Hypoxic Pulmonary Hypertension, Novel Predisposing Factors, Unsuspected Mechanisms

High altitude constitutes an exciting natural laboratory for medical research. Over the past decade, high-altitude studies have provided important new insight into the regulation of the pulmonary circulation. Studies in high-altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide for pulmonary artery pressure homeostasis. Studies of healthy and maladapted high-altitude dwellers have provide important new insight into mechanisms conferring protection against/predisposing to pulmonary hypertension. Finally, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary (and systemic) vascular dysfunction at an early stage. Here, we will summarize recent studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning pulmonary hypertension and to the first direct demonstration of fetal programming of pulmonary vascular dysfunction in humans.

Moderate to vigorous physical activity and sedentary time and cardiometabolic risk factors in children and adolescents.

CONTEXT: Sparse data exist on the combined associations between physical activity and sedentary time with cardiometabolic risk factors in healthy children. OBJECTIVE: To examine the independent and combined associations between objectively measured time in moderate- to vigorous-intensity physical activity (MVPA) and sedentary time with cardiometabolic risk factors. DESIGN, SETTING, AND PARTICIPANTS: Pooled data from 14 studies between 1998 and 2009 comprising 20 871 children (aged 4-18 years) from the International Children's Accelerometry Database. Time spent in MVPA and sedentary time were measured using accelerometry after reanalyzing raw data. The independent associations between time in MVPA and sedentary time, with outcomes, were examined using meta-analysis. Participants were stratified by tertiles of MVPA and sedentary time. MAIN OUTCOME MEASURES: Waist circumference, systolic blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and insulin. RESULTS: Times (mean [SD] min/d) accumulated by children in MVPA and being sedentary were 30 (21) and 354 (96), respectively. Time in MVPA was significantly associated with all cardiometabolic outcomes independent of sex, age, monitor wear time, time spent sedentary, and waist circumference (when not the outcome). Sedentary time was not associated with any outcome independent of time in MVPA. In the combined analyses, higher levels of MVPA were associated with better cardiometabolic risk factors across tertiles of sedentary time. The differences in outcomes between higher and lower MVPA were greater with lower sedentary time. Mean differences in waist circumference between the bottom and top tertiles of MVPA were 5.6 cm (95% CI, 4.8-6.4 cm) for high sedentary time and 3.6 cm (95% CI, 2.8-4.3 cm) for low sedentary time. Mean differences in systolic blood pressure for high and low sedentary time were 0.7 mm Hg (95% CI, -0.07 to 1.6) and 2.5 mm Hg (95% CI, 1.7-3.3), and for high-density lipoprotein cholesterol, differences were -2.6 mg/dL (95% CI, -1.4 to -3.9) and -4.5 mg/dL (95% CI, -3.3 to -5.6), respectively. Geometric mean differences for insulin and triglycerides showed similar variation. Those in the top tertile of MVPA accumulated more than 35 minutes per day in this intensity level compared with fewer than 18 minutes per day for those in the bottom tertile. In prospective analyses (N = 6413 at 2.1 years' follow-up), MVPA and sedentary time were not associated with waist circumference at follow-up, but a higher waist circumference at baseline was associated with higher amounts of sedentary time at follow-up. CONCLUSION: Higher MVPA time by children and adolescents was associated with better cardiometabolic risk factors regardless of the amount of sedentary time.

Physiological function of PARbZip circadian clock-controlled transcription factors.

PARbZip proteins (proline and acidic amino acid-rich basic leucine zipper) represent a subfamily of circadian transcription factors belonging to the bZip family. They are transcriptionally controlled by the circadian molecular oscillator and are suspected to accomplish output functions of the clock. In turn, PARbZip proteins control expression of genes coding for enzymes involved in metabolism, but also expression of transcription factors which control the expression of these enzymes. For example, these transcription factors control vitamin B6 metabolism, which influences neurotransmitter homeostasis in the brain, and loss of PARbZip function leads to spontaneous and sound-induced epilepsy that are frequently lethal. In liver, kidney, and small intestine, PAR bZip transcription factors regulate phase I, II, and III detoxifying enzymes in addition to the constitutive androstane receptor (CAR), one of the principal sensors of xenobiotics. Indeed, knockout mice for the three PARbZip transcription factors are deficient in xenobiotic detoxification and display high morbidity, high mortality, and accelerated aging. Finally, less than 20% of these animals reach an age of 1 year. Accumulated evidences suggest that PARbZip transcription factors play a role of relay, coupling circadian metabolism of xenobiotic and probably endobiotic substances to the core clock circuitry of local circadian oscillators.

A variational approach for calculating Franck-Condon factors including mode-mode anharmonic coupling

We have implemented our new procedure for computing Franck-Condon factors utilizing vibrational configuration interaction based on a vibrational self-consistent field reference. Both Duschinsky rotations and anharmonic three-mode coupling are taken into account. Simulations of the first ionization band of Cl O2 and C4 H4 O (furan) using up to quadruple excitations in treating anharmonicity are reported and analyzed. A developer version of the MIDASCPP code was employed to obtain the required anharmonic vibrational integrals and transition frequencies

Calculation of Franck-Condon factors including anharmonicity: simulation of the C2 H4+ X̃2B 3u←C2 H4X̃1 Ag band in the photoelectron spectrum of ethylene

Our new simple method for calculating accurate Franck-Condon factors including nondiagonal (i.e., mode-mode) anharmonic coupling is used to simulate the C2H4+X2B 3u←C2H4X̃1 Ag band in the photoelectron spectrum. An improved vibrational basis set truncation algorithm, which permits very efficient computations, is employed. Because the torsional mode is highly anharmonic it is separated from the other modes and treated exactly. All other modes are treated through the second-order perturbation theory. The perturbation-theory corrections are significant and lead to a good agreement with experiment, although the separability assumption for torsion causes the C2 D4 results to be not as good as those for C2 H4. A variational formulation to overcome this circumstance, and deal with large anharmonicities in general, is suggested

Excessive alcohol consumption in young men: is there an association with their earlier family situation? A baseline-analysis of the C-SURF-study (Cohort Study on Substance Use Risk Factors).

AIMS: To determine whether parental factors earlier in life (parenting, single parent family, parental substance use problem) are associated with patterns of alcohol consumption among young men in Switzerland. METHODS: This analysis of a population based sample from the Cohort Study on Substance Use Risk Factors (C-SURF) included 5,990 young men (mean age 19.51 years), all attending a mandatory recruitment process for the army. These conscripts reported on parental monitoring and rule-setting, parental behaviour and family structure. The alcohol use pattern was assessed through abstention, risky single occasion drinking (RSOD), volume drinking and dependence. Furthermore, the impact of age, family socio-economic status, educational level of the parents, language region and civil status was analysed. RESULTS: A parental substance use problem was positively associated with volume drinking and alcohol dependence in young Swiss men. Active parenting corresponded negatively with RSOD, volume drinking and alcohol dependence. Single parent family was not associated with a different alcohol consumption pattern compared to standard family. CONCLUSION: Parental influences earlier in life such as active parenting (monitoring, rule-setting and knowing the whereabouts) and perceived parental substance use problem are associated with alcohol drinking behaviour in young male adults. Therefore, health professionals should stress the importance of active parenting and parental substance use prevention in alcohol prevention strategies.

Protective and Aggravating Effects of Nlrp3 Inflammasome Activation in IBD Models: Influence of Genetic and Environmental Factors.

Background: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation due to dysregulation of the mucosal immune system. The cytokines IL-1β and IL-18 appear early in intestinal inflammation and their pro-forms are processed via the caspase-1-activating multiprotein complex, the Nlrp3 inflammasome. Previously, we reported that the uptake of dextran sodium sulfate (DSS) by macrophages activates the Nlrp3 inflammasome and that Nlrp3(-/-) mice are protected in the acute DSS colitis model. Of note, other groups have reported opposing effects in regards to DSS susceptibility in Nlrp3(-/-) mice. Recently, mice lacking inflammasomes were found to develop a distinct intestinal microflora. Methods: To reconcile the contradicting observations, we investigated the role of Nlrp3 deficiency in two different IBD models: acute DSS colitis and TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis. In addition, we investigated the impact of the intestinal flora on disease severity by performing cohousing experiments of wild-type and Nlrp3(-/-) mice, as well as by antibiotic treatment. Results: Nlrp3(-/-) mice treated with either DSS or TNBS exhibited attenuated colitis and lower mortality. This protective effect correlated with an increased frequency of CD103+ lamina propria dendritic cells expressing a tolerogenic phenotype in Nlrp3(-/-) mice in steady state conditions. Interestingly, after cohousing, Nlrp3(-/-) mice were as susceptible as wild-type mice, indicating that transmission of endogenous bacterial flora between the two mouse strains might increase susceptibility of Nlrp3(-/-) mice towards DSS-induced colitis. Accordingly, treatment with antibiotics almost completely prevented colitis in the DSS model. Conclusions: The composition of the intestinal microflora significantly influences disease severity in IBD models comparing wild-type and Nlrp3(-/-) mice. This observation may - at least in part - explain contradictory results concerning the role of the inflammasome in different labs. Further studies are required to define the role of the Nlrp3 inflammasome in noninflamed mucosa under steady state conditions and in IBD.

Factors influencing maternal mental health after the birth of a child with a cleft in benin and in Switzerland.

Objective: The main objective of the study is to identify practical and cultural factors influencing the mental health of mothers of children with an orofacial cleft in Benin and to compare it with a sample of Swiss mothers in the same conditions. Method: Thirty-six mothers of children with an orofacial cleft in Benin and 40 mothers of children with an orofacial cleft in Switzerland were interviewed about practical and emotional aspects concerning their child and their own lives. Then, they completed the Perinatal Postraumatic Stress Questionnaire and the Beck Depression Inventory. Results: Mothers in Benin had significantly higher posttraumatic stress and depression symptoms compared with mothers in Switzerland. Depression symptoms were higher in Beninese mothers coming from urban areas, in Beninese mothers with few or no other children, and in Beninese mothers whose child was operated on at a more advanced age. Discussion: This study stressed the importance of cultural differences in perceptions of orofacial clefts in order to provide appropriate care to patients and their families. In particular, wide campaigns of information should help parents to understand the cleft origin and the medical staff in small dispensaries to provide adequate support and care. This may diminish anxiety concerning the child's short- and long-term prognosis. Creation of a Beninese parental support group for children with clefts and their families could be another way to provide information and support where multidisciplinary care is not available.

Factors psicosocials associats a Inexperiència de dolor crònic en adolescents

El dolor crònic pediàtric és un problema molt important. Malgrat que la informació disponible és molt menor que en adults, els informes publicats no deixen lloc a cap mena de dubte. Per una banda els treballs epidemiològics realitzats en la població general mostren que els problemes de dolor crònic són habituals entre la població infantil i adolescent, mentre que, per una altra, els estudis fets amb població clínica apunten que el dolor crònic pediàtric és causa important de desajust social i un dels problemes que més perjudiquen la qualitat de vida dels nens, i dels seus familiars, a tots els nivells. L’objectiu fonamental d’aquest treball era avançar en el oneixement dels factors psicosocials relacionats amb l’experiència del dolor crònic, de manera que a llarg termini aquesta informació ens permetés plantejar i contrastar programes de prevenció secundària pel dolor i la discapacitat crònics. Han participat un total de 92 joves amb edats compreses entre els 14 i 16 anys (79% de resposta positiva), dels quals el 64.2% eren noies. Majoritàriament experimentaven problemes de dolor abdominal. Els resultats han mostrat que, en efecte, els adolescents amb dolor crònic (dolor igual o superior a tres mesos) tenenuna pitjor qualitat de vida que els nois d’edat semblant però sense problemes crònics de dolor. Específicament, destaquen d’entre els factors estudiats: els pensaments catastròfics, l’estat afectiu, i certes actituds i alguns tipus d’estratègies d’afrontament dels nens. Les reaccions dels pares davant la conducta de dolor dels seus fills també resulta ser un factor de risc que cal considerar: les conductes dels pares tendents a minimitzar el problema estaven relacionades significativament amb el dolor i la discapacitat dels seus fills/es.

Risk Factors in Fatal Cases of Anaphylaxis due to Contrast Media: A Forensic Evaluation.

BACKGROUND: Fatalities following contrast medium exposure are extremely rare in clinical routine, though they may occur as an exception. Some may fall under the purview of the inquiring authorities and forensic pathologists due to their in-hospital occurrence. The purpose of this study was to assess the risk factors for anaphylaxis due to contrast medium administration that can be identified in fatal cases. METHODS: Fatalities occurred during the course of clinical investigations with contrast media described in the literature and fatal reactions to contrast agents that had undergone forensic investigations in our medicolegal center were reviewed with respect to patient characteristics, administered contrast medium, performed biochemical investigations and potential risk factors identified based on clinical history and medical records. RESULTS: Biochemical investigations into the fatal cases examined in our facility revealed increased mast cell tryptase, total IgE and activated mast cells in all subjects. Data obtained from the literature and our own investigations indicated that in only a minority of the fatal cases had there been previous exposure to contrast compounds, while most cases of severe anaphylaxis involved patients who apparently reacted on initial exposure. CONCLUSIONS: Most fatal cases failed to present any identifiable predisposing conditions out of those traditionally considered as risk factors for an anaphylactic reaction to contrast compounds in the medical histories of the patients. Comprehensive clinical histories and thorough reviews of medical data, along with exhaustive forensic investigations, provide information that is relevant in order to better appreciate the interwoven relationships linking all factors potentially involved in the pathogenesis of fatal anaphylaxis to contrast media. © 2014 S. Karger AG, Basel.

Host factors in occupational diisocyanate asthma: a Swiss longitudinal study

Objective: To investigate the usefulness of surrogates for individual susceptibility to organic diisocyanates in occupational asthma. Subjects: All new cases declared to the Swiss National Accident Insurance Company (SUVA) for establishment of a case for compensable occupational disease during 1993. Sixty-nine persons, of whom three were women, were suspected of having occupational asthma due to isocyanates. Of these, 47 subjects fulfilled the criteria to be accepted as an occupational disease case. Methods: All subjects were studied clinically and gave a blood sample for the phenotyping of their alpha-antitrypsin status and for immunological studies. The subjects were also given a peroral dose of caffeine for the determination of their N-acetylation capacity. Finally, those with an occupational disease were subjected to the methacholine provocation test. Results: Forty-four persons with occupational disease, out of 47, were heterozygous antitrypsin carriers and/or slow acetylators of primary amines. In the bronchial provocation with methacholine, 12 of these subjects had an unaltered response and seven had a mild reaction, 13 a moderate one and 15 a severe reaction. Interpretation: The study confirms the finding that slow N-acetylators are susceptible to asthma from exposure to common diisocyanate monomers at work. The same applies to heterozygous antitrypsin-phenotype carriers. Thus, the use of these markers may reinforce the diagnostic procedure, but they cannot completely replace the immunological tests. [Authors]

Factors psicosocials que determinen que algunes víctimes de violència de gènere s’abstinguin de declarar

Estudi qualitatiu dels factors psicosocials que fan que algunes víctimes de violència de gènere s’abstinguin de declarar

Estudi de la regulació del procés de formació de la fusta per a l’obtenció de biomassa i biocombustibles: el paper clau de dos factors de transcripció MYB amb funcions antagòniques

Estudi realitzat a partir d’una estada al Laboratoire de Recherche en Sciences Végétales - Université Toulouse III, entre 2010 i 2012. Durant l’estada s’han pogut complir els principals objectius del projecte de recerca sobre la regulació de la formació de les parets secundàries en un arbre d’importància econòmica, l’eucaliptus. S’ha caracteritzat dos factors de transcripció, EgMYB1 i 2, comparant el seu patró d’expressió espaciotemporal a nivell cel•lular i estudiant l’efecte fenotípic de la pèrdua de funció d’aquests gens. A més, s’ha construït una llibreria de xilema d’eucaliptus adaptada a la tècnica dels dos híbrids i s’ha descobert alguns del partners proteics d’EgMYB1 i 2, els quals estic actualment validant per mètodes alternatius. Augmentant els objectius inicials de la sol•licitud, he aprofitat la recent publicació del genoma de l’Eucalyptus grandis per identificar i caracteritzar el patró d’expressió de vàries famílies gèniques.

Risk factors of obesity and their determinants in preschool children (the Swiss Ballabeina study)

This thesis has been conducted in the context of a lifestyle intervention in 40 Swiss kindergarten classes in the cantons St. Gallen and Vaud, in areas with a high migrant prevalence (Ballabeina study). The main objective of this work was to fill certain gaps of the literature and to bring a better understanding of the risk factors of overweight and obesity and their determinants in preschool children. Our data show that parental migrant status and educational level influence independently of each other adiposity and/or eating habits in these children. In addition, sports club participation at this young age seems to be a better indicator of healthy lifestyle characteristics in terms of physical activity, sedentary behaviour and eating habits than weight status. Finally, we found that in this population higher scores of hyperactivity/inattention are associated with lower adiposity and with both healthy (more physical activity and less sedentary activity) and unhealthy (more television viewing and more unhealthy eating habits) lifestyle characteristics. Thus, our findings can be used by different actors of health and education system to better target their preventive actions and can serve as a basis for future complementary researches. - Cette thèse a été réalisée dans le cadre d'un projet de promotion de la santé mené dans 40 classes enfantines suisses issues de régions à forte prévalence migrante des cantons de St. Gall et de Vaud (étude Ballabeina). L'objectif principal de ce travail était de combler certaines lacunes de la littérature et d'approfondir nos connaissances sur les facteurs de risque du surpoids et de l'obésité et de leurs déterminants chez les enfants d'âge préscolaire. Nos analyses montrent que le statut de migrant des parents et leur niveau d'éducation influencent indépendamment l'un de l'autres l'adiposité et les habitudes alimentaires chez ces enfants. De plus, à ce jeune âge la participation dans un club de sport semble être un meilleur indicateur de style de vie sain en termes d'activité physique, de comportements sédentaires et d'habitudes alimentaires que le statut pondéral. Nous avons également trouvé que dans cette population, un score plus élevé d'hyperactivité/inattention est associé aussi bien à des caractéristiques de style de vie saines (plus d'activité physique, moins d'activité sédentaire) que malsaines (plus de consommation de télévision et moins bonnes habitudes alimentaire. Ainsi, nos résultats peuvent aider les différents acteurs de la santé et de l'éducation à mieux cibler leurs actions de prévention et servir de base à de futures recherches complémentaires.

Pancreatic-specific expression of the glucose transporter type 2 gene: identification of cis-elements and islet-specific trans-acting factors.

A defect in glucose sensing of the pancreatic beta-cells has been observed in several animal models of type II diabetes and has been correlated with a reduced gene expression of the glucose transporter type 2 (Glut2). In a transgenic mouse model, expression of Glut2 antisense RNA in pancreatic beta-cells has recently been shown to be associated with an impaired glucose-induced insulin secretion and the development of diabetes. To identify factors that may be involved in the specific decrease of Glut2 in the beta-cells of the diabetic animal, an attempt was made to localize the cis-elements and trans-acting factors involved in the control of Glut2 expression in the endocrine pancreas. It was demonstrated by transient transfection studies that only 338 base pairs (bp) of the murine Glut2 proximal promoter are needed for reporter gene expression in pancreatic islet-derived cell lines, whereas no activity was detected in nonpancreatic cells. Three cis-elements, GTI, GTII, and GTIII, have been identified by DNAse I footprinting and gel retardation experiments within these 338 bp. GTI and GTIII bind distinct but ubiquitously expressed trans-acting factors. On the other hand, nuclear proteins specifically expressed in pancreatic cell lines interact with GTII, and their relative abundance correlates with endogenous Glut2 expression. These GTII-binding factors correspond to nuclear proteins of 180 and 90 kilodaltons as defined by Southwestern analysis. The 180-kilodalton factor is present in pancreatic beta-cell lines but not in an alpha-cell line. Mutation of the GTI or GTIII cis-elements decreases transcriptional activity directed by the 338-bp promoter, whereas mutation of GTII increases gene transcription. Thus negative and positive regulatory sequences are identified within the proximal 338 bp of the GLUT2 promoter and may participate in the islet-specific expression of the gene by binding beta-cell specific trans-acting factors.