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This study aimed to determine the validity and the reliability of the Stages power meter crank system (Boulder, United States) during several laboratory cycling tasks. Eleven trained subjects completed laboratory cycling trials on an indoor cycle fitted with SRM Professional and Stages systems. The trials consisted of an incremental test at 100 W, 200 W, 300 W, 400 W, and four 7-s sprints. The level of pedaling asymmetry was determined for each cycling intensity during a similar protocol completed on a Lode Excalibur Sport ergometer. The reliability of Stages and SRM power meters was compared by repeating the incremental test during a test-retest protocol on a Cyclus 2 ergometer. Over power ranges of 100-1,250 W, the Stages system produced trivial to small differences compared with the SRM (standardized typical error values of 0.06, 0.24, and 0.08 for the incremental, sprint, and combined trials, respectively). A large correlation was reported between the difference in power output (PO) between the 2 systems and the level of pedaling asymmetry (r = 0.58, p < 0.001). Recalculating PO of the Stages system according to the level of pedaling asymmetry provided only marginal improvements in PO measures. The reliability of the Stages power meter at the submaximal intensities was similar to the SRM Professional model (coefficient of variation: 2.1 and 1.3% for Stages and SRM, respectively). The Stages system is a suitable device for PO measurements, except when a typical error of measurement <3.0% over power ranges of 100-1,250 W is expected. [ABSTRACT FROM AUTHOR]

Introduction: Elite athletes frequently undergo periods of intensified training (IT) within their normal training program. These periods can lead athletes into functional overreaching, characterized by high perceived fatigue, impaired sleep, and performance. Because whole-body cryostimulation (WBC) has been proven to be an effective recovery method in the short term (<76 h), we investigated whether daily WBC sessions during IT could prevent exercise and sleep-related signs of overreaching. Methods: After a normal training week (BASE), 10 elite synchronized swimmers performed two 2-wk IT periods in a randomized crossover fashion using WBC daily (ITWBC) or not (ITCON). separated by 9 d of light training. Swim time trials (400 m) were performed at BASE and after each IT to quantify blood lactate ([La-]B), HR (HR400), salivary alpha amylase ([α-amylase] s400), and cortisol ([cortisol] s400) responses. Swimmers wore a wrist actigraph nightly to monitor sleep patterns. Results: Swim speed (400 m), [La-]s400, and [α-amylase]s400 decreased from BASE to ITCON, although no significant changes were found after ITWBC- Decreased swim speed was correlated to decreased HR400 and [cortisol]s400. During ITCON, significant decreases in actual sleep duration (-21 ±7 min) and sleep efficiency (-1.9% ± 0.8%) were observed, with increased sleep latency (+11 ± 5 min) and fatigue compared with BASE, although these variables did not change during ITWBC. Using a qualitative statistical analysis, we observed that daily WBC use resulted in a 98%, 59%, 66%, and 78% chance of preserving these respective variables compared with ITCON- Conclusion: WBC use during IT helped mitigate the signs of functional overreaching observed during ITCON such as reduced sleep quantity, increased fatigue, and impaired exercise capacity. These results support the daily use of WBC by athletes seeking to avoid functional overreaching during key periods of competition preparation. [ABSTRACT FROM AUTHOR]

Background: Renal cancer accounts for 3% of adult malignancies; renal cell carcinoma (RCC) represents 80% of all renal cancers, and is characterized by late recurrences. Recurrences after kidney transplantation are associated with a high mortality rate. We aimed to determine if recurrences are linked to tumor characteristics and to delays between diagnosis and transplantation., Methods: We retrospectively analyzed data from French kidney-transplanted patients with medical histories of pretransplant renal cancer, focusing on the most common histological subtypes: clear cell and papillary cancers. Characteristics of the tumors, patients, and kidney transplantations were documented, and posttransplant patient survival was analyzed., Results: Of 143 patients, 13 experienced cancer recurrence after kidney transplantation. The mean delay in recurrence was 3 ± 2.3 years posttransplantation, and the cumulative incidences of recurrence were 7.7% at 5 years and 14.9% at 10 years. The risk of recurrence was higher in patients with clear cell RCC (13% vs 0%, P = 0.015). There was no correlation between posttransplant recurrence and the interval before transplantation. Factors associated with a higher risk of cancer recurrence were histological clear cell RCC (P = 0.025), tumor stage pT2 (P = 0.002), and Fuhrman grade IV (P < 0.001). Recurrences were associated with a high mortality rate; 76.9% of patients with recurrences had died by the end of the follow-up period., Conclusions: Recurrences of clear cell RCC are not uncommon after kidney transplantation and are associated with very poor prognoses. These results should be considered before listing patients with a history of renal cancer for transplantation.

Purpose: We analyzed HR variability (HRV) to detect alterations in autonomic function that may be associated with functional overreaching (F-OR) in endurance athletes., Methods: Twenty-one trained male triathletes were randomly assigned to either intensified training (n = 13) or normal training (n = 8) groups during 5 wk. HRV measures were taken daily during a 1-wk moderate training (baseline), a 3-wk overload training, and a 1-wk taper., Results: All the subjects of the intensified training group demonstrated a decrease in maximal incremental running test performance at the end of the overload period (-9.0% ± 2.1% of baseline value) followed by a performance supercompensation after the taper and were therefore diagnosed as F-OR. According to a qualitative statistical analysis method, a likely to very likely negative effect of F-OR on HR was observed at rest in supine and standing positions, using isolated seventh-day values and weekly average values, respectively. When considering the values obtained once per week, no clear effect of F-OR on HRV parameters was found. In contrast, the weekly mean of each HRV parameter showed a larger change in indices of parasympathetic tone in the F-OR group than the control group in supine position (with a 96%/4%/0% chance to demonstrate a positive/trivial/negative effect on Ln RMSSD after the overload period; 77%/22%/1% on LnHF) and standing position [98%/1%/1% on Ln RMSSD; 99%/0%/1% on LnHF; 95%/1%/4% on Ln(LF + HF)]. During the taper, theses responses were reversed., Conclusions: Using daily HRV recordings averaged over each week, this study detected a progressive increase in the parasympathetic modulation of HR in endurance athletes led to F-OR. It also revealed that due to a wide day-to-day variability, isolated, once per week HRV recordings may not detect training-induced autonomic modulations in F-OR athletes.

Mycophenolic acid (MPA) is metabolized primarily by glucuronidation to form the biologically inactive 7-O-glucuronide conjugate (MPAG), which is the major urinary excretion product. MPA is also converted to acyl-glucuronide metabolite (AcylMPAG), which has been suggested to be involved in the generation of MPA-related adverse events such as diarrhea or leucopenia. This conversion of MPA to AcylMPAG is catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). We studied the impact of the -840G>A polymorphisms in the UGT2B7 gene on the pharmacokinetics of AcylMPAG. We also investigated whether the plasma concentrations of AcylMPAG are correlated with MPA-related toxicity to further evaluate its potential clinical significance. In a randomized, controlled trial, comparing fixed-dose mycophenolate mofetil (MMF) with concentration-controlled MMF therapy, patients undergoing renal transplantation were treated with a calcineurin inhibitor, MMF, and corticosteroids. Informed consent was obtained from 332 patients for genotyping. In all patients, blood samples were drawn (three samples within the first 2 hours after administration) on Day 3, Day 10, Week 4, and Months 3, 6, and 12 to measure MPA and AcylMPAG plasma concentrations. The pharmacokinetics of AcylMPAG were correlated with the -840G>A single nucleotide polymorphism (SNP) in the UGT2B7 gene. Heterozygosity for the -840G>A SNP in the UGT2B7 gene was found in 145 patients (145 of 332 [44%]) and 93 (93 of 332 [28%]) patients were homozygous for the -840G>A allele. No difference was found in the dose-normalized AcylMPAG trough (C0) levels and dose-normalized AcylMPAG areas under the concentration-time curve (AUCs) at each visit between carriers and noncarriers of the -840G>A SNP. Also, metabolic ratios, expressed as AcylMPAG/MPA and AcylMPAG/MPAG, were not related to UGT2B7 genotype. The dose-normalized AcylMPAG-C0 and AcylMPAG AUC were higher in the cyclosporine-treated group compared with the tacrolimus-treated patients at each visit. There was no difference in AcylMPAG concentrations (trough or AUC) or AcylMPAG/MPAG ratio between patients with compared with patients without diarrhea. None of the -840G>A UGT2B7 SNPs was disproportionately present among the patients with diarrhea. There was a higher incidence of diarrhea in tacrolimus-treated patients [26 of 163 (16.0%)] compared with cyclosporine-treated individuals [five of 51 (9.8%)], although AcylMPAG concentrations were lower in tacrolimus-treated patients. In this study, we have found no influence of the -840G>A UGT2B7 SNP on AcylMPAG exposure in patients undergoing renal transplantation. There also was no association between this variant genotype and the incidence of diarrhea or leucopenia, two adverse events for which a role for AcylMPAG has been suggested.

Objective: Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5(*)3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation., Methods: A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5(*)3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C(0)) were measured on day 3 and 10, and month 1, 3, 6 and 12., Results: Compared with CYP3A5(*)3/(*)3 individuals (n=110), patients carrying at least one CYP3A5(*)1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C(0) on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C(0) were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36)., Conclusion: We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.

Introduction: The polymorphic enzyme UGT2B7 metabolizes mycophenolic acid into acyl-mycophenolic acid-glucuronide (AcMPAG), a presumably toxic metabolite. This study aimed at investigating in vitro and in vivo the impact on AcMPAG production of: (i) the UGT2B7 gene G-842A single nucleotide polymorphism, in complete linkage disequilibrium with most other known single nucleotide polymorphisms in the promoter region of this gene and with the C802T single nucleotide polymorphism in exon 2 (UGT2B*2); and (ii) of the other immunosuppressants given to renal transplant patients in association with mycophenolate mofetil., Methods: We compared the production of AcMPAG by human liver microsomes genotyped for the UGT2B7 G-842A and C802T single nucleotide polymorphisms, and plasma AcMPAG concentrations in genotyped renal transplant patients administered mycophenolate mofetil associated with sirolimus (n=40), tacrolimus (n=24) or cyclosporin (n=28) and decreasing doses of corticosteroids, over the first 3 months after transplant. The effect of corticosteroids was also investigated in vitro using rats' liver microsomes., Results: The two polymorphisms studied were in complete reverse linkage disequilibrium. AcMPAG production was 1.25 and 1.56-fold higher in G-842A and -842AA human liver microsomes, respectively, compared with GG-842 human liver microsomes (P=0.01). Enzyme kinetics showed 1.4 and 3.7-fold higher Vmax in the respective pools of human liver microsomes. Km values were 0.20, 0.25 and 0.44 mmol/l for the GG-842, G-842A and -842AA genotypes, respectively. This clear increase in Vmax is in favor of the implication of the promoter region polymorphisms, whereas the slighter increase in Km might be due to the UGT2B7*2 single nucleotide polymorphism. Consistently, the UGT2B7 genotype significantly influenced AcMPAG area under the curve (AUC0-9 h)/dose in patients on sirolimus at months 1 and 3 after transplant (P=0.04 for both). No effect was observed in patients on tacrolimus and possibly also on cyclosporin, maybe owing to pharmacokinetic interaction with mycophenolate. AcMPAG production was increased in corticosteroid-induced rat liver microsomes, consistent with the observed in-vivo decrease of mycophenolic acid metabolites AUC0-9 h/dose with time after transplant., Conclusion: Both UGT2B7 polymorphisms and co-medications significantly influenced AcMPAG production, but cyclosporin and tacrolimus hindered the phenotypic impact of this trait.

A roundtable meeting to discuss the use of therapeutic drug monitoring (TDM) to guide immunosuppression with mycophenolate mofetil was held in New York in December 2004. Existing recommendations for the initial months after transplantation were updated. After ensuring adequate levels of mycophenolic acid (MPA, the active metabolite of mycophenolate mofetil) immediately after transplantation, optimal efficacy may require only a few dose adjustments, because intrapatient variability in exposure seems low. Recommendations based on current knowledge were made for posttransplantation sampling time points and for target MPA concentrations. Algorithms for estimating MPA exposure using limited sampling strategies were presented, and a new assay for MPA discussed. It was agreed that because of interpatient variability and the influence of concomitant immunosuppressants, TDM might help optimize outcomes, especially in patients at higher risk of rejection. The value of TDM in the general transplant population will be assessed from large, ongoing, randomized studies.

Limited sampling strategies may be useful in optimizing therapeutic drug monitoring of mycophenolic acid (MPA). Their use, however, may be limited by several patient factors, including comorbidity. In this study the pharmacokinetics of MPA in diabetic and nondiabetic renal transplant recipients were compared, and it was evaluated whether a limited sampling strategy developed and validated for nondiabetic patients can also be used in diabetic patients. The pharmacokinetics of MPA were analyzed on days 7 and 11 after transplantation in 136 renal transplant patients, among whom 7 patients had diabetes. All patients received cyclosporine and corticosteroids as maintenance immunosuppressive therapy. A limited sampling strategy [AUC (mg x h/L) = 7.182 + 4.607 C0 + 0.998 C0.67 + 2.149 C2] was developed and validated for nondiabetic patients and was subsequently tested for its usefulness in diabetic patients. Diabetic renal transplant patients did not have significantly different dose-normalized MPA area under concentration-time curve (AUC), MPA clearance, or MPA maximum concentration (Cmax). However, in diabetic patients Tmax (time of Cmax, 1.59 hours) was higher than for nondiabetic patients (0.67 hours) on day 11 (P = 0.04). The developed and validated limited sampling strategy performed acceptably, estimating MPA AUC in nondiabetic patients with a mean bias of 0.2 mg x h/L (95% confidence interval from -1.3 to 1.6 mg x h/L). Applying the limited sampling strategy in diabetic patients revealed a mean bias of -1.5 (-5.7, 2.7 mg x h/L). In conclusion, although diabetic renal transplant patients exhibit increased Tmax, this does not affect the accuracy of the limited sampling strategy.