Healthy Young Male Subjects Research Articles

Reduced Postprandial Serum Triglyceride After a Meal Prepared Using an Airfryer: A Randomized Crossover Trial (P08-103-19)

ObjectivesElevated circulating non-fasting triglyceride (TG) or postprandial triglyceride (ppTG) is as an independent contributor to risk for coronary heart disease. We hypothesized that a commonly consumed fried meal (including French fries and chicken nuggets) prepared by airfrying would result in a significantly lower ppTG response than the same meal prepared using a conventional deep fat frying approach. MethodsWe conducted a randomized crossover trial to evaluate the effect of airfryer cooking compared to conventional deep fat frying preparation in young healthy male (n = 10) and female subjects (n = 6). A 7-day washout period was included between meal test days. All study participants were blinded to the method of meal preparation. ResultsThe airfryer resulted in a significantly lower postprandial triglyceride response compared to deep fat frying of the same meal (P < 0.001). Glucose, insulin, and free fatty acid response differences were not found. Self-reported satiety did not differ after the meals. Furthermore, air-frying did not influence circulating inflammatory biomarkers, cholesterol, or apolipoproteins. ConclusionsAir frying of common fried meals results in lower postprandial triglyceride excursions in young healthy volunteers in the absence of any effects on satiety. Air-frying represents a useful and practical method to reduce meal fat content in line with current dietary recommendations on triglyceride management and general healthy eating. Funding SourcesThis research was funded by Philips Research China, Philips (China) Investment Co., Ltd., Shanghai, China. Supporting Tables, Images and/or Graphs▪▪▪

Low-frequency ventilatory oscillations in hypoxia are a major contributor to the low-frequency component of heart rate variability

Heart rate variability (HRV) may be influenced by several factors, such as environment (hypoxia, hyperoxia, hypercapnia) or physiological demand (exercise). In this retrospective study, we tested the hypothesis that inter-beat (RR) intervals in healthy subjects exercising under various environmental stresses exhibit oscillations at the same frequency than ventilatory oscillations. Spectra from RR intervals and ventilation ([Formula: see text]E) were collected from 37 healthy young male subjects who participated in 5 previous studies focused on ventilatory oscillations (or periodic breathing) during exercise in hypoxia, hyperoxia and hypercapnia. Bland and Altman test and multivariate regressions were then performed to compare respective frequencies and changes in peak powers of the two signals. Fast Fourier analysis of RR and [Formula: see text]E signals showed that RR was oscillating at the same frequency than periodic breathing, i.e., ~ 0.09Hz (11s). During exercise, in these various conditions, the difference between minimum and maximum HRV peak power was positively correlated to the same change in ventilation peak power (P < 0.05). Low-frequency (LF) peak power was correlated to tidal volume (P < 0.01) and breathing frequency (P < 0.001). This study suggests that low-frequency ventilatory oscillations in hypoxia are a major contributor to the LF band power of heart rate variability. CLINICAL TRIAL REG. NO.: NCT02201875.

Safety and Efficacy Study of N‐SORB® a Proprietary KD120 MEC Metabolically‐ Activated Enzyme Formulation: A Randomized, Double‐blind, placebo Controlled Study

BackgroundEnzymes are crucial for all aspects of metabolic function. Digestive enzymes from natural sources have been credited with beneficial effects in the digestion and absorption of food. N‐SORB is a novel KD120 multienzyme complex (MEC) of metabolically activated enzymes composed of proteases, amylases, lipases, alpha galactosidase, and glucoamylase from natural sources. These enzymes are encapsulated in an SK713 SLP (non‐GMO soy lecithin phospholipid) absorption technology (‘Prodosome®’).ObjectiveThis randomized double‐blind placebo‐controlled investigation assessed the safety and efficacy of Prodosomed N‐Sorb KD120 MEC on various parameters of the blood, immunity, body composition, physical health, and quality of life in young healthy male and female subjects over a 90‐day period.MethodsInstitutional Review Board Approval was obtained from University of Wyoming School of Pharmacy, Laramie, WY. Forty‐six young male and female (mean age: 25.8 ± 12.1 years) healthy volunteers, were randomly assigned to receive either N‐SORB (1 mL, twice daily) or placebo over a period of 90 consecutive days. Complete blood count as well as blood glucose, liver enzymes, and lipid profile were assessed pre‐ and post‐intervention. Serum cytokine levels were determined by using a Bio‐Plex Pro Human Cytokine 8‐plex Assay. Whole body composition analysis was performed by dual‐energy X‐Ray absorptivity (DEXA) to determine body fat mass, lean mass and android and gynoid fat. Body, weight, blood pressure, and physical health were assessed. WHOQOL‐BREF and a Pittsburgh Sleep Quality Index (PSQI) questionnaires were used for quality of life and sleep quality assessments respectively. Adverse events were monitored before, during and after the completion of the study.ResultsOf the 46 subjects enrolled, 41 subjects successfully completed the trial. Compared to placebo, changes in blood cell counts including hematocrit, hemoglobin, mean corpuscular volume, platelets and lymphocytes provide evidence of consistent improvement, which were reconfirmed by Quality of Life (QOL) parameters that significantly improved in the N‐SORB group. No significant changes in BUN, serum creatinine, ALP, AST, ALT, and lipid profile were observed between the placebo and treatment groups. No adverse reports were reported.ConclusionThis randomized, double blind, placebo‐controlled clinical study demonstrates that short‐term intervention with N‐SORB improves the QOL in young healthy volunteers and didn't alter cardiometabolic parameters, lipid profile or body composition. Subjects receiving N‐SORB reported an overall improvement in quality of life.Support or Funding InformationThe Study was Partially Supported by VNI Inc, Lederach, FLThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Trunk kinematic, kinetic, and neuro-muscular response to foot center of pressure translation along the medio-lateral foot axis during gait

Footwear devices that shift foot center of pressure (COP), thereby impacting lower-limb biomechanics to produce clinical benefit, have been studied regarding degenerative diseases of knee and hip joints, exhibiting evidence of clinical success. Ability to purposefully affect trunk biomechanics has not been investigated for this type of footwear. Fifteen healthy young male subjects underwent gait and electromyography analysis using a biomechanical device that shifts COP via moveable convex elements attached to the shoe sole. Analyses were performed in three COP configurations for pairwise comparison: (1) neutral (control) (2) laterally deviated, and (3) medially deviated. Sagittal and frontal-plane pelvis and spine kinematics, external oblique activity, and frontal and transverse-plane lumbar moments were affected by medio-lateral COP shift. Transverse-plane trunk kinematics, activity of the lumbar longissimus, latissimus dorsi, rectus abdominus, and quadratus lumborum, and sagittal-plane lumbar moment, were not significantly impacted. Two linear mixed effects models assessed predictive impact of (I) COP location, and (II) trunk kinematics and neuromuscular activity, on the significant lumbar moment parameters. The COP was a significant predictor of all modeled frontal and transverse-plane lumbar moment parameters, while pelvic and spine rotation, and lumbar longissimus activity were significant predictors of one frontal-plane lumbar moment parameter. Model results suggest that, although trunk biomechanics and muscle activity were altered by COP shift, COP offset influences lumbar kinetics directly, or via lower-limb changes not assessed in this study, but not by means of alteration of trunk kinematics or muscle activity. Further study may reveal implications in treatment of low back pain.

Plasma asymmetric dimethylarginine concentrations are not related to differences in maximal oxygen uptake in endurance trained and untrained men.

What is the central question of this study? Is there an association of plasma concentration of asymmetric dimethylarginine, which is related to exercise capacity in patients with cardiovascular diseases, with oxygen delivery and subsequently exercise capacity in healthy subjects in the absence of the potentially confounding influence of inflammation and oxidative stress? What is the main finding and its importance? Plasma asymmetric dimethylarginine concentrations are not related to exercise capacity in healthy subjects, while O2 delivery in the working skeletal muscle during the maximal graded-exercise test is not associated with any of the l-arginine analogues. ADMA alone does not play a crucial role in local muscle perfusion and in maintaining exercise capacity. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis that could limit oxygen (O2 ) delivery in the working skeletal muscles by altering endothelium-dependent vasodilatation. Exercise capacity is associated with plasma ADMA concentrations in patients with cardiovascular diseases, but this issue has still not been investigated in healthy subjects. We aimed to determine whether plasma ADMA concentrations were negatively associated with exercise capacity in young healthy male subjects. Ten men with maximal oxygen uptake ( )> 65mLkg-1 min-1 were included in the high exercise capacity group (HI-FIT), and 10 men with < 45mLkg-1 min-1 were included in the low exercise capacity group (LO-FIT). Plasma ADMA and other l-arginine analogue concentrations were measured before and after a maximal graded-exercise test by liquid chromatography-tandem mass spectrometry. Microvascular O2 delivery during exercise was estimated through the pattern from the sigmoid model of muscle deoxygenation in the vastus lateralis measured by near infrared spectroscopy. was 60% higher in the HI-FIT group (median: 70.2mLkg-1 min-1 ; IQR: 68.0-71.9mLkg-1 min-1 ) than in the LO-FIT group (median: 43.8mLkg-1 min-1 ; IQR: 34.8-45.3mLkg-1 min-1 ). Plasma ADMA concentrations did not differ between the LO-FIT and HI-FIT groups before (0.50± 0.06 vs. 0.54± 0.07μmolL-1 , respectively) and after the maximal incremental exercise test (0.49± 0.08 vs. 0.55± 0.03μmolL-1 , respectively). There was no significant association of plasma ADMA concentrations with the pattern of local muscle deoxygenation and exercise capacity. Exercise capacity and microvascular O2 delivery are not related to plasma ADMA concentrations in young healthy male subjects. Our findings show that ADMA does not play a crucial role in local muscle perfusion and in maintaining exercise capacity without pathological conditions.

The Endothelial Mechanotransduction Protein Platelet Endothelial Cell Adhesion Molecule-1 Is Influenced by Aging and Exercise Training in Human Skeletal Muscle.

Aim: The aim was to determine the role of aging and exercise training on endothelial mechanosensor proteins and the hyperemic response to shear stress by passive leg movement.Methods: We examined the expression of mechanosensor proteins and vascular function in young (n = 14, 25 ± 3 years) and old (n = 14, 72 ± 5 years) healthy male subjects with eight weeks of aerobic exercise training. Before and after training, the hyperaemic response to passive leg movement was determined and a thigh muscle biopsy was obtained before and after passive leg movement to assess the acute effect of increased shear stress. Biopsies were analyzed for protein amount and phosphorylation of mechanosensor proteins; Platelet endothelial cell adhesion molecule-1 (PECAM-1), Vascular endothelial cadherin, Vascular endothelial growth factor receptor-2 and endothelial nitric oxide synthase (eNOS).Results: Before training, the old group presented a lower hyperaemic response to passive leg movement and a 35% lower (P < 0.05) relative basal phosphorylation level of PECAM-1 whereas there was no difference for the other mechanosensor proteins. After training, the eNOS protein amount, the amount of PECAM-1 protein and the passive leg movement-induced phosphorylation of PECAM-1 were higher in both groups. The hyperaemic response to passive leg movement was higher after training in the young group only.Conclusion: Aged individuals have a lower hyperaemic response to passive leg movement and a lower relative basal phosphorylation of PECAM-1 than young. The higher PECAM-1 phosphorylation despite a similar hyperemic level in the aged observed after training, suggests that training improved shear stress responsiveness of this mechanotransduction protein.

Plasma Orexin-A Levels Do Not Undergo Circadian Rhythm in Young Healthy Male Subjects.

Orexin-A (OXA) has been originally isolated from a precursor peptide prepro-orexin from the lateral hypothalamus. The orexin system has been attributed to important functions in sleep, arousal and regulation of energy homeostasis. In addition to its high levels in cerebrospinal fluid, OXA is present in blood. However, reported peptide concentrations in plasma vary significantly depending on the method used. Therefore, a specific and sensitive OXA radioimmunoassay (RIA) with solid phase extraction method was developed to determine whether plasma OXA concentrations is affected by acute feeding and/or wake and sleep in young healthy males. Blood samples were collected for 24 h from nine healthy males (aged 20–24 years; BMI 20.7–26.5) every 2 h starting at 11 a.m. Food was served at 12 p.m, 5:30 p.m, 8 p.m and 8 a.m and the sleep time was between 10 p.m and 7 a.m. Plasma samples were analyzed in addition for cortisol and melatonin levels. Blood pressure was monitored through the experimental period. OXA antibody was raised in rabbits. OXA antiserum had only minor cross-reactivity with prepro-orexin precursor (<0.001%), amino-terminal peptide (<0.001%), carboxy-terminal peptide (0.001%), and orexin-B (0.3%) with high sensitivity (0.15 pg/tube). Plasma OXA levels varied between 0.5 and 16 pg/ml in seven subjects and were undetectable (below 0.5 pg/ml) in two subjects. The OXA concentrations did not correlate to feeding nor wake/sleep, whereas cortisol, melatonin and mean arterial blood pressure presented a clear circadian rhythm in each subject. In conclusion, OXA is present in blood in low amounts and its levels do not follow autonomic nor neuroendocrine circadian rhythms. Thereby, studies examining regulatory mechanisms and influences of OXA from blood samples should interpret results very cautiously.

Mechanism of reducing knee adduction moment by shortening of the knee lever arm via medio-lateral manipulation of foot center of pressure: A pilot study

Prominent conservative treatment options for medial-compartment knee osteoarthritis include footwear that reduces knee adduction moment (KAM) correlated with detrimental loads in the medial compartment of the knee, thus providing clinical benefit. The proposed mechanism by which they reduce KAM is a lateral shift in foot center of pressure (COP) and a consequent shortening of the knee lever arm (KLA), thereby reducing KAM, which can be simply calculated as KLA multiplied by the frontal plane ground reaction force (FP-GRF). The present study investigated this mechanism for a unique biomechanical device capable of shifting COP by means of moveable convex elements attached to the shoe. Fourteen healthy young male subjects underwent gait analysis in two COP configurations of the device for comparison: (1) laterally and (2) medially deviated. Average midstance KLA and KAM were decreased by 8.2% and 8.7%, respectively, in the lateral COP compared to medial. Ground reaction force parameters, frontal plane knee angle (FP-KA), and spine lateral flexion angle (SLF) did not differ between COP configurations. No study parameters differed for terminal stance. Linear mixed effects models showed that COP and FP-GRF components, but not FP-KA and SLF, were significant predictors of KLA. In addition, KLA and FP-GRF were significant predictors of KAM; although, FP-GRF did not change significantly with medio-lateral COP shift, while KLA did. This suggests that the mechanism by which the study device reduces KAM is primarily through shortening of KLA brought on by a lateral shift in COP.

Changes in the Central Fatigue by Manipulating the Level of Extrinsic Motivation

Purpose: The possibility of interaction between physical and mental fatigues was investigated in this study. Should any interaction between the physical and psychological fatigue takes place, it must accompany the changes in the brain. Therefore, the level of central activation ratio (central fatigue) has been measured as a function of monetary reward to elicit the extrinsic motivation. Methods: Twenty four healthy young male subjects performed quadriceps isotonic extensions until they experience the muscular fatigue. Then, the notification of the monetary reward depending on the level of extension force for the next 3 attempts were given to the experimental group, while no such information was given to the control group. During these post-fatigue isometric maximum voluntary contraction trials, the transcranial magnetic stimulation was delivered on the motor cortex to measure the central activation ratio. Two-way repeated ANOVA were performed. Results: Pre- vs. Post-fatigue comparisons confirmed that the subjects regardless of the group experienced the peripheral fatigue although the level of peripheral fatigue was less pronounced in the group with extrinsic motivation. On the other hand, the central activation ratio of the extrinsic motivation group did not displayed any decrease as the control group did. Conclusion: The results from this study provided an evidence showing the effects of motivation on the muscular fatigue. What’s intriguing is, however, the level of fatigue at the brain level showed no significant sign of fatigue when the monetary reward was suggested. It is presumable to suggest that the high motivation made our subjects prone to the central fatigue, and such effects might have decrease the peripheral muscle fatigue in turn.

A Single Bout of Exercise Reduces Postprandial Lipemia but Has No Delayed Effect on Hemorheological Variables.

High plasma triglyceride (TG) concentration in fasting state could cause hemorheological abnormality, thus increasing the incidence of metabolic diseases. Exercise has been reported to effectively reduce postprandial TG response. This study aimed to investigate whether a single bout of pre-prandial exercise can affect lipemia and hemorheological variables after a high-fat meal. Nine healthy young male subjects completed two experimental trials. The subjects walked for 1 h at 50% maximal oxygen uptake (V̇O₂max) (the exercise, EX trial), or rested (the control, CON trial). In the next morning, the subjects consumed a high-fat meal, and the postprandial lipemia and hemorheological responses were monitored for 6 h. The results showed that postprandial plasma TG concentrations were significantly lower in the EX trial compared to the CON trial. The postprandial low-density lipoproteins (LDL) concentration declined in the first 2 h and then gradually returned to the baseline level in both trials. The postprandial blood viscosity also decreased in the CON trial. There was no significant difference in postprandial blood viscosity, red blood cell (RBC) deformation index and aggregation degree between the trials. There was no significant correlation between plasma TG concentration and blood viscosity. In conclusion, brisk walking effectively reduced postprandial TG concentration, but has no significant impact on postprandial blood viscosity, RBC deformation index and RBC aggregation index.

Metabolic Activity of the Liver during Exercise—A Metabolomics Approach

The liver plays a pivotal role in substrate metabolism during fasting and exercise. Chances in the hepatic uptake or release of metabolites regulate the hepatic energy supply for other organs. Here we evaluated substrate flow over the hepato-splanchnic bed by assessing arterial-to-venous differences based on UPLC and CE-MS metabolomics analysis at rest and during exercise. Catheterized healthy young male subjects (n = 10) performed 2 h of ergometer cycling followed by 4 h of recovery. In response to exercise there was pronounced hepatic uptake of lactate, pyruvate, various amino acids and dicarboxylic acids, indicating high demand for gluconeogenic substrates and increase in anaplerotic reactions of the citric acid cycle. Medium chain fatty acids e.g., caproic acid showed a clear hepatic uptake during exercise, underlining their potential role as regulators of gluconeogenesis and mitochondrial substrate oxidation. While most long chain fatty acids showed increased hepatic uptake, saturated fatty acids with carbon chain &amp;gt; 18 were released. In contrast to other amino acids, branched chain amino acids were not taken up or released from the liver at any time point. Notably, the hepato-splanchnic bed showed pronounced uptake of oxygen and release of CO2 during exercise indicating up-regulation of energy consuming metabolic processes. In conclusion, the data provide novel insight in the regulation of hepatic metabolism at rest and during exercise. Disclosure P. Plomgaard: None. C. Hu: None. J.S. Hansen: Employee; Self; Novo Nordisk A/S. X. Zhao: None. M. Hoene: None. X. Wang: None. N. Secher: None. H. Haering: None. R. Lehmann: None. G. Xu: None. C. Weigert: None.

Chlorella Intake Further Enhances Anaerobic And Aerobic Capacities Increased By High Intensity Intermittent Training

High intensity intermittent training (HIIT) enhances anaerobic and aerobic capacities. Our recent study have demonstrated in animal study that the 6-week combination of chlorella intake and HIIT further elevated glycolytic and oxidative phosphorylation as ATP supply in skeletal muscle as compared with chlorella alone and HIIT alone, resulting in enhancement of anaerobic and aerobic exercise capacities. However, the combined effects of chlorella intake and HIIT on anaerobic and aerobic capacities in human remain unclear. PURPOSE: The aim of this study was to investigate whether the combination of chlorella intake and HIIT further enhanced anaerobic and aerobic capacities as compared with HIIT alone in human. METHODS: Twelve healthy young male subjects (21 ± 1 years) were participated in this study. Subjects completed 3-week of exhaustive HIIT, consisting of 6-7 bouts of 20-second cycling on a leg ergometer at an intensity of 170% maximal oxygen uptake (VO2max) with a 10-second rest between each bout, 3 days/week. They orally took chlorella or placebo (10 tablets) after the breakfast and dinner between the 3-week in a double-blind, randomized, crossover design with 4 weeks between each intervention. We measured VO2max as an indicator of aerobic capacity and maximal oxygen deficit (MOD) as an indicator of anaerobic capacity. RESULTS: After each HIIT intervention, VO2max was significantly increased in both chlorella and placebo groups (P<0.05). However, the amount of change in VO2max after the intervention was significantly higher in chlorella intake than placebo intake (P<0.05). After each HIIT intervention, MOD was significantly increased in both chlorella and placebo groups (P<0.05). However, the amount of change in MOD after the intervention was significantly higher in chlorella intake than placebo intake (P<0.05). CONCLUSIONS: These results suggest that the combination of chlorella intake and HIIT may further enhance anaerobic and aerobic capacities in human. Supported by Grants-in-Aid for Scientific Research (#17H02183, #16K13059, M. Iemitsu)

0008 Night-Time Administration Of ACT-541468, A Novel Dual Orexin Receptor Antagonist: Characterization Of Its Pharmacokinetics, Next-Day Residual Effects, Safety, And Tolerability

ACT-541468 is a potent dual orexin receptor antagonist. The orexin system regulates sleep and arousal and is targeted by ACT-541468. Night-time pharmacokinetics (PK), next-day residual effects, safety, and tolerability following evening administration of ACT-541468 were investigated. Double-blind, placebo-controlled, randomized, repeated-dose study in 20 young adult healthy male and female subjects (16/4 active/placebo) following evening administration of 25 mg ACT-541468 for 7 days. PK were assessed in the evening (trough), in the morning (8 h post-dose), and on Day 8 with a PK profile during the elimination phase of the drug to determine the half-life (t½). Four subjects had an additional 8th study drug administration to determine PK parameters at night. Next-day pharmacodynamic (PD) effects (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analog scale (VAS), Digit Symbol Substitution Test (DSST), Simple Reaction Time Test (SRTT), Karolinska Sleepiness Scale (KSS), Leeds Sleep Evaluation Questionnaire (LSEQ), and VAS Bowdle for evaluation of psychedelic effects) were assessed in the morning. During the night subjects were not disturbed. Plasma concentrations reached steady-state on Day 3 without relevant accumulation. The geometric mean t½ on Day 8 was 6.0 h. The night-time median time to maximum plasma concentration, geometric mean t½, geometric mean maximum plasma concentration, and area under the curve from zero to 24 h were 1.5 h, 6.1 h, 475 ng/mL, and 3729 ng·h/mL, respectively. No relevant effects on any of the PD variables, neither objective (SPV, adaptive tracking, body sway, DSST, SRTT) nor subjective (VAS Bond and Lader, KSS, LSEQ, VAS Bowdle) were observed. Evening administration of ACT-541468 was well tolerated with no apparent next-day impairment of motor and cognitive functions which supports the further development of ACT-541468 in insomnia disorders. Clemens Muehlan and Jasper Dingemanse are employees at Idorsia, the sponsor of the clinical study. The investigators Joop van Gerven, Rob Zuiker, and Sander Brooks are employees of CHDR. The authors disclosed no other relevant affiliations or financial interest.

Neuroplasticity following short-term strength training occurs at supraspinal level and is specific for the trained task.

Different modalities of strength training cause performance enhancements, which are specific for the trained task. However, the involved mechanisms are still largely unknown. It has been demonstrated that strength training could induce neuroplasticity, which might underlie the performance improvements during the first training sessions. Thus, we hypothesized to find task-specific neuroplasticity after a short-term strength training of two distinct strength tasks. Young healthy male subjects were exposed to 4 sessions of either maximal isometric explosive (EXPL group, N = 9) or slow sustained (SUS group, N = 10) knee extensions. Pre- and post-training, we measured H-reflexes and motor evoked potentials (MEPs) in the vastus lateralis (VL) at the onset of both strength tasks. Pre- and post-training, H-reflexes remained unchanged in both groups. MEP areas were lower in the trained task in both groups and remained unchanged in the untrained task. This study demonstrated that short-term strength training induces specific neuroplasticity for the trained task only. The fact that MEPs were lower but H-reflex amplitudes remained unchanged at the onset of the trained tasks suggests that strength training elicited neuroplasticity at supraspinal level that most likely reflect an improved task-specific corticospinal efficiency.

Association analysis of the ACTN3 R577X polymorphism with passive muscle stiffness and muscle strain injury.

Passive muscle stiffness is considered to be a major factor affecting joint flexibility and is thought to relate to the occurrence of muscle strain injury. In skinned muscle fiber experiments, the R577X polymorphism of the α-actinin-3 gene (ACTN3) has been associated with passive muscle stiffness. Our primary purpose was to clarify whether the ACTN3 R577X polymorphism influences passive stiffness of human muscle in vivo. We also examined whether the ACTN3 R577X polymorphism is associated with the occurrence of hamstring strain injury. Seventy-six healthy young male subjects were genotyped for the ACTN3 R577X (rs1815739) polymorphism. Shear modulus (an index of stiffness) of each hamstring muscle (biceps femoris, semitendinosus, and semimembranosus) was assessed using ultrasound shear wave elastography, and history of hamstring strain injury was collected via a questionnaire. The muscle shear moduli of the semitendinosus and semimembranosus were significantly higher in R-allele (RR+RX genotype) carriers than in XX genotype carriers, whereas the shear modulus of the biceps femoris did not differ among the ACTN3 R577X genotypes. Frequency of past hamstring strain injury also did not differ between the 3 genotypes nor between the R-allele and XX genotype carriers. This study indicates that RR and RX genotypes of the ACTN3 R577X polymorphism (corresponding to the presence of α-actinin-3 in type II muscle fibers) are associated with increased passive muscle stiffness of the human hamstring in vivo. However, this altered mechanical property might not affect the risk of hamstring muscle strain injury.

Probenecid Inhibits α-Adrenergic Receptor-Mediated Vasoconstriction in the Human Leg Vasculature.

Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.

EFFECTS OF A PROPRIETARY BLEND RICH IN GLYCOSIDE BASED STANDARDIZED FENUGREEK SEED EXTRACT (IBPR) ON INFLAMMATORY MARKERS DURING ACUTE ECCENTRIC RESISTANCE EXERCISE IN YOUNG SUBJECTS

Objective: To assess the efficacy of a proprietary blend rich in glycoside based standardized fenugreek seed extract (400 mg) and minor quantities of curcumin and cinnamon (25 mg each) supplementation (IBPR) on inflammatory markers related to skeletal muscle soreness using double-blind placebo control, parallel design.Methods: A total of 20 healthy non-resistance trained young male and female subjects were assigned to ingest either IBPR or matching placebo for 14 days before the eccentric exercise bout. Subjects were instructed to perform 24 sets with 10 eccentric knee extensor repetitions (with one leg at 30°/s on an isokinetic device). Subjects had their blood drawn at baseline, immediately post, 1 hr, 3 hrs, and 24 hrs post-eccentric exercise. Efficacy in terms of serum levels of anti-inflammatory cytokines interleukin-10 (IL-10), pro-inflammatory cytokines (IL-1ra, IL-1b, IL-6, and tumor necrosis factor) and safety in terms of kidney function (blood urea nitrogen (BUN), serum creatinine, BUN to creatinine ratio), and differential leukocyte count were measured. The data of each parameter were analyzed by two-way repeated measure ANOVA.Results: Significant time-dependent effects were observed in IL1b, IL6, and creatinine values from baseline whereas significant treatment dependent effect was seen in IL-1ra. IBPR was found to be safe and well tolerated.Conclusion: IBPR supplementation showed a significant anti-inflammatory efficacy on eccentric exercise-induced inflammatory markers of skeletal muscle soreness in non-resistance trained subjects.

Opposite effects of binge drinking on consciously vs. subliminally induced cognitive conflicts

Binge-drinking is very prevalent and potentially harmful, yet very little is known about the specificity of its effects on behavior and the underlying neurophysiologic mechanisms. While it is generally accepted that alcohol impairs top-down cognitive control and conflict monitoring, it has remained unclear whether this also applies to subliminally triggered conflicts, as alcohol may not impair automated processes to the same extent.To investigate this, we used a within-subjects design in a sample of n = 22 healthy young male subjects who performed a complex response conflict paradigm while an EEG was recorded. Behavioral data showed that a binge-like intoxication of 1.1‰ increased the response conflict induced by consciously perceived flankers, but paradoxically decreased the response conflict induced by subliminal primes. The latter was found to be reflected in decreased amplitude differences in the visual N1, which reflects attentional aspects of stimulus processing, and the N2 as well as a following central negativity, which are thought to reflect conflict monitoring and cognitive effort. On the neuroanatomical level, we found the decrease in subliminally induced response conflicts to be based on changes in fronto-parietal networks (including BA 7/the precuneus, BA 40/the postcentral gyrus, BA 23 & 24/the cingulate cortex and BA 13/the insular cortex) that subserve attention allocation, the processing of complex stimuli and cognitive conflict.It can be concluded that alcohol intoxication paradoxically reduces subliminally triggered response conflicts, which may be caused by decreased allocation of attention towards less salient/noticeable stimuli.

Endothelial mechanotransduction proteins and vascular function are altered by dietary sucrose supplementation in healthy young male subjects.

Mechanotransduction in endothelial cells is a central mechanism in the regulation of vascular tone and vascular remodelling Mechanotransduction and vascular function may be affected by high sugar levels in plasma because of a resulting increase in oxidative stress and increased levels of advanced glycation end-products (AGE). In healthy young subjects, 2weeks of daily supplementation with 3×75g of sucrose was found to reduce blood flow in response to passive lower leg movement and in response to 12W of knee extensor exercise. This vascular impairment was paralleled by up-regulation of platelet endothelial cell adhesion molecule (PECAM)-1, endothelial nitric oxide synthase, NADPH oxidase and Rho family GTPase Rac1 protein expression, an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. There were no measurable changes in AGE levels. The findings of the present study demonstrate that daily high sucrose intake markedly affects mechanotransduction proteins and has a detrimental effect on vascular function. Endothelial mechanotransduction is important for vascular function but alterations and activation of vascular mechanosensory proteins have not been investigated in humans. In endothelial cell culture, simple sugars effectively impair mechanosensor proteins. To study mechanosensor- and vascular function in humans, 12 young healthy male subjects supplemented their diet with 3×75g sucrose day-1 for 14days in a randomized cross-over design. Before and after the intervention period, the hyperaemic response to passive lower leg movement and active knee extensor exercise was determined by ultrasound doppler. A muscle biopsy was obtained from the thigh muscle before and after acute passive leg movement to allow assessment of protein amounts and the phosphorylation status of mechanosensory proteins and NADPH oxidase. The sucrose intervention led to a reduced flow response to passive movement (by 17±2%) and to 12W of active exercise (by 9±1%), indicating impaired vascular function. A reduced flow response to passive and active exercise was paralleled by a significant up-regulation of platelet endothelial cell adhesion molecule (PECAM-1), endothelial nitric oxide synthase, NADPH oxidase and the Rho family GTPase Rac1 protein expression in the muscle tissue, as well as an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. The phosphorylation status was not acutely altered with passive leg movement. These findings indicate that a regular intake of high levels of sucrose can impair vascular mechanotransduction and increase the oxidative stress potential, and suggest that dietary excessive sugar intake may contribute to the development of vascular disease.