Health-related fitness assessment in childhood and adolescence: a European approach based on the AVENA, EYHS and HELENA studies

Results from cross-sectional and longitudinal studies such as Alimentación y Valoración del Estado Nutricional en Adolescentes: Food and Assessment of the Nutritional Status of Spanish Adolescents (AVENA) and the European Youth Heart Study (EYHS) respectively, highlight physical fitness as a key health marker in childhood and adolescence. Moderate and vigourous levels of physical activity stimulate functional adaptation of all tissues and organs in the body (i.e. improve fitness), thereby also making them less vulnerable to lifestyle-related degenerative and chronic diseases. To identify children and adolescents at risk for these major public health diseases and to be able to evaluate the effects of alternative intervention strategies in European countries and internationally, comparable testing methodology across Europe has to be developed, tested, agreed upon and included in the health monitoring systems currently under development by the European Commission (EC): the Directorate General for Health and Consumer Affairs (DG SANCO); the Statistical Office of the European Communities (EUROSTAT), etc. The Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study group plans, among other things, to describe the health-related fitness of adolescents in a number of European countries. Experiences from AVENA and EYHS will be taken advantage of. This review summarises results and experiences from the developmental work so far and suggests a set of health-related fitness tests for possible use in future health information systems.On behalf of the HELENA Study Group     

A dropout analysis of the second phase of the Swedish part of the European Youth Heart Study

The European Youth Heart Study (EYHS) addresses cardiovascular disease risk factors and their determinants in European children and adolescents. The Swedish part of the study began with cross-sectional data collection in 9- and 15-year-old schoolchildren in 1998–1999 (EYHS-I). Repeated observations of the key indicators were performed in 2004–2005 (EYHS-II). The purpose of this study was to assess potential dropout effects in EYHS-II. Participants in both EYHS-I and EYHS-II (n=459) were compared with dropouts who participated only in the EYHS-I (n=678) in relation to baseline physical activity, cardiorespiratory fitness and socioeconomic and anthropometric characteristics. Bivariate comparisons were performed using chi-square tests and gamma tests for nominal and ordinal data, respectively. Continuous data were compared by t tests and Mann−Whitney tests depending on the distribution. The Bonferroni correction was used to control for multiple hypothesis testing. Multiple logistic regression with backward elimination of variables was applied to study independent effects of variables on the probability of becoming a dropout. Analyses were performed separately for the younger and older age groups. The dropout proportion in EYHS-II was 60%. Subjects from the older age group were less likely to participate in the follow-up study (32% vs. 50%, p<0.001). In bivariate analyses, only maternal education was associated with dropout rates in the younger age group after Bonferroni correction. Males were more likely to drop out in both younger [odds ratio (OR)=1.72; 95% confidence interval (CI): 1.10, 2.96] and older (OR=1.96; 95% CI: 1.09, 3.54) age groups while basic maternal education was associated with outcome only in the younger group (OR=4.31; 95% CI: 1.78, 2.95) in regression analysis. The Swedish EYHS-II had high dropout rate after EYHS-I, but the dropouts did not differ from the participants in relation to physical activity, physical fitness, and anthropometric indices. Males were more likely to drop out than were females in both age groups. Differential dropout in relation to maternal education was observed in the younger age group.     

Increased liability of tramadol–warfarin interaction in individuals with mutations in the cytochrome<Emphasis Type="Italic"> P</Emphasis><Subscript>450</Subscript> 2D6 gene

Objective This study aimed to investigate the importance of cytochrome P₄₅₀ enzymes for the reported interaction between tramadol and warfarin.Materials and methods Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.Results Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.Conclusion The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.     

Drug block of I(kr): model systems and relevance to human arrhythmias

The long QT-related arrhythmia torsades de pointes (TdP) can arise with mutations in HERG and during treatment with drugs that block cardiac I Kr, the current encoded by HERG. Multiple test systems have been used to assess drug block of I Kr. This study evaluated the I Kr blocking potency of a series of antiarrhythmics associated with a range of clinical risks of TdP in two such systems: mouse AT-1 cells (in which I Kr is the major repolarizing current) and Ltk cells transiently transfected with HERG (n = 4-10 cells per drug). For each compound, the concentration required to produce 50% block of I Kr or HERG tail currents (IC 50 ) was determined. There was an excellent correlation ( r = 0.98, p < 10 -5 ) between values obtained in the two systems. However, the relation between the liability of a drug to cause TdP appeared dissociated from I Kr blocking potency. Quinidine, dofetilide, ibutilide, procainamide, and disopyramide are all associated with TdP, but only the first three were potent blockers (IC 50 < or = 1 microM ), whereas procainamide and disopyramide were not (IC 50 > 50 microM ). Conversely, verapamil and amiodarone, drugs not associated with TdP, were also blockers (IC 50 < or = 1 microM ). We conclude that I Kr blocking potency can be readily assessed in either AT-1 cells or systems in which HERG is heterologously expressed. However, not all drugs causing TdP are potent I Kr blockers, and I Kr block is not necessarily associated with TdP. Other properties of these drugs, therefore, contribute to their propensity to cause TdP.     

Effects of a quaternary bupivacaine derivative on delayed rectifier K(+) currents

Block of hKv1.5 channels by R-bupivacaine has been attributed to the interaction of the charged form of the drug with an intracellular receptor. However, bupivacaine is present as a mixture of neutral and charged forms both extra- and intracellularly. We have studied the effects produced by the R(+) enantiomer of a quaternary bupivacaine derivative, N-methyl-bupivacaine, (RB(+)1C) on hKv1.5 channels stably expressed in Ltk(-) cells using the whole-cell configuration of the patch-clamp technique. When applied from the intracellular side of the membrane, RB(+)1C induced a time- and voltage-dependent block similar to that induced by R-bupivacaine. External application of 50 microM RB(+)1C reduced the current at +60 mV by 24+/-2% (n=10), but this block displayed neither time- nor voltage-dependence. External RB(+)1C partially relieved block induced by R-bupivacaine (61+/-2% vs 56+/-3%, n=4, P<0.05), but it did not relieve block induced by internal RB(+)1C. In addition, it did not induce use-dependent block, but when applied in combination with internal RB(+)1C a use-dependent block that increased with pulse duration was observed. These results indicate that RB(+)1C induces different effects on hKv1.5 channels when applied from the intra or the extracellular side of the membrane, suggesting that the actions of bupivacaine are the resulting of those induced on the external and the internal side of hKv1.5 channels.     

Efficacy of nerve growth factor in regeneration of the mandibular nerve: a preliminary report.

An experimental study evaluating the potential utility of nerve growth factor (NGF) on sensory nerve regeneration was conducted in a rabbit mandibular nerve model. In 10 animals, bilateral 7-mm nerve gaps were created and repaired with the placement of 10-mm Silastic (American Scientific Products, McGaw Park, IL) conduits into which NGF (left side) and a control solution (cytochrome C, right side) was instilled. After 90 days, the nerve repairs were removed and the two sides compared by clinical appearance, and histologic and electrophysiologic assessment. The conduits instilled with control solution failed to result in nerve regeneration in any of the animals. The conduits with NGF solution, however, consistently displayed neural connections between the proximal and distal ends with the presence of slowed, but recordable, conduction velocities. The axonal numbers in the NGF repairs were significantly less than those of the normal nerve, but when adjusted for fascicular size, the axonal densities were comparable. In addition, osteoid tissue was observed around many of the NGF-induced nerve regenerates, but not on the control solution side, suggesting a possible influence of this protein on bone formation.     

Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome

Voltage-gated K(+) channels control excitability in neuronal and various other tissues. We identified three unique alpha-subunits of voltage-gated K(+)-channels in the human genome. Analysis of the full-length sequences indicated that one represents a previously uncharacterized member of the Kv6 subfamily, Kv6.3, whereas the others are the first members of two unique subfamilies, Kv10.1 and Kv11.1. Although they have all of the hallmarks of voltage-gated K(+) channel subunits, they did not produce K(+) currents when expressed in mammalian cells. Confocal microscopy showed that Kv6.3, Kv10.1, and Kv11.1 alone did not reach the plasma membrane, but were retained in the endoplasmic reticulum. Yeast two-hybrid experiments failed to show homotetrameric interactions, but showed interactions with Kv2.1, Kv3.1, and Kv5.1. Co-expression of each of the previously uncharacterized subunits with Kv2.1 resulted in plasma membrane localization with currents that differed from typical Kv2.1 currents. This heteromerization was confirmed by co-immunoprecipitation. The Kv2 subfamily consists of only two members and uses interaction with "silent subunits" to diversify its function. Including the subunits described here, the "silent subunits" represent one-third of all Kv subunits, suggesting that obligatory heterotetramer formation is more widespread than previously thought.     

HIV‐1 vaccine clinical trials: the Brazilian experience

Although the development of an effective HIV‐1 vaccine has proved very challenging for more than two decades, it remains the best hope to control the HIV pandemic. Since Brazil has particular epidemiological features, as well as adequate policies and infrastructure, the country has been an interesting site for HIV vaccine trials. Since 1995, eight trials were performed in Brazil enrolling over 2000 subjects. Peptide vaccine candidates were initially designed to elicit neutralising antibodies as an attempt to provide sterilising immunity against HIV‐1. This strategy, however, has proved extremely difficult, and candidates were poorly immunogenic. Therefore, the next vaccine candidates focused mainly on the induction of cell mediated immune responses that would limit AIDS progression and transmission by suppressing viremia. Such candidates were naked DNA or viral vectors in either prophylactic or therapeutic approaches. Even though several candidates were immunogenic, protective immune responses against HIV‐1 remain to be achieved. However, several studies with non‐human primates and human elite controllers demonstrate that effective immune responses against HIV‐1 may be elicited, supporting the belief that an HIV‐1 vaccine is possible. Much has been learned, and now the development of an effective HIV‐1 vaccine requires resetting priorities with focus on basic research, considering the merits of neutralising antibodies and CMI, as well as the role of innate immunity on HIV‐1 protection. In this new perspective, large‐scale trials should be replaced by smaller preliminary efficacy studies. Copyright © 2009 John Wiley & Sons, Ltd.