Healthy Young Male Subjects Research Articles

Acute volume expansion attenuates hyperthermia-induced reductions in cerebral perfusion during simulated hemorrhage

Hyperthermia reduces the capacity to withstand a simulated hemorrhagic challenge, but volume loading preserves this capacity. This study tested the hypotheses that acute volume expansion during hyperthermia increases cerebral perfusion and attenuates reductions in cerebral perfusion during a simulated hemorrhagic challenge induced by lower-body negative pressure (LBNP). Eight healthy young male subjects underwent a supine baseline period (pre-LBNP), followed by 15- and 30-mmHg LBNP while normothermic, hyperthermic (increased pulmonary artery blood temperature ~1.1°C), and following acute volume infusion while hyperthermic. Primary dependent variables were mean middle cerebral artery blood velocity (MCAvmean), serving as an index of cerebral perfusion; mean arterial pressure (MAP); and cardiac output (thermodilution). During baseline, hyperthermia reduced MCAvmean (P = 0.001) by 12 ± 9% relative to normothermia. Volume infusion while hyperthermic increased cardiac output by 2.8 ± 1.4 l/min (P < 0.001), but did not alter MCAvmean (P = 0.99) or MAP (P = 0.39) compared with hyperthermia alone. Relative to hyperthermia, at 30-mmHg LBNP acute volume infusion attenuated reductions (P < 0.001) in cardiac output (by 2.5 ± 0.9 l/min; P < 0.001), MAP (by 5 ± 6 mmHg; P = 0.004), and MCAvmean (by 12 ± 13%; P = 0.002). These data indicate that acute volume expansion does not reverse hyperthermia-induced reductions in cerebral perfusion pre-LBNP, but that it does attenuate reductions in cerebral perfusion during simulated hemorrhage in hyperthermic humans.

Effects of 6-h exposure to low relative humidity and low air pressure on body fluid loss and blood viscosity

The purpose of this study was to investigate the effects of 6-h exposure to low relative humidity (RH) and low air pressure in a simulated air cabin environment on body fluid loss (BFL) and blood viscosity. Fourteen young healthy male subjects were exposed to four conditions, which combined RH (10% RH or 60% RH) and air pressure (NP: sea level or LP: equivalent to an altitude of 2000m). Subjects remained seated on a chair in the chamber for 6h. Their diet and water intake were restricted before and during the experiment. Insensible water loss (IWL) in LP10% condition was significantly greater than in NP60% condition; thus, combined 10%RH and LP conditions promoted a greater amount of IWL. The BFL under the LP condition was significantly greater than that under the NP condition. Blood viscosity significantly increased under LP conditions. Increases in red blood cell counts (RBCs) and BFL likely contributed to the increased blood viscosity. These findings suggest that hypobaric-induced hypoxia, similar to the conditions in the air cabin environment, may cause increased blood viscosity and that the combined low humidity and hypobaric hypoxia conditions increase IWL.

Drug-Drug Interaction Study of ACT-178882, a New Renin Inhibitor, and Diltiazem in Healthy Subjects

The cytochrome P450 (CYP) enzyme, CYP3A4, metabolizes ACT-178882, a new direct renin inhibitor. This study investigated the effect of diltiazem, a moderate inhibitor of CYP3A4, on the single-dose pharmacokinetics of ACT-178882 in healthy subjects. In this open-label, two-way crossover, drug-drug interaction study, healthy young male subjects received treatments A and B in a randomized fashion. Treatment A consisted of a single dose of 100mg ACT-178882 and treatment B of diltiazem 300mg once a day for 13days and a single dose of 100mg ACT-178882 on day 4. Serial blood samples for the measurement of ACT-178882 were drawn pre-dose and up to 120h post-dose during treatment A and pre-dose ACT-178882 and up to 240h post-dose during treatment B. Trough blood samples for the measurement of diltiazem were taken on days 1-5 of dosing during treatment B. Safety was assessed by recording of vital signs and electrocardiogram, clinical laboratory tests and adverse event reporting. Fourteen subjects were enrolled and completed the study. In the absence of diltiazem, the mean (95 % confidence interval [CI]) maximum concentration (Cmax) and area under the curve from time zero to infinity (AUC∞) were 26.8 (20.1-35.8) ng/mL and 454 (351-587) ng·h/mL, respectively. In the presence of diltiazem these values were 43.5 (36.8-51.4) ng/mL and 918 (781-1078) ng·h/mL, respectively. The median time to Cmax (tmax) for ACT-178882 was prolonged from 3.5 to 5.0h by diltiazem whereas its apparent terminal half-life (t½) was unaffected by diltiazem, 22.9 and 24.2h for treatments A and B, respectively. Using treatment A as reference, the geometric mean ratio (90 % CI) was 1.62 (1.36-1.94) for Cmax and 2.02 (1.75-2.34) for AUC∞, indicating a significant interaction between ACT-178882 and diltiazem. One (7.1 %) and 3 (21.3 %) of 14 subjects reported an adverse event during treatment A and B, respectively, with headache being the most frequently reported, with three events. There were no clinically relevant effects of treatments on vital signs, electrocardiogram or clinical laboratory variables. Concomitant administration of diltiazem doubled the exposure to ACT-178882 without affecting t½. The clinical significance of this increase is at present unknown and will need to be investigated in future clinical studies. Treatment with ACT-178882 alone or in combination with diltiazem was safe and well tolerated.

A prospective randomized longitudinal study involving 6 months of endurance or resistance exercise. Conduit artery adaptation in humans

Abstract This randomized trial evaluated the impact of different exercise training modalities on the function and size of conduit arteries in healthy volunteers. Young (27 ± 5 years) healthy male subjects were randomized to undertake 6 months of either endurance training (ET; n = 10) or resistance training (RT; n = 13). High-resolution ultrasound was used to determine brachial, femoral and carotid artery diameter and wall thickness (IMT) and femoral and brachial flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-mediated dilatation. Improvements in peak oxygen uptake occurred with ET (from 3.6 ± 0.7 to 3.8 ± 0.6 l min(-1), P = 0.024) but not RT. Upper body muscular strength increased following RT (from 57.8 ± 17.7 to 69.0 ± 19.5 kg, P < 0.001), but not ET. Both groups exhibited increases in lean body mass (ET, 1.4 ± 1.8 kg and RT, 2.3 ± 1.3 kg, P < 0.05). Resistance training increased brachial artery resting diameter (from 3.8 ± 0.5 to 4.1 ± 0.4 mm, P < 0.05), peak FMD diameter (+0.2 ± 0.2 mm, P < 0.05) and GTN-mediated diameter (+0.3 ± 0.3 mm, P < 0.01), as well as brachial FMD (from 5.1 ± 2.2 to 7.0 ± 3.9%, P < 0.05). No improvements in any brachial parameters were observed following ET. Conversely, ET increased femoral artery resting diameter (from 6.2 ± 0.7 to 6.4 ± 0.6 mm, P < 0.05), peak FMD diameter (+0.4 ± 0.4 mm, P < 0.05) and GTN-induced diameter (+0.3 ± 0.3 mm, P < 0.05), as well as femoral FMD-to-GTN ratio (from 0.6 ± 0.3 to 1.1 ± 0.8, P < 0.05). Resistance training did not induce changes in femoral artery parameters. Carotid artery IMT decreased in response to both forms of training. These findings indicate that 6 months of supervised exercise training induced changes in brachial and femoral artery size and function and decreased carotid artery IMT. These impacts of both RT and ET would be expected to translate to decreased cardiovascular risk.

Correlation between obesity and cardio respiratory fitness

Background: Maximal oxygen consumption (VO2max) is considered the gold standard of cardio-pulmonary and muscle cell fitness. Reduced cardiopulmonary fitness is associated with increased cardiovascular disease. Low cardio respiratory fitness in young adults has emerged as an important factor for developing cardiovascular comorbidies later in middle age. Obesity is a serious & widespread problem globally. Increased body fat as predicted by body mass index is an additional factor for developing cardiovascular diseases. Aims & Objective: The current study was designed to evaluate cardio respiratory fitness in terms of VO2max in young healthy males and to correlate between obesity and cardio respiratory fitness. Material and Methods: Sixty young healthy male subjects in the age group of 18 to 22 years were included in this study group. Body mass index was measured as weight in kilograms divided by height in meters square. Cardio respiratory fitness in terms of VO2max was predicted by following the protocol of Treadmill Jogging Test (TMJ). Results: There was a highly significant negative correlation between obesity and VO2max, r= -0.88 p

Consolidate effect of Vibhagha Pranayama, Nadishuddi Pranayama, Savithiri Pranayama and Kapalabhati Pranayama on the pulmonary functional status of young healthy male subjects

IntroductionPranayama is believed to increase the respiratory stamina, relax the chest muscles, expand the lungs, raise energy levels, calm the body and cause over-all improvement in lung functions. In the present study an attempt had been made to assess the authenticity of such changes.Methods60 male medical students in first year MBBS in the age group of 18 to 20 were recruited for this study. Thirty were in the control group who did not practice pranayama and the other thirty were in the study group who underwent the regular practice of pranayama daily for 30 minutes in the morning. Four types of pranayama namely Vibhagha pranayama, Kapalabhati pranayama, Nadi suddhi pranayama and Savithri pranayama were chosen for this study. Pulmonary function test was done to measure vital capacity, forced vital capacity, forced expiratory volume in first second, peak expiratory flow rate and maximum ventilatory volume before and after six weeks.ResultsThere was significant increase in all these variables (p &lt; 0.001) in the study group after 6 weeks of pranayama, whereas, control group did not show any significant change in these variables.The results of this study show the combined effect of different types of pranayama in improving the lung functions within the short period of six weeks.

24-Hour Intraocular Pressure of Young Healthy Humans in Supine Position: Rhythm and Reproducibility

We evaluated the supine 24-hour IOP rhythm reproducibility over 6 weeks in healthy humans. Six healthy young male subjects underwent six 24-hour sessions of IOP measurements over a 6-week period. Subjects were housed in a sleep laboratory in a constant controlled supine position and in a strictly controlled environment. IOP was measured hourly using a pneumatonometer. A nonlinear least-squares dual harmonic regression analysis was used to model the 24-hour IOP rhythm. The intra- and intersubject variability of acrophase, bathyphase, amplitude, and IOP values were evaluated. A significant nyctohemeral IOP rhythm was noted in 30 of 36 (83%) sessions. Mean nocturnal IOP was significantly higher than diurnal IOP (20.1 0.2 MM HG [SD] VS. 18.8 0.1 MM HG, P 0.001) in all subjects. Amplitudes were not statistically different among subjects (P = 0.52). IN contrast, acrophase and bathyphase were statistically different (P 0.05). Intrasubject homogeneity of distribution over time of the acrophase and bathyphase was significant in 3 of 6 and 4 of 6 subjects, respectively. Intraclass correlation coefficients of midline estimating statistic of rhythm (MESOR) and IOP values AT 2: 00, 3:00, 4:00, 10:00, and 11:00 AM, and 2:00 PM showed fair to good agreement among sessions. In a constant supine position, all subjects exhibited a nyctohemeral IOP rhythm present at an average rate of 80% of all sessions. With the currently available methods of tonometry, intrasubject reproducibility of rhythmic parameters and IOP values is limited. IOP values in the morning and IOP MESOR were the most reproducible parameters among the six visits.

Augmentation index as a specific marker of large arteries distensibility

lthough high blood pressure has been undoubtedlyshown to be a major risk factor for cardiovascularmorbidity and mortality at all ages and in bothsexes, the suitability and accuracy of traditional bloodpressure measurements for cardiovascular risk staging isnow a matter of lively debate [1]. In this context, thepossible additional contribution carried by central bloodpressure values assessment and by pulse wave analysis hasbeen underlined by a number of studies [2,3].Indeed, the technique of pulse wave analysis, usingnoninvasive high fidelity arterial tonometers, has recentlybecome increasingly popular [4,5]. This method can pro-vide not only quantitative, although indirect, informationconcerning the levels of central blood pressure, but alsoqualitative data on the ascending aortic waveform. Analysisof such waveforms can, in fact, define the elastic propertiesof the arterial wall and can estimate the importance and thetransmission speed of reflected waves [6,7].In the last years, augmentation index (AIx) has beenfrequently used in the context of pulse waveform analysisand has been suggested to represent a parameter able toreliablyreflectthelevelofarterialstiffnessintheassessmentof cardiovascular risk. Assessment of AIx provides anindication of the role played by reflected waves in deter-mining pulse pressure. The contribution of the backwardwave to pulse pressure is related to the timing of its super-imposition onto the forward wave, as well as to its magni-tude and shape. AIx is calculated as the ratio between theaugmented central pressure, due to reflected waves, andpulse pressure. Conditions of markedly increased arterialstiffness are characterized by an early superimposition ofbackward waves onto the forward wave, causing anincrease in central SBP. Assessment of AIx has, thus, beenproposedasasimpleapproachtoquantifytheroleofwavereflection in determining an elevation of central bloodpressure values.However, it has to be acknowledged that several otherfactors, apart from the viscoelastic properties of the aortaand of large arteries [8], may affect AIx, in particular: themagnitude and variability of reflected waves, mainly inrelation to systemic vascular resistance; the length of theaorta (related to an individual’s height), because at anygiven level ofarterial distensibility, thenearer the reflectionsites are to the ascending aorta, the shorter is the timeneeded for the reflected wave to reach it; the participant’sheart rate, an increase in heart rate being accompanied byanincreaseinpulsewavevelocity,butalsobyadecreaseinaugmented pressure [3], that is in AIx; the phenomenon ofpressure waves attenuation while travelling along the arte-rial tree; and the role of gender, several studies havingshown significantly higher values of AIx in female than inmale individuals of comparable height (Fig. 1).Thus, given the contribution of several factors to AIxmagnitude, use of this parameter as a specific index of theviscoelastic properties of large arteries is incorrect and maylead to inaccurate estimates. In fact, in clinical practice it isnot uncommon to find a marked discrepancy betweenpulse wave velocity (considered as the gold standardmarker of arterial distensibility [9]) and AIx values, whichmay indeed be due to the multiple factors involved indetermining the latter parameter.The article by Cheng et al. [10], published in this issue ofthe Journal of Hypertension, was aimed at exploringthe potential contribution of cardiac motion and arterialproperties, respectively, to arterial pressure waveformparameters, in particular to AIx.The conclusion of this study is that AIx may not bepredominantly determined by arterial properties, but, onthe contrary, it largely depends on left ventricular systolicfunction. Thus, based on these data, the use of AIx as asurrogate index of arterial stiffness might need to be recon-sidered [10].These conclusions are based on data collected in 20healthy male individuals (median age 22.3 years), withoutcardiovascular risk factors and free of chronic diseases. Ithas to be emphasized that although the selective inclusionin this study of a healthy young male cohort has carried theadvantage of minimizing the possible confounding effects

Cold-induced vasodilatation response in the fingers at 4 different water temperatures

We evaluated the cold-induced vasodilatation (CIVD) response at 4 different water temperatures. Nine healthy young male subjects immersed their right hands in 35 °C water for 5 min, and immediately thereafter for 30 min in a bath maintained at either 5, 8, 10, or 15 °C. The responses of finger skin temperatures, subjective ratings of thermal comfort and temperature sensation scores were compared between the 4 immersion trials. The number of subjects who exhibited a CIVD response was higher during immersion of the hand in 5 and 8 °C (100%) compared with 10 and 15 °C water (87.5% and 37.5%, respectively). The CIVD temperature amplitude was 4.2 ± 2.6, 3.4 ± 2.0, 2.1 ± 1.6, and 2.8 ± 2.0 °C at 5, 8, 10, and 15 °C trials, respectively; higher in 5 and 8 °C compared with 10 and 15 °C water (p = 0.003). No differences in CIVD were found between the 5 and 8 °C immersions. However, during immersion in 5 °C, subjects felt "uncomfortable" while in the other trials felt "slightly uncomfortable" (p = 0.005). The temperature sensation score was "cold" for 5 °C and "cool" for the other trials, but no statistical differences were observed. Immersion of the hand in 8 °C elicits a CIVD response of similar magnitude as immersion in 5 °C, but with less thermal discomfort.

Exercise Alleviates Lipid-Induced Insulin Resistance in Human Skeletal Muscle–Signaling Interaction at the Level of TBC1 Domain Family Member 4

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.

드롭랜딩 시 높이 변화에 따른 인체 분절의 충격흡수 전략에 관한 연구

The purpose of current study was to investigate the effects of the heights on the lower extremities, torso and neck segments for energy dissipation during single-leg drop landing from different heights. Twenty eight young healthy male subjects(age: <TEX>$23.21{\pm}1.66yr$</TEX>, height: <TEX>$176.03{\pm}4.22cm$</TEX>, weight: <TEX>$68.93{\pm}5.36kg$</TEX>) were participated in this study. The subjects performed the single-leg drop landing from the various height(30, 45 & 60 cm). Force plates and motion-capture system were used to capture ground reaction force and kinematics data, respectively. The results were as follows. First, the ROM at the ankle, knee, hip and trunk was increased with the increased heights but the ROM at the neck was increased in the 60cm. Second, the angular velocity, moment and eccentric work at the ankle, knee, hip, trunk, and neck was increased with the increased heights. Third, the contribution to total work at the knee joint was not significantly different, while the ankle joint rate was decreased and hip and neck rate was increased in the 60cm, and trunk rate was increased with the increased heights. Lastly, the increase in landing height was able to augment the level of energy dissipation not only at the lower extremities but also at the trunk and neck. The findings showed that drop landing affect trunk and neck with lower extremity joints. Therefore, we need to consider that trunk and neck strengthening including stability should be added to reduce sports injury during prevention training.

24‐hour intraocular pressure of healthy humans in supine position: rhythm and reproducibility

AbstractPurpose To evaluate the reproducibility over time of 24H intraocular pressure (IOP) rhythm in healthy humans in supine position.Methods In a sleep laboratory, six healthy young Caucasian male subjects were included in each six weekly 24H sessions of hourly IOP measurements in a control supine position using the pneumatonometer Digilab Modular One. IOP 24H rhythm was modelled using a nonlinear least squares dual harmonic regression analysis. The intra‐ and inter‐subject variability of acrophase, bathyphase, amplitude and IOP values were evaluated.Results A significant nyctohemeral IOP rhythm was noted in 30/36 (83%) sessions. Nocturnal IOP was significantly higher than diurnal IOP (20.1 ± 0.2 vs. 18.8 ± 0.1 mmHg). Reproducible distribution over 24H of intra‐subject acrophase and bathyphase was found respectively in 3/6 (50%) and 4/6 (67%) subjects. Intra‐subject means of amplitude were not statistically different between subjects. IOP values at 2:00, 3:00, 4:00, 10:00, 11:00 AM and 2:00 PM and IOP mesor had fair to good agreement between sessions.Conclusion Most healthy subjects exhibited a nyctohemeral rhythm of IOP with fair reproducible characteristics in supine position. Amplitude is the best reproducible parameter. This result strongly suggests that chronobiological lower IOP therapies could be powerfully studied using paired intra‐subject 24H nyctohemeral rhythm data comparison, during repeated sessions overtime before and after treatment.

Randomized, placebo-controlled, double blind, single- and multiple-dose study to evaluate the pharmacokinetics, safety and tolerability of avagacestat (BMS-708163) in healthy young male and elderly male and female Chinese subjects

Randomized, placebo-controlled, double blind, single- and multiple-dose study to evaluate the pharmacokinetics, safety and tolerability of avagacestat (BMS-708163) in healthy young male and elderly male and female Chinese subjects

Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects

Skeletal muscle mitochondrial content varies extensively between human subjects. Biochemical measures of mitochondrial proteins, enzyme activities and lipids are often used as markers of mitochondrial content and muscle oxidative capacity (OXPHOS). The purpose of this study was to determine how closely associated these commonly used biochemical measures are to muscle mitochondrial content and OXPHOS. Sixteen young healthy male subjects were recruited for this study. Subjects completed a graded exercise test to determine maximal oxygen uptake (VO2peak) and muscle biopsies were obtained from the vastus lateralis. Mitochondrial content was determined using transmission electron microscopy imaging and OXPHOS was determined as the maximal coupled respiration in permeabilized fibres. Biomarkers of interest were citrate synthase (CS) activity, cardiolipin content, mitochondrial DNA content (mtDNA), complex I–V protein content, and complex I–IV activity. Spearman correlation coefficient tests and Lin's concordance tests were applied to assess the absolute and relative association between the markers and mitochondrial content or OXPHOS. Subjects had a large range of VO2peak (range 29.9–71.6ml min−1 kg−1) and mitochondrial content (4–15% of cell volume).Cardiolipin content showed the strongest association with mitochondrial content followed by CS and complex I activities. mtDNA was not related to mitochondrial content. Complex IV activity showed the strongest association with muscle oxidative capacity followed by complex II activity.We conclude that cardiolipin content, and CS and complex I activities are the biomarkers that exhibit the strongest association with mitochondrial content, while complex IV activity is strongly associated with OXPHOS capacity in human skeletal muscle.

Pharmacokinetic Studies on Metoprolol - Eudragit Matrix Tablets and Bioequivalence Consideration with Mepressor&lt;sup&gt;®&lt;/sup&gt;

Purpose: To investigate the pharmacokinetics of of a developed metoprolol and a reference standard (Mepressor&reg;).Methods: Metoprolol tartrate-loaded Eudragit&reg; FS microparticles were formulated and compressed into tablets. The tablets were tested for their physicochemical properties according to United States Pharmacopoeia (USP) criteria. In vivo studies of the formulations were carried out in 28 young healthy fasting male volunteers based on a randomized open label 4&times;4 crossover study design with a washout period of 7 days.Results: In vitro tests showed that the developed and reference standard of metoprolol tablets met compendia (USP) requirements. Zero order release of drug was observed from all the tablets. In vivo data demonstrated that there were significant (p &lt; 0.05) differences in tmax, Cmax, MRT, AUC0&minus;t, and AUC0&ndash;&infin; between the reference and test (developed) formulations. However, the 90 % class interval for the mean ratios of the ln-transformed Cmax, AUC0-t and AUC0-&alpha; for the reference, T1, T2, and T3 lied in the bioequivalence range (80 to 125 %) indicating bioequivalence between the compared formulations.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Conclusion: It can be concluded from this single-dose study that the reference and test (developed) formulations met the predetermined criteria for bioequivalence in young healthy fasting male human subjects as the bioequivalence factor lie in the pre-determined limits for bioequivalence. Thus, the two formulations can be considered bioequivalent.Keywords: Metoprolol tartrate, Eudragit&reg; FS, Microparticles, Bioavailability, Pharmacokinetics.

Circulating Brain-Derived Neurotrophic Factor Concentration Is Downregulated by Intralipid/Heparin Infusion or High-Fat Meal in Young Healthy Male Subjects

OBJECTIVEInsulin resistance and type 2 diabetes are associated with an increased risk of neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) regulates neuronal differentiation and synaptic plasticity, and its decreased levels are supposed to play a role in the pathogenesis of Alzheimer’s disease and other disorders. The aim of the current study was to estimate the effects of hyperinsulinemia and serum free fatty acids (FFA) elevation on circulating BDNF concentration in humans.RESEARCH DESIGN AND METHODSWe studied 18 healthy male subjects (mean age 25.6 ± 3.0 years; mean BMI 26.6 ± 4.8 kg/m2). Serum and plasma BDNF concentration was measured in the baseline state and in the 120 and 360 min of euglycemic hyperinsulinemic clamp with or without intralipid/heparin infusion. Furthermore, plasma BDNF was measured in 20 male subjects (mean age 22.7 ± 2.3 years; mean BMI 24.9 ± 1.5 kg/m2) 360 min after a high-fat meal.RESULTSInsulin sensitivity was reduced by ∼40% after 6 h of intralipid/heparin infusion (P < 0.001). During both clamps, serum and plasma BDNF followed the same pattern. Hyperinsulinemia had no effect on circulating BDNF. Raising FFA had no effect on circulating BDNF in 120 min; however, it resulted in a significant decrease by 43% in serum and by 35% in plasma BDNF after 360 min (P = 0.005 and 0.006, respectively). High-fat meal also resulted in a decrease by 27.8% in plasma BDNF (P = 0.04).CONCLUSIONSOur data show that raising FFA decreases circulating BDNF. This might indicate a potential link between FFA-induced insulin resistance and neurodegenerative disorders.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.

Effect of Water Load, Saline Load and Lipton Tea on Urine Output and Urine Ph in Young Healthy Male and Female Human Subjects

The study was aimed at comparing the diuretic effect of saline load, water load and Lipton tea in between healthy male and female undergraduate medical students ( 18-26yrs). They were randomly grouped into five groups having both male and female subjects : control(A),water(B), normal saline(C), Hypertonic saline,1%(D), Lipton tea(E). The day before the experiment, instructions were given; the experimental groups drank their solution 12ml/kg body weight then the urine output was measured at 30mins interval. Paired t-test was used to analyse result between male and female intra group difference in urine output and pH with significant level having p value ≤ 0.05. The data are presented as mean±SEM. In water group at 30mins showed diuretic effect in both male and female (132.6±31.44 and 223.8±76) respectively and peaked at 60mins (202.4±38.96 and 304±36.78) in male and female. Lipton tea also showed diuretic effect which started in the females at 30mins (68.2±8.92) while it started at 60mins(185.6±34.24) in the males. It is therefore concluded that male and female subjects have same response to volume loading, however they were little variations in their pattern of response to this volume loading.

Cognitive manipulation targeted at decreasing the conditioning pain perception reduces the efficacy of conditioned pain modulation

Although painfulness of the conditioning stimulus (CS) is required for the activation of conditioned pain modulation (CPM), it is still unclear whether CPM expression depends on the objective physical intensity of the CS or the subjective perception of its pain. Accordingly, we cognitively manipulated the perceived CS pain, rendering the physical aspects of the CPM paradigm untouched. Baseline CPM was measured among 48 young healthy male subjects using the parallel paradigm with contact heat as test pain and hand immersion in hot water as CS. Subjects were then randomized into 4 groups, all of which were cognitively manipulated as to the CS-induced pain: group 1, placebo (CS less painful); group 2, nocebo (CS more painful); and groups 3 and 4, the informed control groups for groups 1 and 2, respectively. CPM was reassessed after the manipulation. Comparing the groups by MANCOVA (multivariate analysis of covariance) revealed that placebo exerted decreased CS pain and consequent attenuation of CPM magnitudes, while nocebo elicited increased CS pain, but without CPM elevation ( P < .0001). Within the placebo group, the reduction in CS pain was associated with diminished CPM responses ( r = 0.767; P = .001); however, no such relationship characterized the nocebo group. Pain inhibition under CPM seems to depend on the perceived level of the CS pain rather than solely its physical intensity. Cognitively decreasing the perceived CS pain attenuates CPM magnitude, although a ceiling effect may limit CPM enhancement after cognitively increased CS pain. These findings emphasize the relevance of cognitive mechanisms in determining endogenous analgesia processes in humans.

Brain oxidative stress: Detection and mapping of anti-oxidant marker ‘Glutathione’ in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy

Glutathione (GSH) serves as an important anti-oxidant in the brain by scavenging harmful reactive oxygen species that are generated during different molecular processes. The GSH level in the brain provides indirect information on oxidative stress of the brain. We report in vivo detection of GSH non-invasively from various brain regions (frontal cortex, parietal cortex, hippocampus and cerebellum) in bilateral hemispheres of healthy male and female subjects and from bi-lateral frontal cortices in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). All AD patients who participated in this study were on medication with cholinesterase inhibitors. Healthy young male (age 26.4±3.0) and healthy young female (age 23.6±2.1) subjects have higher amount of GSH in the parietal cortical region and a specific GSH distribution pattern (parietal cortex>frontal cortex>hippocampus∼cerebellum) has been found. Overall mean GSH content is higher in healthy young female compared to healthy young male subjects and GSH is distributed differently in two hemispheres among male and female subjects. In both young female and male subjects, statistically significant (p=0.02 for young female and p=0.001 for young male) difference in mean GSH content is found when compared between left frontal cortex (LFC) and right frontal cortex (RFC). In healthy young female subjects, we report statistically significant positive correlation of GSH content between RFC and LFC (r=0.641, p=0.004) as well as right parietal cortex (RPC) and left parietal cortex (LPC) (r=0.797, p=0.000) regions. In healthy young male subjects, statistically significant positive correlation of GSH content was observed between LFC and LPC (r=0.481, p=0.032) regions. This statistical analysis implicates that in case of a high GSH content in LPC of a young male, his LFC region would also contain high GSH and vice versa. The difference in mean of GSH content between healthy young female control and female AD patients in RFC region (p=0.003) and difference in mean of GSH content between healthy young male control and male AD patients (p=0.05) in LFC region is found to be statistically significant. It is the first scientific report correlating alteration (in selective brain regions) of GSH level with clinical status of male and female subjects using non-invasive imaging technique.