss men.

PURPOSE: To examine the relationship between the nonmedical prescription drug use (NMPDU) of six drug classes and health. METHODS: Data on young adults males (mean age, 19.96 years) from the baseline and follow-up of the Cohort Study on Substance Use Risk Factors (C-SURF) were used (n = 4,958). Two sets of logistic regression models were fitted to examine the associations between NMPDU of opioid analgesics, sedatives or sleeping pills, anxiolytics, antidepressants, beta blockers and stimulants, and health status (assessed using the Medical Outcomes Study 12-Item Short Form Survey Instrument [SF-12 v2]). We first computed odds ratios between NMPDU at baseline and poor mental and physical health at follow-up, adjusting for poor mental or physical health at baseline. We then computed odds ratios between poor mental and physical health at baseline and NMPDU at follow-up, adjusting for NMPDU at baseline. RESULTS: Three key findings regarding mental health were (1) there was a reciprocal risk between poor mental health and sedatives and anxiolytics; (2) poor mental health increased NMPDU of opioid analgesics and antidepressants but not vice versa; and (3) there were no associations with stimulants. Three key findings regarding physical health were (1) poor physical health increased the risk of NMPDU of anxiolytics; (2) the only reciprocal risk was between physical health and NMPDU of opioid analgesics; and (3) there were no associations with stimulants. CONCLUSION: These results, among the first ever on reciprocal effects between NMPDU and mental and physical health status, give unique information concerning the adverse effects of NMPDU on health and vice versa. The study shows that NMPDU is not only a sign of self-medication but may induce health problems.

Thermogenesis in men and women induced by fructose vs glucose added to a meal.

Energy expenditure (EE) was measured by indirect calorimetry in 20 subjects (10 men and 10 women) for 30 min before and 6 h after the ingestion of a mixed meal containing 20% protein, 33% fat, and either 75 g glucose or 75 g fructose as carbohydrate source (47%). Diet-induced thermogenesis (DIT) and the rate of carbohydrate oxidation were significantly greater with fructose (12.4 +/- 0.6% and 54.8 +/- 2.1 g/6 h, respectively) than with glucose (10.7 +/- 0.7%, p less than 0.01, and 48.3 +/- 2.4 g/6 h, p less than 0.01, respectively). The DIT of male (12.1 +/- 1% and 13.9 +/- 0.8% with glucose and fructose, respectively) was greater than that of female subjects (9.2 +/- 0.7%, p less than 0.05, and 11.0 +/- 0.7%, p less than 0.05, respectively). In contrast to the glucose meal, negligible changes in plasma levels of glucose and insulin were observed with the fructose meal but plasma levels of lactate increased more with fructose than with glucose (peak values: 3.3 +/- 0.6 vs 1.5 +/- 0.1 mmol/L, respectively). When fructose provides the only carbohydrate source of a mixed meal, it induces a larger increase in carbohydrate oxidation and thermogenesis than when glucose is the carbohydrate source.

Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease.

Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

Patterns and transitions in substance use among young Swiss men: a latent transition analysis approach

This study investigates the potential stages of drug use. Data from the longitudinal Cohort Study on Substance Use Risk Factors were used (N = 5,116). Drug use (alcohol, tobacco, and 16 illicit drugs) over the previous 12 months was assessed at two time points. Patterns and trajectories of drug use were studied using latent transition analysis (LTA). This study's substantive contributions are twofold. First, the pattern of drug use displayed the well-known sequence of drug involvement (licit drugs to cannabis to other illicit drugs), but with an added distinction between two kinds of illicit drugs ("middle-stage" drugs: uppers, hallucinogens, inhaled drugs; and "final-stage" drugs: heroin, ketamine, GHB/GBL, research chemicals, crystal meth, and spice). Second, subgroup membership was stable over time, as the most likely transition was remaining in the same latent class.

Acute post-exercise oxygen uptake, hormone and plasma metabolite response in obese men.

This study aimed to compare oxygen uptake (  V˙O2), hormone and plasma metabolite responses during the 30 min after submaximal incremental exercise (Incr) performed at the same relative/absolute exercise intensity and duration in lean (L) and obese (O) men. Eight L and 8 O men (BMI: 22.9±0.4; 37.2±1.8 kg · m(-2)) completed Incr and were then seated for 30 min.   V˙O2 was monitored during the first 10 min and from the 25-30(th) minutes of recovery. Blood samples were drawn for the determination of hormone (catecholamines, insulin) and plasma metabolite (NEFA, glycerol) concentrations. Excess post-exercise oxygen consumption (EPOC) magnitude during the first 10 min was similar in O and in L (3.5±0.4; 3.4±0.3 liters, respectively, p=0.86). When normalized to percent change (  V˙O2END=100%), %   V˙O2END during recovery was significantly higher from 90-120 s in O than in L (p≤0.04). There were no significant differences in catecholamines (p≥0.24), whereas insulin was significantly higher in O than in L during recovery (p=0.01). The time-course of glycerol was similar from 10-30 min of recovery (-42% for L; -41% for O, p=0.85), whereas significantly different patterns of NEFA were found from 10-30 min of recovery between groups (-18% for L; +8% for O, p=0.03). Despite similar EPOC, a difference in   V˙O2 modulation between groups was observed, likely due to faster initial rates of   V˙O2 decline in L than in O. The different patterns of NEFA between groups may suggest a lower NEFA reesterification during recovery in O, which was not involved in the rapid EPOC component.

Pain, frailty and comorbidity on older men: the CHAMP study.

Intrusive pain is likely to have a serious impact on older people with limited ability to respond to additional stressors. Frailty is conceptualised as a functional and biological pattern of decline accumulating across multiple physiological systems, resulting in a decreased capacity to respond to additional stressors. We explored the relationship between intrusive pain, frailty and comorbid burden in 1705 community-dwelling men aged 70 or more who participated in the baseline phase of the CHAMP study, a large epidemiological study of healthy ageing based in Sydney, Australia. 9.4% of men in the study were frail (according to the commonly-used Cardiovascular Health Study frailty criteria).Using a combination of self-report and clinical measures, we found an association between frailty and intrusive pain that remained after accounting for demographic characteristics, number of comorbidities, self-reported depressed mood and arthritis (adjusted odds ratio 1.7 (95% confidence interval (CI) 1.1-2.7), p=0.0149). The finding that adjusting for depressed mood, but not a history of arthritis, attenuated the relationship between frailty and intrusive pain points to a key role for central mechanisms. Additionally, men with the highest overall health burden (frail plus high comorbid burden) were most likely to report intrusive pain (adjusted odds ratio 3.0 (95% CI 1.6-5.5), p=0.0004). These findings provide support for the concept that intrusive pain is an important challenge for older men with limited capacity to respond to additional physical stressors. To our knowledge, this is the first study to explore specifically the relationship between pain and frailty.

Development and application of computational methodologies in qualitative modeling

La présente thèse s'intitule "Développent et Application des Méthodologies Computationnelles pour la Modélisation Qualitative". Elle comprend tous les différents projets que j'ai entrepris en tant que doctorante. Plutôt qu'une mise en oeuvre systématique d'un cadre défini a priori, cette thèse devrait être considérée comme une exploration des méthodes qui peuvent nous aider à déduire le plan de processus regulatoires et de signalisation. Cette exploration a été mue par des questions biologiques concrètes, plutôt que par des investigations théoriques. Bien que tous les projets aient inclus des systèmes divergents (réseaux régulateurs de gènes du cycle cellulaire, réseaux de signalisation de cellules pulmonaires) ainsi que des organismes (levure à fission, levure bourgeonnante, rat, humain), nos objectifs étaient complémentaires et cohérents. Le projet principal de la thèse est la modélisation du réseau de l'initiation de septation (SIN) du S.pombe. La cytokinèse dans la levure à fission est contrôlée par le SIN, un réseau signalant de protéines kinases qui utilise le corps à pôle-fuseau comme échafaudage. Afin de décrire le comportement qualitatif du système et prédire des comportements mutants inconnus, nous avons décidé d'adopter l'approche de la modélisation booléenne. Dans cette thèse, nous présentons la construction d'un modèle booléen étendu du SIN, comprenant la plupart des composantes et des régulateurs du SIN en tant que noeuds individuels et testable expérimentalement. Ce modèle utilise des niveaux d'activité du CDK comme noeuds de contrôle pour la simulation d'évènements du SIN à différents stades du cycle cellulaire. Ce modèle a été optimisé en utilisant des expériences d'un seul "knock-out" avec des effets phénotypiques connus comme set d'entraînement. Il a permis de prédire correctement un set d'évaluation de "knock-out" doubles. De plus, le modèle a fait des prédictions in silico qui ont été validées in vivo, permettant d'obtenir de nouvelles idées de la régulation et l'organisation hiérarchique du SIN. Un autre projet concernant le cycle cellulaire qui fait partie de cette thèse a été la construction d'un modèle qualitatif et minimal de la réciprocité des cyclines dans la S.cerevisiae. Les protéines Clb dans la levure bourgeonnante présentent une activation et une dégradation caractéristique et séquentielle durant le cycle cellulaire, qu'on appelle communément les vagues des Clbs. Cet évènement est coordonné avec la courbe d'activation inverse du Sic1, qui a un rôle inhibitoire dans le système. Pour l'identification des modèles qualitatifs minimaux qui peuvent expliquer ce phénomène, nous avons sélectionné des expériences bien définies et construit tous les modèles minimaux possibles qui, une fois simulés, reproduisent les résultats attendus. Les modèles ont été filtrés en utilisant des simulations ODE qualitatives et standardisées; seules celles qui reproduisaient le phénotype des vagues ont été gardées. L'ensemble des modèles minimaux peut être utilisé pour suggérer des relations regulatoires entre les molécules participant qui peuvent ensuite être testées expérimentalement. Enfin, durant mon doctorat, j'ai participé au SBV Improver Challenge. Le but était de déduire des réseaux spécifiques à des espèces (humain et rat) en utilisant des données de phosphoprotéines, d'expressions des gènes et des cytokines, ainsi qu'un réseau de référence, qui était mis à disposition comme donnée préalable. Notre solution pour ce concours a pris la troisième place. L'approche utilisée est expliquée en détail dans le dernier chapitre de la thèse. -- The present dissertation is entitled "Development and Application of Computational Methodologies in Qualitative Modeling". It encompasses the diverse projects that were undertaken during my time as a PhD student. Instead of a systematic implementation of a framework defined a priori, this thesis should be considered as an exploration of the methods that can help us infer the blueprint of regulatory and signaling processes. This exploration was driven by concrete biological questions, rather than theoretical investigation. Even though the projects involved divergent systems (gene regulatory networks of cell cycle, signaling networks in lung cells), as well as organisms (fission yeast, budding yeast, rat, human), our goals were complementary and coherent. The main project of the thesis is the modeling of the Septation Initiation Network (SIN) in S.pombe. Cytokinesis in fission yeast is controlled by the SIN, a protein kinase signaling network that uses the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this thesis, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model has made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN. Another cell cycle related project that is part of this thesis was to create a qualitative, minimal model of cyclin interplay in S.cerevisiae. CLB proteins in budding yeast present a characteristic, sequential activation and decay during the cell cycle, commonly referred to as Clb waves. This event is coordinated with the inverse activation curve of Sic1, which has an inhibitory role in the system. To generate minimal qualitative models that can explain this phenomenon, we selected well-defined experiments and constructed all possible minimal models that, when simulated, reproduce the expected results. The models were filtered using standardized qualitative ODE simulations; only the ones reproducing the wave-like phenotype were kept. The set of minimal models can be used to suggest regulatory relations among the participating molecules, which will subsequently be tested experimentally. Finally, during my PhD I participated in the SBV Improver Challenge. The goal was to infer species-specific (human and rat) networks, using phosphoprotein, gene expression and cytokine data and a reference network provided as prior knowledge. Our solution to the challenge was selected as in the final chapter of the thesis.