Arrhythmic risk evaluation during exercise at high altitude in healthy subjects: role of microvolt T-wave alternans

Background: Altitude‐induced sympathetic hyperactivity can elicit rhythm disturbances in healthy subjects, in particular during exercise. Aim: To asses the real susceptibility of healthy myocardium to malignant ventricular arrhythmias during exercise at high altitude using microvolt T‐wave alternans (MTWA). Methods: We evaluated eight healthy trained participants (one female, 42 ± 9 years) during a mountain climbing expedition on Gashembrum II (Pakistan, 8,150 m). MTWA and heart rate variability (HRV) were measured in each subject at sea level and at high altitude, both under rest conditions and during exercise. MTWA was determined with the modified moving average method. HRV was expressed as root mean square of successive differences. Results: Rest HRV at high altitude was significantly lower compared to rest HRV at sea level (36 ± 5 vs 56 ± 9 ms, P = 0.003). HRV during exercise was significantly lower with respect to rest condition both in normoxia (46 ± 7 vs 56 ± 9 ms, P = 0.0001) and hypoxia (27 ± 4 vs 36 ± 5 ms, P = 0.005). Moreover, HRV was significantly lower during exercise at high altitude compared to exercise at sea level (27 ± 4 vs 46 ± 7 ms, P = 0.0002) and arrhythmias were more frequent during exercise in hypoxia. Nevertheless, MTWA was absent under rest conditions both at sea level and at high altitude and minimally evoked during exercise in both conditions (22 ± 3 μV and 23 ± 3 μV, respectively, P = 0.2). Conclusions: In spite of an enhanced sympathetic activity, MTWA testing during exercise at high altitude was negative in all participants. Healthy trained subjects during exercise under hypoxia seem to be at low risk for dangerous arrhythmias.     

Comparison of the pharmacokinetics of sulfamethoxazole in male chinese volunteers at low altitude and acute exposure to high altitude versus subjects living chronically at high altitude: An open-label,controlled, prospective study

Background: Sulfamethoxazole is an antibacterial sulfonamide used primarily for the treatment of a wide variety of bacterial infections in combination with trimethoprim. Despite being used as prophylactic treatment for respiratory infections associated with high altitude, little information is available on the pharmacokinetic properties of sulfamethoxazole in subjects living at high altitude, especially in a Chinese population.Objective: This study was conducted to investigate the pharmacokinetics of sulfamethoxazole in healthy Chinese subjects after acute and chronic exposure to high altitude.Methods: An open-label, controlled, prospective study was conducted in healthy Chinese male volunteers. Sulfamethoxazole 1200 mg was administered orally to volunteers in 3 groups: those residing at low altitude (~400 m [~1300 ft]); these same volunteers after 16 hours (acute) of exposure to high altitude (~3780 m [~12,400 ft]); and a separate group of volunteers who had been living at high altitude (~3780 m) for ≥1 year (chronic). The phases of the low-altitude and acute-exposure groups were separated by a 1-week washout period. Blood samples were collected from an indwelling venous catheter into heparinized tubes before (baseline) study drug administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours after study drug administration. Sulfamethoxazole in whole blood, plasma, and plasma water, and its metabolite, N⁴-acetyl-sulfamethoxazole, in plasma were determined by HPLC. Tolerability was determined using blood chemistry testing, continuous 12-lead ECG, and blood pressure monitoring.Results: A total of 23 healthy Chinese male volunteers living at low altitude (race, all Han Chinese; mean [SD] age, 20.4 [1.1] years [range, 19–24 years]; weight, 64.2 [5.9] kg [range, 56.0–75.0 kg]; and height, 172.1 [4.9] cm [range, 163.0–180.0 cm]) and 21 healthy Chinese male volunteers living at high altitude (race, all Han Chinese; mean [SD] age, 21.2 [1.3] years [range, 19–24 years]; weight, 62.4 [8.2] kg [range, 50.0–75.0 kg]; and height, 171.4 [5.8] cm [range, 162.0–182.0 cm]) were enrolled in the study; 20 from each group completed the study. Concentration of sulfamethoxazole in plasma water decreased significantly after exposure to high altitude; therefore, the protein binding was significantly higher in the acute- (80.4%) and chronic-exposure (72.5%) groups compared with the low-altitude group (65.7%; both, P < 0.001). The binding of sulfamethoxazole to red blood cells was 6.0%, 6.9%, and 9.3% in the low-altitude, acute-, and chronic-exposure groups, respectively. The chronic-exposure group was 55% higher than the low-altitude group (P < 0.001). The following values were recorded in the low-altitude, acute-, and chronic-exposure groups after administration of sulfamethoxazole, respectively: mean (SD) t_½, 9.30 (1.11), 10.37 (0.88), and 11.15 (1.53) hours; mean residence time (MRT_0–48), 12.06 (0.94), 13.15 (0.67), and 13.00 (1.01) hours; elimination rate constant (k_e), 0.076 (0.010), 0.067 (0.006), and 0.063 (0.009) hours^?1; AUC_0–48, 1202.5 (238.3), 1416.3 (202.6), and 1298.5 (256.0) μ/mL/h; and clearance (CL), 1.01 (0.22), 0.83 (0.13), and 0.92 (0.22) L/kg/h. The t_½ was 11.5% and 19.9% higher in the acute- and chronic-exposure groups, respectively, compared with the low-altitude group, and 7.5% higher in the chronic-exposure group than in the acute-exposure group. MRT was 9.0% and 7.8% higher in the acute- (P < 0.05) and chronic-exposure (P < 0.001) groups, respectively, than in the low-altitude group. AUC_0–48 was 17.8% higher and CL was 17.8% lower in the acute-exposure group compared with the low-altitude group (both, P < 0.05).Conclusion: This study found significant changes in the disposition of sulfamethoxazole in these healthy male Chinese subjects after either acute or chronic exposure to an altitude of ~3780 m in comparison to those residing at an altitude of ~400 m.     

Relationship between physical factors and tibial motion in healthy subjects: 2D and 3D analyses

This study was undertaken to determine the relationship between physical factors and vertical axial rotation through the tibial shaft caused by passive knee and subtalar joint rotation in healthy subjects. The data collected were analyzed in detail to determine the relationship between various physical parameters, such as age, body mass, height, and sex, and tibial rotation. A total of 484 healthy subjects were examined with the measuring the vertical axial rotation through tibial shaft (MVARTS) system. Evaluators passively measured internal and external tibial rotation. The effects of any 2 simultaneous variables and outcomes with a single variable were analyzed; the results were documented graphically. Data were also examined through multiple regression analysis (stepwise regression). Agreement between right and left internal tibial rotations was observed to be strong, as was agreement between right and left external rotations. Female patients exhibited a greater amount of internal/external rotation than did male patients. Differences between female and male patients were noted to be significant. A highly significant and inverse relationship between physical parameters and tibial rotations was noted. Findings suggest that as age, body mass, and height increase, tibial motion is reduced.     

Sizing the mitral annulus in healthy subjects and patients with mitral regurgitation: 2D versus 3D measurements from cardiac CT

The purpose of our study was (1) to assess retrospectively, in healthy subjects and in patients with moderate and severe functional mitral regurgitation (FMR), the normal mitral annular dimensions, (2) to determine differences in mitral annular geometry between healthy subjects and patients with FMR, and (3) to evaluate potential errors in 2-dimensional (2D) measurements given the 3D nature of the mitral annulus. 15 patients with no cardiac abnormalities (referred to as normals), 13 with moderate and 15 with severe FMR as determined by echocardiography underwent contrast-enhanced cardiac 64-slice Computed tomography (CT) with prospective electrocardiography-gating for excluding coronary artery disease. With an advanced visualization, segmentation, and image analysis software, the area, intercommissural distance (CC), septolateral distance (SLD), and the anterior and posterior circumference of the MA were measured in diastole. We found significant (P < .001) differences between normals and patients with severe FMR for area, SLD and posterior circumference in 3D (P < .001) and 2D (P < .001). Similarly, the SLD and the posterior circumference in both 3D (P = .002) and 2D (P = .001) were significantly smaller in patients with moderate FMR as compared to those with severe FMR. In contrast, there were no significant differences between groups regarding the CC and the anterior circumference both in 3D and 2D (all, P > .05). Measurements in 3D differed significantly from those with 2D for all circumference measurements and groups (P < .01), with a systematic underestimation of the posterior circumference of 2.1 ± 1.5 mm in normals, 1.8 ± 1.3 mm in patients with moderate FMR, and 1.9 ± 1.9 mm in patients with severe FMR for 2D. Our study provides in vivo human CT data on MA dimensions in normals and patients with FMR, indicating differences in patients for the area, posterior circumference and SLD but not for the anterior circumference and CC. Systematic differences exist between 2D and 3D measurements for all circumferential measurements.     

A novel intronic mutation, 2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects

BACKGROUND: Individuals with the cytochrome P450 (CYP) 2D6 intermediate metabolizer (IM) phenotype have low residual enzyme activity and compose about 10% to 15% of white populations. Their identification is clinically relevant but remains unsatisfactory because of incomplete characterization of the major allele involved, termed CYP2D6*41 (-1584C, R296C, S486T). METHODS: To search for novel mutations, resequencing of the entire CYP2D6 gene was performed in selected individuals. Genotype-phenotype correlation analysis was done in a population sample of 308 white subjects phenotyped with sparteine and previously genotyped for all major alleles. RESULTS: A total of 16 novel polymorphic positions were identified, of which 7 were located within 2.4 kilobases of previously uncharacterized 2D7-2D6 intergenic sequence and 9 were located within intronic regions. The novel mutation 2988G>A in intron 6 appeared to be specifically associated with the IM phenotype. Further analysis in the population sample demonstrated that 2988G>A was strongly linked to allele *41 but not to any other alleles including *1, *2, *2xN, *4, *6, *7, *8, *9, *10, and *35. The overall frequency of the novel polymorphism was 8.4% in the normal white population. Compared with conventionally determined *41, 2988G>A was shown to have improved predictivity for the IM phenotype. With 2988G>A being taken into account, alleles *1, *2, and *35 (-1584G, V11M, R296C, S486T) were found to be phenotypically equivalent. CONCLUSIONS: CYP2D6 genotyping can be considerably simplified by using 2988G>A as a marker for *41 and by omitting genotyping for the functionally equivalent alleles *2 and *35.     

Post-exercise heart rate recovery in healthy,obeses, and COPD subjects: relationships with blood lactic acid and PaO<Subscript>2</Subscript> levels

Because blood acidosis and arterial oxygenation (PaO₂) play key roles in the chemoreflex control of cardiac activity, we hypothesized that heart rate (HR) decay rate after maximal exercise may be linked to post-exercise increase in blood lactate (LA) level and/or the resting PaO₂. Twenty healthy subjects and thirty five patients at risks of cardiovascular diseases (20 obeses; 15 patients with chronic obstructive pulmonary disease, COPD) performed a maximal cycling exercise. During the recovery period, HR was continuously measured for consecutive 10-s epochs allowing to compute linear or second order polynomial equations and to calculate every minute HR variations compared to peak HR value (ΔHR). PaO₂ was measured at rest and post-exercise maximal LA level was determined. A second order polynomial equation (y = a ₂ x ² + b ₂ x + c) best fitted the post-exercise HR decay rate. The a ₂ and b ₂ coefficients and ΔHR did not depend on age, sex, and body mass index. Despite a large scattering of HR decay rate, even present in healthy subjects, a ₂ and ΔHR were significantly lower in obeses and COPDs. In the whole population, both a ₂ coefficient and ΔHR were negatively correlated with maximal post-exercise LA level. ΔHR was lowered in hypoxemic patients. Thus, the slowest post-exercise HR decay rate was measured in subjects having the highest peak LA increase or hypoxemia. Thus, even in healthy subjects, the post-exercise HR decay rate is lowered in individuals having an accentuated exercise-induced LA increase and/or hypoxemia. The mechanisms of delayed post-exercise HR recovery are only suspected because significant correlations cannot assess cause-to-effect relationships.     

N‐acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double‐blind controlled trial in healthy subjects

Paracetamol (APAP) may lead to hepatic changes even at therapeutic dosages. Glutathione (GSH) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N‐Acetylcysteine (NAC) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP. This study aims at evaluating if 1‐ NAC modifies APAP pain efficacy and 2‐ NAC prevents glutathione depletion with APAP at therapeutic doses. This double‐blind randomized controlled study (NCT02206178) was carried out in 24 healthy volunteers. APAP was given for 4 days (1 g ×4 daily) with NAC or with placebo. Thermal pain tests, whole blood GSH, and hepatic enzymes (ASAT, ALAT) were measured before (D0) and after (D4) oral APAP‐NAC or APAP‐placebo intake. anova for repeated measures adapted to cross‐overdesign was performed and a two‐tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0–240 min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway‐Medoc^®. APAP antinociceptive effect was similar in both groups. GSH was maintained to its baseline value in the APAP/NAC group but diminished in the APAP/placebo group (P = 0.033). This study shows for the first time that APAP antinociceptive effectiveness is not influenced by NAC. It also shows that the effect of APAP at therapeutic dosage on GSH may be counteracted by NAC. These issues are particularly important for patients as APAP is often prescribed for years as a first‐line pain treatment and further trials in patients are now warranted.     

3D correction over 2 years with anterior vertebral body growth modulation: A finite element analysis of screw positioning,cable tensioning and postoperative functional activities

BackgroundAnterior vertebral body growth modulation is a fusionless instrumentation to correct scoliosis using growth modulation. The objective was to biomechanically assess effects of cable tensioning, screw positioning and post-operative position on tridimensional correction.MethodsThe design of experiments included two variables: cable tensioning (150/200 N) and screw positioning (lateral/anterior/triangulated), computationally tested on 10 scoliotic cases using a personalized finite element model to simulate spinal instrumentation, and 2 years growth modulation with the device. Dependent variables were: computed Cobb angles, kyphosis, lordosis, axial rotation and stresses exerted on growth plates. Supine functional post-operative position was simulated in addition to the reference standing position to evaluate corresponding growth plate’s stresses.FindingsSimulated cable tensioning and screw positioning had a significant impact on immediate and after 2 years Cobb angle (between 5°–11°, p < 0.01). Anterior screw positioning significantly increased kyphosis after 2 years (6°–8°, p = 0.02). Triangulated screw positioning did not significantly impact axial rotation but significantly reduced kyphosis (8°–10°, p = 0.001). Growth plates' stresses were increased by 23% on the curve's convex side with cable tensioning, while screw positioning rather affected anterior/posterior distributions. Supine position significantly affected stress distributions on the apical vertebra compared to standing position (respectively 72% of compressive stresses on convex side vs 55%).InterpretationThis comparative numerical study showed the biomechanical possibility to adjust the fusionless instrumentation parameters to improve correction in frontal and sagittal planes, but not in the transverse plane. The convex side stresses increase in the supine position may suggest that growth modulation could be accentuated during nighttime.     

γ2-MSH increases during graded exercise in healthy subjects: comparison with plasma catecholamines,neuropeptides, aldosterone and renin activity

Summary. To evaluate the possibility that the proopiomelanocortin (POMC)-derived peptide γ₂-melanocyte stimulating hormone (γ₂-MSH) has a role in circulatory regulation in man we studied circulating levels of this peptide at three different stages of physical activity in 10 young healthy subjects. The results were compared to simultaneously measured plasma levels of catecholamines, neuropeptide Y, vasopressin, renin activity, aldosterone and human α-atrial natriuretic peptide (α-hANP) and of the vasodilatory peptides calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. The plasma levels of γ₂-MSH-LI (like immunoreactivity) increased from 1009 ± 101 pmol 1^-1 at supine rest to 1281 ± 79 pmol 1^-1 when measured after 10 min walking (P<0·05), and remained at this increased level also after a consecutive further increase of physical activity (4 min stair rush), 1293 ± 87 pmol 1^-1 (P<0·05 vs. at rest). The increase in circulating γ₂-MSH-LI levels preceded the elevation of the venous plasma noradrenaline level, but did not rise further with more pronounced activation of the sympathetic nervous system at the highest grade of physical activity examined.     

Simultaneous determination of methadone and morphine at a modified electrode with 3D β-MnO2 nanoflowers: application for pharmaceutical sample analysis

The present research synthesized manganese dioxide nano-flowers (β-MnO₂-NF) via a simplified technique for electro-catalytic utilization. Moreover, morphological characteristics and X-ray analyses showed Mn in the oxide form with β-type crystallographic structure. In addition, the research proposed a new efficient electro-chemical sensor to detect methadone at the modified glassy carbon electrode (β-MnO₂-NF/GCE). It has been found that oxidizing methadone is irreversible and shows a diffusion controlled procedure at the β-MnO₂-NF/GCE. Moreover, β-MnO₂-NF/GCE was considerably enhanced in the anodic peak current of methadone related to the separation of morphine and methadone overlapping voltammetric responses with probable difference of 510 mV. In addition, a linear increase has been observed between the catalytic peak currents gained by the differential pulse voltammetry (DPV) of morphine and methadone and their concentrations in the range between 0.1–200.0 μM and 0.1–250.0 μM, respectively. Furthermore, the limits of detection (LOD) for methadone and morphine were found to be 5.6 nM and 8.3 nM, respectively. It has been found that our electrode could have a successful application for detecting methadone and morphine in the drug dose form, urine, and saliva samples. Thus, this condition demonstrated that β-MnO₂-NF/GCE displays good analytical performances for the detection of methadone.

Electrochemical sensor based on β-MnO₂ nanoflower-modified glassy carbon electrode for the simultaneous detection of methadone and morphine was fabricated.     

A convenient enzymatic method for the determination of 4-methyl-2-oxopentanoate in plasma: comparison with high performance liquid chromatographic analysis

A simple and rapid spectrophotometric method for the estimation of 4-methyl-2-oxopentanoate in plasma samples by use of NAD+-dependent D-2-hydroxyisocaproate dehydrogenase from Lactobacillus casei ssp. pseudoplantarum is described. It is based on the kinetic measurement of the decrease of NADH absorbance at 334 nm. Applicability is demonstrated by comparative measurement of 4-methyl-2-oxopentanoate content in plasma of patients with maple syrup urine disease by the enzymatic and a reversed phase high performance liquid chromatographic method.     

Clinical implications of gait analysis in the rehabilitation of adult patients with "Prader-Willi" Syndrome: a cross-sectional comparative study ("Prader-Willi" Syndrome vs matched obese patients and healthy subjects)

Background  

Being severely overweight is a distinctive clinical feature of Prader-Willi Syndrome (PWS). PWS is a complex multisystem disorder, representing the most common form of genetic obesity. The aim of this study was the analysis of the gait pattern of adult subjects with PWS by using three-Dimensional Gait Analysis. The results were compared with those obtained in a group of obese patients and in a group of healthy subjects.     

Pharmacokinetics of gabapentin after a single day and at steady state following the administration of gastric-retentive- extended-release and immediate-release tablets: a randomized, open-label, multiple-dose, three-way crossover, exploratory study in healthy subjects

BACKGROUND: Gabapentin absorption is mediated by a saturable transporter system located in the upper gastrointestinal tract, indicating a short window of absorption. Therefore, conventional sustained formulations would likely result in decreased bioavailability, as the dosage form would pass through the window of absorption before the drug could be completely released. OBJECTIVE: The aim of this study was to compare the pharmacokinetics of an oral, gastric-retentive, gabapentin extended-release (G-ER) formulation with a gabapentin immediate-release (G-IR) formulation after single and multiple daily doses in healthy subjects. METHODS: In this open-label, multiple-dose, 3-way crossover, exploratory study, healthy male and female subjects (aged 18-65 years) were randomized to receive doses of 1800 mg G-ER in accordance with the following regimens: G-ER QD (8 pm), G-ER BID in divided doses (600 mg at 8 am and 1,200 mg at 8 pm), or G-IR TID (600 mg at 8 am, 2 pm, and 8 pm) on day 1 and on days 4 through 8 of each study period. The subjects underwent a 10-day washout between study periods. Gabapentin plasma concentrations were measured in serial plasma samples collected >or=48 hours following dosing on days 1 and 8 using a validated high performance liquid chromatography/tandem mass spectrometry system with a lowest limit of quantitation of 75 ng/mL. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. RESULTS: Of the 24 subjects enrolled in the study, 21 (11 males, 10 females; mean age, 37 years [range, 23- 60 years]; mean height, 172 cm [range, 158-188 cm], mean weight, 77 kg [range, 56-95 kg]; mean body mass index, 26.2 kg/m2 [range, 21.5-29.7 kg/m2]) completed the study. The completing subjects consisted of 8 whites, 7 blacks, 3 Asians, and 3 Hispanics. At steady state, exposure of both G-ER regimens (QD and BID) appeared similar compared with that of G-IR. However, BID dosing resulted in apparently lower C(max) (mean ratio: 81%; CI 90%, 76%-86%) and greater C(min) values (mean ratio: 118%; CI 90%, 107%-130%), while G-ER QD dosing was associated with numerically greater C(max) (mean ratio: 116%; CI 90%, 109%-123%), and lower C(min) values (mean ratio: 52%; CI 90%, 48%-56%) compared with G-IR TID during a 24-hour dosing period. A total of 47 treatment-emergent AEs occurred in 17 patients during the study. The most common AEs were headache (25% G-ER BID divided dose, 10% G-ER QD dosing, and 14% in G-IR TID dosing), dizziness (6%, 0%, and 19%), and muscle cramp (19%, 0%, and 10%). AEs were most prevalent in the G-IR study group. CONCLUSIONS: This exploratory study found that in these healthy subjects, the daily exposure provided by less frequent G-ER dosing was not significantly different from same daily dose with G-IR, administered more frequently. The G-ER BID dosing resulted in less fluctuation, while the G-ER QD dosing produced higher maximum concentrations compared with a G-IR TID regimen.