Mitochondria-targeted antioxidant supplementation improves 8 km time trial performance in middle-aged trained male cyclists.

BACKGROUND: Exercise increases skeletal muscle reactive oxygen species (ROS) production, which may contribute to the onset of muscular fatigue and impair athletic performance. Mitochondria-targeted antioxidants such as MitoQ, which contains a ubiquinone moiety and is targeted to mitochondria through the addition of a lipophilic triphenylphosphonium cation, are becoming popular amongst active individuals as they are designed to accumulate within mitochondria and may provide targeted protection against exercise-induced oxidative stress. However, the effect of MitoQ supplementation on cycling performance is currently unknown. Here, we investigate whether MitoQ supplementation can improve cycling performance measured as time to complete an 8 km time trial. METHOD: In a randomized, double-blind, placebo-controlled crossover study, 19 middle-aged (age: 44 ± 4 years) recreationally trained (VO2peak: 58.5 ± 6.2 ml·kg- 1·min- 1, distance cycled per week during 6 months prior to study enrollment: 158.3 ± 58.4 km) male cyclists completed 45 min cycling at 70% VO2peak followed by an 8 km time trial after 28 days of supplementation with MitoQ (20 mg·day- 1) and a placebo. Free F2-isoprostanes were measured in plasma samples collected at rest, after 45 min cycling at 70% VO2peak and after completion of the time trial. Respiratory gases and measures of rating of perceived exertion (RPE) were also collected. RESULTS: Mean completion time for the time trial was 1.3% faster with MitoQ (12.91 ± 0.94 min) compared to placebo (13.09 ± 0.95 min, p = 0.04, 95% CI [0.05, 2.64], d = 0.2). There was no difference in RPE during the time trial between conditions (p = 0.82) despite there being a 4.4% increase in average power output during the time trial following MitoQ supplementation compared to placebo (placebo; 270 ± 51 W, MitoQ; 280 ± 53 W, p = 0.04, 95% CI [0.49, 8.22], d = 0.2). Plasma F2-isoprostanes were lower on completion of the time trial following MitoQ supplementation (35.89 ± 13.6 pg·ml- 1) compared to placebo (44.7 ± 16.9 pg·ml- 1 p = 0.03). CONCLUSION: These data suggest that MitoQ supplementation may be an effective nutritional strategy to attenuate exercise-induced increases in oxidative damage to lipids and improve cycling performance.

Carbohydrate Supplementation and the Influence of Breakfast on Fuel Use in Hypoxia.

PURPOSE: This study investigated the effect of carbohydrate supplementation on substrate oxidation during exercise in hypoxia after preexercise breakfast consumption and omission. METHODS: Eleven men walked in normobaric hypoxia (FiO2 ~11.7%) for 90 min at 50% of hypoxic V˙O2max. Participants were supplemented with a carbohydrate beverage (1.2 g·min-1 glucose) and a placebo beverage (both enriched with U-13C6 D-glucose) after breakfast consumption and after omission. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate carbohydrate (exogenous and endogenous [muscle and liver]) and fat oxidation. RESULTS: In the first 60 min of exercise, there was no significant change in relative substrate oxidation in the carbohydrate compared with placebo trial after breakfast consumption or omission (both P = 0.99). In the last 30 min of exercise, increased relative carbohydrate oxidation occurred in the carbohydrate compared with placebo trial after breakfast omission (44.0 ± 8.8 vs 28.0 ± 12.3, P < 0.01) but not consumption (51.7 ± 12.3 vs 44.2 ± 10.4, P = 0.38). In the same period, a reduction in relative liver (but not muscle) glucose oxidation was observed in the carbohydrate compared with placebo trials after breakfast consumption (liver, 7.7% ± 1.6% vs 14.8% ± 2.3%, P < 0.01; muscle, 25.4% ± 9.4% vs 29.4% ± 11.1%, P = 0.99) and omission (liver, 3.8% ± 0.8% vs 8.7% ± 2.8%, P < 0.01; muscle, 19.4% ± 7.5% vs 19.2% ± 12.2%, P = 0.99). No significant difference in relative exogenous carbohydrate oxidation was observed between breakfast consumption and omission trials (P = 0.14). CONCLUSION: In acute normobaric hypoxia, carbohydrate supplementation increased relative carbohydrate oxidation during exercise (>60 min) after breakfast omission, but not consumption.

Cross-sectional and longitudinal relation between serum 25-hydroxyvitamin D and body mass index: the Tromsø study.

PURPOSE: The serum 25-hydroxyvitamin D (25(OH)D) levels are lower in obese than lean subjects. The present study examines the cross-sectional and longitudinal relations between body mass index (BMI) and serum 25(OH)D, and the serum 25(OH)D response to vitamin D supplementation in relation to BMI. METHODS: The Tromsø study is a longitudinal population-based multipurpose study. The fourth survey was conducted in 1994 and the sixth in 2008. The intervention study was a 1-year placebo-controlled randomized intervention trial, where the results from the 93 subjects given 40,000 IU per week are presented. RESULTS: A total of 10,229 subjects were included in the 2008 cross-sectional study. There was a significant negative association between serum 25(OH)D levels and BMI which was also present during the winter months. Serum 25(OH)D levels varied through seasons, but not BMI. In the longitudinal study from 1994 to 2008 which included 2,656 subjects, change in BMI was a significant negative predictor of change in 25(OH)D. In the intervention study, there was a significant and negative correlation between BMI and serum 25(OH)D both at baseline and at the end of the study. The increase in serum 25(OH)D after 1 year was significantly and inversely related to baseline BMI. CONCLUSIONS: We have confirmed the strong association between serum 25(OH)D and BMI. The very obese need higher vitamin D doses than lean subjects to achieve the same serum 25(OH)D levels.

Influence of metoprolol on systolic and diastolic function in children with heart failure.

The aim of this study was to assess the effect ofmetoprolol on cardiac function in children with heart failure. This randomized double-blind placebo controlled clinical trial was performed in children with heart failure due to left ventricle volume overload structural heart disease such as VSD, PDA, AI and MR who referred to pediatric cardiology clinics in sari in 2007. The patients divided into case and control groups. All cases were matched as viewpoints of age, sex, weight, kinds of primary disease and cardiac drugs (except for metoprolol).Metoprolol with single daily dose of 1 mg kg(-1) and placebo were given to patients in case and control groups respectively. Echocardiography with cardiac indices of systolic and diastolic function was done as baseline and monthly for 3 months in all the patients. Data were analyzed using SPSS software and statistical t-test. Thirty patients (16 cases and 14 controls) were enrolled in the study. CI, MPI and dv/dt (dt) decreased significantly at first month. Significant changes in LVEF and EPSS appeared on the second month and in E wave and E/A appeared on the third month. The results were in favor of systolic and diastolic improvement. Metoprolol causes improvement of cardiac systolic and diastolic function in children with heart failure due to cardiac defect. Therefore, metoprolol is recommended in patients with heart failure in above mentioned diseases that have not been controlled adequately in spite of receiving standard cardiac failure drug therapy such as an inotrope, a diuretic and a vasodilator agent.

The nitric oxide synthase inhibitor, Ng-nitro-L-arginine-methyl-ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy humans.

The aim of this study was to determine whether the nitric oxide (NO) synthase inhibitor, N(g)-nitro-L-arginine-methyl-ester (L-NAME), reverses the effects of acute hyperglycaemia on gastric emptying and antropyloroduodenal (APD) motility. The study had a four-way randomized crossover (hyperglycaemia vs euglycaemia; L-NAME vs placebo) design in a clinical laboratory setting. Seven healthy volunteers [four males; age 30.3 +/- 3.8 years; body mass index (BMI) 23.6 +/- 1.2 kg m(-2)] were the study subjects. After positioning a transnasal manometry catheter across the pylorus, the blood glucose concentration was maintained at either 15 or 5 mmol L(-1) using a glucose/insulin clamp. An intravenous infusion of L-NAME (180 microg kg(-1 )h(-1)) or placebo (0.9% saline) was commenced (T = -30 min) and continued for 150 min. At T = -2 min, subjects ingested a drink containing 50 g of glucose made up to 300 mL with water. Gastric emptying was measured using 3D ultrasound, and APD motility using manometry. Hyperglycaemia slowed gastric emptying (P < 0.05), and this effect was abolished by L-NAME. L-NAME had no effect on gastric emptying during euglycaemia. Hyperglycaemia suppressed fasting antral motility [motility index: 3.9 +/- 0.8 (hyperglycaemia) vs 6.5 +/- 0.6 (euglycaemia); P < 0.01]; l-NAME suppressed postprandial antral motility [motility index: 3.6 +/- 0.2 (L-NAME) vs 5.1 +/- 0.2 (placebo); P < 0.001]. Postprandial basal pyloric pressure was higher during hyperglycaemia (P < 0.001), and lower after administration of L-NAME (P < 0.001). Slowing of gastric emptying induced by hyperglycaemia is mediated by NO, and may involve the modulation of tonic pyloric activity.

Sham acupuncture devices--practical advice for researchers.

Several validated sham acupuncture devices have recently become available. While some debate exists on whether such needles are the best placebo control for an RCT of acupuncture, practical advice based on research experience is missing from the literature. This paper shares our concrete experience using the most commonly used such sham needle (the 'Streitberger needle' and its paired verum needle) in a large RCT (n=135) which included a two-week run-in period. The placebo run-in gave us an opportunity to use the sham device on all participants, who were then re-randomised to receive genuine acupuncture or to continue treatment with the device. The blinding was successful both at the end of the run-in and at the conclusion of the trial despite the re-randomisation. We also report our experience with the sham needle in neuroimaging experiments where the magnetic machinery poses considerable challenges for acupuncture research.

The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome.

Clara cell 10-kD protein (CC10) is a potent anti-inflammatory protein that is normally abundant in the respiratory tract. CC10 is deficient and oxidized in premature infants with poor clinical outcome (death or the development of bronchopulmonary dysplasia). The safety, pharmacokinetics, and anti-inflammatory activity of recombinant human CC10 (rhCC10) were evaluated in a randomized, placebo-controlled, double-blinded, multicenter trial in premature infants with respiratory distress syndrome. A total of 22 infants (mean birth weight: 932 g; gestational age: 26.9 wk) received one intratracheal dose of placebo (n = 7) or 1.5 mg/kg (n = 8) or 5 mg/kg (n = 7) rhCC10 within 4 h of surfactant treatment. Pharmacokinetic analyses demonstrated that the serum half-life was 11.6 (1.5 mg/kg group) and 9.9 h (5 mg/kg group). Excess circulating CC10 was eliminated via the urine within 48 h. rhCC10-treated infants showed significant reductions in total cell count (p < 0.0002), neutrophil counts (p < 0.001), and total protein concentrations (p < 0.01) and tended to have decreased IL-6 (p < 0.07) in tracheal aspirate fluid collected over the first 3 d of life. Infants in all three groups showed comparable growth. At 36 wk postmenstrual age, five of seven infants were still hospitalized and two of seven infants were receiving oxygen in the placebo group compared with two of seven hospitalized and one of seven receiving oxygen in the 1.5-mg/kg group and four of six hospitalized and three of six receiving oxygen in the 5-mg/kg group. A single intratracheal dose of rhCC10 was well tolerated and had significant anti-inflammatory effects in the lung. Multiple doses of rhCC10 will be investigated for efficacy in reducing pulmonary inflammation and ameliorating bronchopulmonary dysplasia in future studies.

Effects of drotrecogin alfa (activated) in human endotoxemia.

In a phase III clinical trial, drotrecogin alfa (activated) was shown to improve survival and promote faster improvement of cardiovascular and respiratory dysfunction in patients with severe sepsis. To further examine mechanisms involved in the action of this drug, a healthy human endotoxin model was used. Healthy volunteers (eight per group) received drotrecogin alfa (activated) or placebo intravenously for 8 h in a randomized, double-blind, controlled manner. After 2 h of study drug infusion, endotoxin (2 ng/kg) was infused and measurement of physiologic responses and biomarkers continued for 24 h. Consistent with results from severe sepsis clinical trials, drotrecogin alfa (activated) improved mean arterial pressure during the period of infusion after endotoxin exposure. In contrast to severe sepsis clinical trials using drotrecogin alfa (activated) but similar to another human endotoxin study, no significant antithrombotic, profibrinolytic, or anti-inflammatory effects were observed. These results suggest a novel role for drotrecogin alfa (activated) in the human endotoxin model.

The placebo response. Recent research and implications for family medicine.

The placebo response is commonly invoked as a factor in the therapeutic relationship between the family physician and the patient, but important recent literature can be difficult for family physicians to access. Coordinated interdisciplinary research into the placebo response as it occurs in primary care settings is lacking. Although there is controversy about the nature and scope of the placebo response, important suggestions are emerging about its psychological mechanisms (expectancy and conditioning) and the biochemical pathways that act as psychosomatic linkages (endorphins, catecholamines and cortisol, psychoneuroimmumunology). The available research justifies interventions by family physicians that maximize the placebo response in everyday patient encounters. These include the sustained partnership approach, working with patients on the narratives they construct to explain illness, listening to patients, providing them with satisfactory explanations, expressing care and concern, and enhancing their sense of control. Notable opportunities exist for family medicine investigators to expand the understanding of this phenomenon.