Longitudinal study of repeated sprint performance in youth soccer players of contrasting skeletal maturity status

The purpose of the study was to evaluate the developmental changes in performance in a repeated-sprint ability (RSA) test in young soccer players of contrasting maturity status. A total of 83 regional level Portuguese youth soccer players, aged 11-13 years at baseline was assessed annually. Stature, body mass, 7x34.2-m sprint protocol (25-s active recovery), 20-m multi-stage continuous shuttle endurance run and counter-movement jump (CMJ) without the use of the arms were measured. Fat-free mass (FFM) was determined by age and gender-specific formulas. Developmental changes in total sprint time across ages were predicted using multilevel modeling. Corresponding measurements were performed on an independent cross-sectional sub-sample of 52 youth soccer players 11-17 years to evaluate the predictive model. CA, CA(2), maturational status (SA-CA), body size (mass and stature), FFM, aerobic endurance, lower limb explosive strength and annual volume training significantly improved the statistical fit of the RSA multilevel model. In 'late' maturing athletes, the best model for predicting change in RSA was expressed by the following equation: 86.54 - 2.87 x CA + 0.05 x CA(2) - 0.25 x FFM + 0.15 x body mass + 0.05 x stature - 0.05 x aerobic endurance - 0.09 x lower limb explosive strength - 0.01 x annual volume training. The best fitting models for players who were 'on time' and 'early' maturing were identical to the best model for late maturing players, less 0.64 seconds and 1.74 seconds, respectively. Multilevel modeling provided performance curves that permitted the prediction of individual RSA performance across adolescent years in regional level soccer players

Requirements for generic anti-epileptic medicines: a regulatory perspective

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Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

The Complete Genome Sequence of Thermoproteus tenax: A Physiologically Versatile Member of the Crenarchaeota

Here, we report on the complete genome sequence of the hyperthermophilic Crenarchaeum Thermoproteus tenax (strain Kra 1, DSM 2078(T)) a type strain of the crenarchaeotal order Thermoproteales. Its circular 1.84-megabase genome harbors no extrachromosomal elements and 2,051 open reading frames are identified, covering 90.6% of the complete sequence, which represents a high coding density. Derived from the gene content, T. tenax is a representative member of the Crenarchaeota. The organism is strictly anaerobic and sulfur-dependent with optimal growth at 86 degrees C and pH 5.6. One particular feature is the great metabolic versatility, which is not accompanied by a distinct increase of genome size or information density as compared to other Crenarchaeota. T. tenax is able to grow chemolithoautotrophically (CO2/H-2) as well as chemoorganoheterotrophically in presence of various organic substrates. All pathways for synthesizing the 20 proteinogenic amino acids are present. In addition, two presumably complete gene sets for NADH:quinone oxidoreductase (complex I) were identified in the genome and there is evidence that either NADH or reduced ferredoxin might serve as electron donor. Beside the typical archaeal A(0)A(1)-ATP synthase, a membrane-bound pyrophosphatase is found, which might contribute to energy conservation. Surprisingly, all genes required for dissimilatory sulfate reduction are present, which is confirmed by growth experiments. Mentionable is furthermore, the presence of two proteins (ParA family ATPase, actin-like protein) that might be involved in cell division in Thermoproteales, where the ESCRT system is absent, and of genes involved in genetic competence (DprA, ComF) that is so far unique within Archaea

Response to tricyclic antidepressants: independent of gender?

OBJECTIVE: The authors examined gender differences in response to tricyclic antidepressants. METHOD: A total of 30 randomized, placebo-controlled trials that included 3,886 patients (1,555 men and 2,331 women), submitted between 1979 and 1991 in order to obtain marketing authorization, were reviewed. Gender differences in response to treatment were tested in various multiple regression models using a variety of response definitions. RESULTS: Different response definitions all pointed to no gender difference in the efficacy of tricyclic antidepressants. The estimated effect size was similar for women younger and older than age 50 and for men. CONCLUSIONS: Tricyclic antidepressant response is independent of gende

Switching to generic anti-epileptic medicines:A regulatory perspective

Introduction: Currently, there is a lot of discussion about whether generic substitution of anti-epileptic drugs (AEDs) with the same active moiety but from different manufacturers can take place safely. Many AEDs are considered to have a narrow therapeutic index, and the consequences of an epileptic attack are severe, in a physical, psychological and social respect. Therefore, there is ample ground to look critically at generic substitution of anti-epileptic medicines. In this context, the Dutch regulatory agency evaluated the exposureof generic AEDs and the occurrence of epilepsy related events. Methods: Reports received by the Dutch Pharmacovigilance Centre Lareb were screened for issues related to generic substitution of AEDs. Public literature dealing with generic substitution of AEDs was reviewed and checked for potential pharmacological issues related to generic substitution of AEDs. Finally, the exposures upon changing between different topiramate and gabapentin generics was evaluated based on internal bioequivalence data. Results: In only 26 of in total 2,103 reports in the Lareb database mentioning an AED as the suspected drug, a possible relationship was indicated with the substitution from a branded AED to a generic one. However, these data should be treated with care, since underreporting is a well-known phenomenon. The majority of publications on generic substitution of AEDs concerned potential instead of actual cases, with many publications based on surveys regarding prescribers' overall experience with switching. Potential issues raised in these publications relate to bioequivalence requirements, use of healthy volunteers instead of patients, variability in exposure, problems with medicine supply, and costs of adverse events. Overall, with very few exceptions, no differences in exposure upon generic substitution of AEDs were actually reported. Generic-generic substitution was also indicated as a potential problem. However, our investigations on topiramate and gabapentin generic-generic substitution indicated that this does not result in significant differences in exposure. Estimated ratios of AUC and Cmax upon substituting generics ranged from 94.1-113.1% and 91.2-103.1% for topiramate and from 95.6-114.9% and 92.5 111.5% for gabapentin, respectively. Conclusion: Overall, no evidence was found for a causal pharmacological relationship between switching to or between generic AEDs and the occurrence of epilepsy-related adverse events. Based on the strict requirements on generics, pharmacological differences between innovator and generic AEDs are considered unlikely, and have indeed hardly been reported. Alternative explanations for increased susceptibility to seizures with generic AEDs may be envisioned, like e.g., new or withdrawn co-medication, compliance, frequent switching, and differences in shape and colour of generics

Interchangeability of generic anti-epileptic drugs: a quantitative analysis of topiramate and gabapentin.

Item does not contain fulltextPURPOSE: The objective of this study was to determine whether the so-called "shift" or "drift" problem might occur when generic anti-epileptic drugs are interchanged, and thus to assess if generic anti-epileptic drugs are interchangeable and can be used in an efficacious and safe way on the basis of their bioequivalence to one and the same reference product. METHODS: The bioequivalence of topiramate and gabapentin generics was evaluated. For proper interstudy comparison, individual exposure data (AUC and C(max)) for each bioequivalence study present in the registration dossier was normalized based on the absolute exposure data of one of two innovators. The exposure-normalized plasma concentration curves of the generic product arms between studies were compared, providing indirect evidence of bioequivalence of the different generics. Additionally, comparisons were made for generic-generic as well as innovator-innovator exchange based on absolute exposure data from individual bioequivalence studies. RESULTS: In almost all cases, estimated 90% confidence intervals of the AUC and C(max) ratios for generic-generic interchange were within the routine 80-125% criterion. When absolute, non-corrected exposure data were used for this interstudy comparison, in a number of cases 90% confidence intervals outside the 80-125% criterion were found upon interchanging generics from two studies. However, a similar pattern of 90% confidence intervals outside the 80-125% criterion was observed for the comparison of innovator arms, despite the fact that the innovator was identical in all studies. CONCLUSION: Our results strongly indicate that the so-called drifting problem upon generic-generic substitution does not result in important differences in exposure upon exchanging topiramate generics or gabapentin generics.01 oktober 201