SR 2D micro-XRF imaging on entire rat thin sections in view of a pharmacokinetic study of a new bromine containing drug agains tuberculosis

Tuberculosis (TB) is a common and often deadly infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis in humans. Because of population growth, the absolute number of new cases is still increasing. Multi-drug-resistant tuberculosis (MDR-TB) is defined as resistance to the two most effective first-line TB drugs and is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Recently, a new experimental diarylquinoline anti-tuberculosis drug was discovered at Janssen Pharmaceutica, referred to as TMC207 and shown in Fig. 1. Before TMC207 can be made commercially available, one of the necessary investigations is a thorough pharmacokinetic study to investigate its absorption, distribution, metabolism and excretion (ADME)

Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery

Background-Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Methods and Results-Here, we report that VEGF(partial derivative/partial derivative) mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. Conclusions-These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients. (Circulation. 2010; 122: 273-281.

A life course examination of the physical environmental determinants of physical activity behaviour: A “Determinants of Diet and Physical Activity” (DEDIPAC) umbrella systematic literature review.

Background: Participation in regular physical activity is associated with a multitude of health benefits across the life course. However, many people fail to meet PA recommendations. Despite a plethora of studies, the evidence regarding the environmental (physical) determinants of physical activity remains inconclusive. Objective: To identify the physical environmental determinants that influence PA across the life course. Methods: An online systematic literature search was conducted using MEDLINE, ISI Web of Science, Scopus and SPORTDiscus. The search was limited to studies published in English (January 2004 to April 2016). Only systematic literature reviews (SLRs) and meta-analyses (MAs) of observational studies, that investigated the association between physical determinants and physical activity outcomes, were eligible for inclusion. The extracted data were assessed on the importance of determinants, strength of evidence and methodological quality. Results: The literature search identified 28 SLRs and 3 MAs on 67 physical environmental characteristics potentially related to physical activity that were eligible for inclusion. Among preschool children, a positive association was reported between availability of backyard space and outdoor toys/equipment in the home and overall physical activity. The availability of physical activity programs and equipment within schools, and neighbourhood features such as pedestrian and cyclist safety structure were positively associated with physical activity in children and adolescents. Negative street characteristics, for example, lack of sidewalks and streetlights, were negatively associated with physical activity in adults. Inconsistent associations were reported for the majority of reviewed determinants in adults. Conclusion: This umbrella SLR provided a comprehensive overview of the physical environment determinants of physical activity across the life course and has highlighted, particularly amongst youth, a number of key determinants that may be associated with overall physical activity. Given the limited evidence drawn mostly from cross-sectional studies, longitudinal studies are needed to further explore these associations

An attempt to incorporate flexibility in physics laboratories: laboratory immersion

Non-traditional students in scientific and technological higher education have problems with participating in laboratory sessions. We present a possible solution for the physics practical classes in order to make scientific and technological higher education more flexible and accessible for all students: laboratory immersion.status: publishe

Effect of intensive insulin therapy on the somatotropic axis in critically ill children

INTRODUCTION Critical illness evokes a ‘catabolic’ response within the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Despite improving patient outcome, intensive insulin therapy (IIT) in critically ill adults unexpectedly lowered IGF-I and increased GH, possibly explained by concomitant malnutrition. In the pediatric intensive care unit (PICU), targeting blood glucose levels to age-adjusted normal fasting values also reduced morbidity and mortality, despite increased incidence of (brief) hypoglycemia. Hormonal responses in children may differ from adults and higher amounts of feeding are administered in critically ill children. We therefore hypothesized that IIT in PICU patients could reactivate the somatotropic axis. METHODS This was a pre-planned subanalysis of all 700 pediatric critically ill patients included in a prospective, randomized study on IIT. Patients were randomly assigned to target blood glucose levels of 50-80 mg/dL in infants (age <1 year, n=317) and 70-100 mg/dL in children (age ≥1 year, n=383) with insulin infusion throughout ICU stay (IIT), or to insulin infusion only to prevent blood glucose from exceeding 215 mg/dL (conventional insulin therapy, CIT). We analyzed blood samples taken upon PICU admission, day 3 and day 7 from patients who were still in PICU on these days. In addition, using a nested case-control design, samples taken before and after hypoglycemia were analyzed in 63 patients experiencing hypoglycemia and in 63 matched patients without hypoglycemia. Circulating insulin, C-peptide, GH, IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3 and acid labile subunit (ALS) were determined by radio-immunoassays (RIA). Bio-available IGF-I was quantified using a kinase receptor activation assay. In the nested case-control study, we also quantified circulating cortisol and glucagon. RESULTS On day 3 and day 7, circulating insulin was somewhat higher (p=0.026 and p=0.004) whereas C-peptide was >10-fold lower (all p<0.001) in the IIT group than in the CIT group. On day 3, IIT increased circulating GH (p=0.041), while there was no difference on day 7. Total IGF-I was unaltered. In contrast, bio-available IGF-I was lower on day 3 (p=0.002), but not on day 7, in the IIT group. IIT also decreased IGFBP-3 and ALS levels on day 3 (p=0.001 and p=0.007) and day 7 (p=0.003 and p=0.038) as compared with CIT. In contrast, IGFBP-1 levels were increased by IIT on day 3 only (p=0.044). Multivariate logistic regression analysis suggested that only the lowering of portal insulin, as reflected by C-peptide, may have mediated an important part of the mortality benefit. In the nested case-control study, after “hypoglycemia”, only IGFBP-1 remained high in the cases whereas it decreased in controls (p=0.055). No changes in cortisol or glucagon occurred with hypoglycemia. CONCLUSION While improving outcome of PICU patients, IIT further accentuated the illness-associated ‘catabolic’ response within the somatotropic axis, despite feeding. Too low blood glucose targets may have played a role. However, the elimination of the portal insulin effect by exogenous insulin, as reflected by C-peptide, may also explain the changes within the GH axis. This C-peptide effect appeared to statistically explain at least part of the survival benefit with IIT.status: publishe