The influence of time-of-day consumption and training status on the ergogenic properties of caffeine

Purpose: The objectives were to determine the effects of time-of-day consumption and training status on the benefits of caffeine supplementation for cycling performance and peak muscle strength. METHODS: Twenty untrained and trained subjects completed four trials consisting of isokinetic peak torque testing and 3-km time trials (TT). Subjects ingested either 6 mg/kg of caffeine or a placebo one hour prior to each trial. Treatments were: morning + placebo, morning + caffeine, evening + placebo, evening + caffeine. Magnitude based inferences were used to evaluate treatment differences. RESULTS: Caffeine (‘very likely’ and ‘likely’) improved 3-km TT performance in the morning and evening. 3-km TT performance was ‘likely’ improved more in the morning than evening for total subject pool and trained subjects. Untrained subjects ‘likely’ benefited more during the 3-km TT from supplementation than trained in both the morning and evening. Caffeine supplementation was ‘likely’ trivial and ‘unclear’ for the majority of peak muscle strength conditions. CONCLUSIONS: Caffeine supplementation improved 3-km TT performance in the morning for trained and untrained, with lesser benefits in the evening, while untrained benefited more than trained. Peak muscle strength was largely unaffected by caffeine supplementation, regardless of time-of-day consumption or training status

Maximum likelihood estimation of reviewers' acumen in central review setting: categorical data

Successfully evaluating pathologists' acumen could be very useful in improving the concordance of their calls on histopathologic variables. We are proposing a new method to estimate the reviewers' acumen based on their histopathologic calls. The previously proposed method includes redundant parameters that are not identifiable and results are incorrect. The new method is more parsimonious and through extensive simulation studies, we show that the new method relies less on the initial values and converges to the true parameters. The result of the anesthetist data set by the new method is more convincing

A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study.

High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, ependymoma, and high-grade glioma (HGG) undergoing resection were stratified and randomized to pre-resection treatment with lapatinib 900 mg/m(2) dose bid for 7-14 days or no treatment. Western blot analysis of ERBB expression and pathway activity in fresh tumor obtained at surgery estimated ERBB receptor signaling inhibition in vivo. Drug concentration was simultaneously assessed in tumor and plasma. In the phase II study, patients, stratified by histology, received lapatinib continuously, to assess sustained response. Eight patients, on the MB trial (four medulloblastomas, four ependymomas), received a median of two courses (range 1-6+). No intratumoral target inhibition by lapatinib was noted in any patient. Tumor-to-plasma ratios of lapatinib were 10-20 %. In the 34 patients (14 MB, 10 HGG, 10 ependymoma) in the phase II study, lapatinib was well-tolerated at 900 mg/m(2) dose bid. The median number of courses in the phase II trial was two (range 1-12). Seven patients (three medulloblastoma, four ependymoma) remained on therapy for at least four courses range (4-26). Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.Fil: Fouladi, Maryam. St. Jude Children’s Research Hospital; Estados UnidosFil: Stewart, Clinton F.. St. Jude Children’s Research Hospital; Estados UnidosFil: Blaney, Susan M.. Baylor College of Medicine. Texas Children’s Cancer Center; Estados UnidosFil: Onar Thomas, Arzu. St. Jude Children’s Research Hospital; Estados UnidosFil: Schaiquevich, Paula Susana. St. Jude Children’s Research Hospital; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Packer, Roger J.. Children’s National Medical Center; Estados UnidosFil: Goldman, Stewart. Anne and Robert H. Lurie Children’s Hospital of Chicago; Estados UnidosFil: Geyer, J. Rusell. Children’s Hospital and Regional Medical Center; Estados UnidosFil: Gajjar, Amar. St. Jude Children’s Research Hospital; Estados UnidosFil: Kun, Larry E.. St. Jude Children’s Research Hospital; Estados UnidosFil: Boyett, James M.. St. Jude Children’s Research Hospital; Estados UnidosFil: Gilbertson, Richard J.. St. Jude Children’s Research Hospital; Estados Unido

Cytokine Response to Traditional and Cluster Sets in Resistance-trained Women

Resistance exercise that incorporates intra-set rest between repetition blocks (i.e., cluster sets [CS]) can produce a smaller metabolic stress and endocrine response than traditional sets (TS). PURPOSE: To examine the effect of CS on the acute cytokine response in resistance trained women. METHODS: 12 resistance-trained women (mean ± SE; 23.7 ± 1.1 years; 160.1 ± 1.5 cm; 62.5 ± 1.7 kg; 5 ± 1 years training) completed 3 sessions in the follicular phase. One-repetition maximum (1RM) back squat (BS) (98.7 ± 4.1 kg), and BS:body mass (1.6 ± 0.1) were determined in Session 1. For Session 2 (3 days post Session 1) and Session 3 (7 days post Session 2), subjects were randomly assigned to either 4 sets of 10 reps with 120 seconds (s) inter-set rest (TS) or 4 x (2 x 5 reps) with 30s intra-set rest and 90s inter-set rest (CS). All performed both protocols at 70% 1RM BS. Instructions were to perform every rep “as explosively as possible”. Blood was collected pre-exercise (PRE), immediately after sets 1, 2, 3, 4 (IP), and at 5 (+5), 15 (+15), 30 (+30), and 60 (+60) min post-exercise and analyzed for interleukin (IL)-1β, IL-2, IL-6, IL-8, IL 10, and IL-15. Data were analyzed using repeated measures ANOVAs (2 × 9). RESULTS: A significant main effect of time (p\u3c0.05) was found for IL-1β, IL-2, IL-8, IL-10, and IL-15. Concentration of IL-1β was smaller at +5 (3.9 ± 0.4 ng/mL), +15 (3.6 ± 0.4) +30 (3.5 ± 0.3), and +60 (3.7 ± 0.4) compared to IP (4.1 ± 0.4). IL-2 was greater after set 1 (10.8 ± 1.0 ng/mL), and set 2 (11.0 ± 1.2) compared to PRE (10.2 ± 1.0), and smaller at +30 (9.9 ± 1.0) compared to IP (11.0 ± 1.0). IL-8 was greater after set 1 (8.4 ± 0.6 ng/mL), set 2 (8.6 ± 0.7), and set 3 (8.5 ± 0.7) compared to PRE (8.0 ± 0.6). IL-10 was smaller at +30 (31.3 ± 7.4 ng/mL) compared to PRE (34.0 ± 7.4), and also smaller at +15 (32.6 ± 7.9) +30 (31.3 ± 7.4), and +60 (33.4 ± 8.6) compared to IP (38.0 ± 8.6). IL-15 was greater at IP (15.5 ± 4.0 ng/mL) compared to PRE (13.4 ± 3.5), and smaller at PRE (13.4 ± 3.5), +30 (11.9 ± 3.3), and +60 (11.6 ± 3.2) compared to IP (15.5 ± 4.0). No condition × time point effects were observed. CONCLUSION: Both TS and CS induced an acute cytokine response in resistance-trained women; incorporating intra-set rest (CS) did not appear to affect this cytokine response

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p < 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Morphological Substrates for Atria Arrhythmogenesis in a Heart With Atrioventricular Septal Defect

Due to advances in corrective surgery, congenital heart disease has an ever growing patient population. Atrial arrhythmias are frequently observed pre- and post-surgical correction. Pharmaceutical antiarrhythmic therapy is not always effective, therefore many symptomatic patients undergo catheter ablation therapy. In patients with atrioventricular septal defects (AVSD), ablation therapy itself has mixed success; arrhythmogenic recurrences are common, and because of the anatomical displacement of the atrioventricular node, 3-degree heart block post-ablation is a real concern. In order to develop optimal and safe ablation strategies, the field of congenital cardiac electrophysiology must combine knowledge from clinical electrophysiology with a thorough understanding of the anatomical substrates for arrhythmias. Using image-based analysis and multi-cellular mathematical modeling of electrical activation, we show how the anatomical alterations characteristic of an AVSD serve as arrhythmogenic substrates. Using ex-vivo contrast enhanced micro-computed tomography we imaged post-mortem the heart of a 5 month old male with AVSD at an isometric spatial resolution of 38 μm. Morphological analysis revealed the 3D disposition of the cardiac conduction system for the first time in an intact heart with this human congenital malformation. We observed displacement of the compact atrioventricular node inferiorly to the ostium of the coronary sinus. Myocyte orientation analysis revealed that the normal arrangement of the major atrial muscle bundles was preserved but was modified in the septal region. Models of electrical activation suggest the disposition of the myocytes within the atrial muscle bundles associated with the “fast pathway,” together with the displaced atrioventricular node, serve as potential substrates for re-entry and possibly atrial fibrillation. This study used archived human hearts, showing them to be a valuable resource for the mathematical modeling community, and opening new possibilities for the investigations of arrhythmogenesis and ablation strategies in the congenitally malformed heart

A statistical framework to evaluate virtual screening

<p>Abstract</p> <p>Background</p> <p>Receiver operating characteristic (ROC) curve is widely used to evaluate virtual screening (VS) studies. However, the method fails to address the "early recognition" problem specific to VS. Although many other metrics, such as RIE, BEDROC, and pROC that emphasize "early recognition" have been proposed, there are no rigorous statistical guidelines for determining the thresholds and performing significance tests. Also no comparisons have been made between these metrics under a statistical framework to better understand their performances.</p> <p>Results</p> <p>We have proposed a statistical framework to evaluate VS studies by which the threshold to determine whether a ranking method is better than random ranking can be derived by bootstrap simulations and 2 ranking methods can be compared by permutation test. We found that different metrics emphasize "early recognition" differently. BEDROC and RIE are 2 statistically equivalent metrics. Our newly proposed metric SLR is superior to pROC. Through extensive simulations, we observed a "seesaw effect" – overemphasizing early recognition reduces the statistical power of a metric to detect true early recognitions.</p> <p>Conclusion</p> <p>The statistical framework developed and tested by us is applicable to any other metric as well, even if their exact distribution is unknown. Under this framework, a threshold can be easily selected according to a pre-specified type I error rate and statistical comparisons between 2 ranking methods becomes possible. The theoretical null distribution of SLR metric is available so that the threshold of SLR can be exactly determined without resorting to bootstrap simulations, which makes it easy to use in practical virtual screening studies.</p

Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts

<p>Abstract</p> <p>Background</p> <p>Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordance among five neuropathologists and the prognostic utility of histopathological variables, particularly tumor grading.</p> <p>Results</p> <p>In phase 1, using WHO criteria and without first discussing any issue related to grading ependymomas, pathologists assessed and independently graded ependymomas from 3 of 4 trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III, a difference that increased when one cohort (CNS9204) was reassessed in phase 2, during which the pathologists discussed ependymoma grading, jointly reviewed all CNS9204 tumors, and defined a novel grading system based on the WHO classification. In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading. Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904. Strength of consensus on grade was significantly associated with PFS in only one trial cohort (AIEOP). Consensus on the scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) correlated with PFS in AIEOP, but in no other trial.</p> <p>Conclusions</p> <p>We conclude that concordance on grading ependymomas can be improved by using a more prescribed scheme based on the WHO classification. Unfortunately, this appears to have utility in limited clinical settings.</p

Time of Day and Training Status Both Impact the Efficacy of Caffeine for Short Duration Cycling Performance

This project was designed to assess the effects of time of day and training status on the benefits of caffeine supplementation for cycling performance. Twenty male subjects (Age, 25 years; Peak oxygen consumption, 57 mL·kg−1·min−1) were divided into tertiles based on training levels, with top and bottom tertiles designated as ‘trained’ (n = 7) and ‘untrained’ (n = 7). Subjects completed two familiarization trials and four experimental trials consisting of a computer-simulated 3-km cycling time trial (TT). The trials were performed in randomized order for each combination of time of day (morning and evening) and treatment (6mg/kg of caffeine or placebo). Magnitude-based inferences were used to evaluate all treatment effects. For all subjects, caffeine enhanced TT performance in the morning (2.3% ± 1.7%, ‘very likely’) and evening (1.4% ± 1.1%, ‘likely’). Both untrained and trained subjects improved performance with caffeine supplementation in the morning (5.5% ± 4.3%, ‘likely’; 1.0% ± 1.7%, ‘likely’, respectively), but only untrained subjects rode faster in the evening (2.9% ± 2.6%, ‘likely’). Altogether, our observations indicate that trained athletes are more likely to derive ergogenic effects from caffeine in the morning than the evening. Further, untrained individuals appear to receive larger gains from caffeine in the evening than their trained counterparts