Objectively-measured and self-reported physical activity and fitness in relation to inflammatory markers in European adolescents: the HELENA Study

ObjectiveAtherogenesis involves an inflammatory process that occurs early in life even though clinical symptoms are not observed until adulthood. Two important protective factors for low-grade inflammation may be physical activity (PA) and fitness. We examined the independent associations of objective and subjective measurements of PA and fitness with low-grade inflammation in European adolescents.MethodsA total of 1045 adolescents, aged from 12.5 to 17.5 years old from 10 European cities, were selected from the HELENA-Cross-Sectional Study. Objectively-measured and self-reported PA variables were obtained by accelerometry and the International PA Questionnaire for Adolescents, respectively. Overall, cardiorespiratory, muscular and motor fitness variables were assessed by standardized field-based fitness tests and the International Fitness Scale. C-reactive protein (CRP), complement factors 3 (C3) and 4 (C4), interleukin-6 and TNF-α inflammatory markers were measured.ResultsObjectively-measured vigorous PA was inversely associated with C3 (β = ?0.094, P = 0.021) but it did not remain significant after any objective fitness indicator was included in the model. Other objectively measured or self-reported assessments of PA were not significantly associated with inflammatory markers. All objective measures of fitness were inversely associated with CRP, C3 and C4, whereas only self-reported motor fitness remained significantly associated with C3, C4 and TNF-α. All these observations were independent of age, sex, city and body mass index or waist circumference.ConclusionHigh PA in adolescence may play an indirect role on lessening low-grade inflammation through improvements in fitness.     

Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane. ALDP deficiency results in impaired peroxisomal β-oxidation and the subsequent accumulation of very long-chain fatty acids (VLCFA; > C22:0) in plasma and tissues. VLCFA are primarily derived from endogenous synthesis by ELOVL1. Therefore inhibiting this enzyme might constitute a feasible therapeutic approach. In this paper we demonstrate that bezafibrate, a PPAR pan agonist used for the treatment of patients with hyperlipidaemia reduces VLCFA levels in X-ALD fibroblasts. Surprisingly, the VLCFA-lowering effect was independent of PPAR activation and not caused by the increase in either mitochondrial or peroxisomal fatty acid β-oxidation capacity. In fact, our results show that bezafibrate reduces VLCFA synthesis by decreasing the synthesis of C26:0 through a direct inhibition of fatty acid elongation activity. Taken together, our data indicate bezafibrate as a potential pharmacotherapeutic treatment for X-ALD. A clinical trial is currently ongoing to evaluate the effect in patients with X-ALD.     

Age-related loss of cardiac preconditioning: impact of protein kinase A

Helium induces preconditioning (He-PC) by mitochondrial calcium-sensitive potassium (mK_Ca) channel-activation, but this effect is lost in the aged myocardium. Both, the upstream signalling pathway of He-PC and the underlying mechanisms for an age-related loss of preconditioning are unknown. A possible candidate as upstream regulator of mK_Ca channels is protein kinase A (PKA).We investigated whether 1) regulation of PKA is involved in He-PC and 2) regulation of PKA is age-dependent.Young (2-3 months) and aged (22-24 months) Wistar rats were randomised to eight groups (each n = 8). All animals underwent 25 min regional myocardial ischemia and 120 min reperfusion. Control (Con, Age Con) animals were not further treated. Young rats inhaled 70% helium for 3 × 5min (He-PC). The PKA-blocker H-89 (10 μg/kg) was administered with and without helium (He-PC + H-89, H-89). Furthermore, we tested the effect of direct activation of mK_Ca channels with NS1619. The adenylyl cyclase activator forskolin (For) was administered in young (300 μg/kg) and aged animals (300 and 1000 μg/kg).He-PC reduced infarct size from 60 ± 4% (Con) to 37 ± 10% (p < 0.05). Infarct size reduction was completely abolished by H-89 (58 ± 5%; p < 0.05), but H-89 alone had no effect (57 ± 2%). NS1619 reduced infarct size in the same concentration in both, young and aged rats (35 ± 6%; p < 0.05 vs. Con and 34 ± 8%; p < 0.05 vs. Age Con). Forskolin in a concentration of 300 μg/kg reduced infarct size in young (37 ± 6%; p < 0.05) but not in aged rats (48 ± 13%; n.s.). In contrast, 1000 μg/kg Forskolin reduced infarct size also in aged rats (28 ± 3%; p < 0.05).He-PC is mediated by activation of PKA. Alterations in PKA regulation might be an underlying mechanism for the age-dependent loss of preconditioning.     

The pediatric surgeon's road to research independence: utility of mentor-based National Institutes of Health grants

Background

The current research environment for academic surgeons demands that extramural funding be obtained. Financial support from the National Institutes of Health (NIH) is historically the gold standard for funding in the biomedical research community, with the R01 funding mechanism viewed as indicator of research independence. The NIH also supports a mentor-based career development mechanism (K-series awards) in order to support early-stage investigators. The goal of this study was to investigate the grants successfully awarded to pediatric surgeon-scientists and then determine the success of the K-series award recipients at achieving research independence.

Methods

In July 2012, all current members of the American Pediatric Surgery Association (APSA) were queried in the NIH database from 1988–2012 through the NIH Research Portfolio Online Reporting Tools. The following factors were analyzed: type of grant, institution, amount of funding, and funding institute or center.

Results

Among current APSA members, there have been 83 independent investigators receiving grants, representing 13% of the current APSA membership, with 171 independent grants funded through various mechanisms. Six percent currently have active NIH funding, with $7.2 million distributed in 2012. There have been 28 K-series grants awarded. Of the recipients of expired K08 awards, 39% recipients were subsequently awarded an R01 grant. A total of 63% of these K-awarded investigators transitioned to an independent NIH award mechanism.

Conclusions

Pediatric surgeon-scientists successfully compete for NIH funding. Our data suggest that although the K-series funding mechanism is not the only path to research independence, over half of the pediatric surgeons who receive a K-award are successful in the transition to independent investigator.