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Aim: To evaluate the potential of three benzohydrazones ( 1 - 3 ), four acylhydrazones derived from isoniazid (INH-acylhydrazones) ( 4 - 7 ) and one hydrazone ( 8 ) as antituberculosis agents.  Materials & methods: Inhibitory and bactericidal activities were determined for the reference Mycobacterium tuberculosis ( Mtb ) strain and clinical isolates. Cytotoxicity, drug combinations and ethidium bromide accumulation assays were also performed. Results: The tested compounds ( 1 - 8 ) presented excellent antituberculosis activity with surprisingly inhibitory (0.12-250 μg/ml) and bactericidal values, even against multidrug-resistant Mtb clinical isolates. Compounds showed high selectivity index, with values reaching 1833.33, and a limited spectrum of activity. Some of the compounds ( 2 & 8 ) are also great inhibitors of bacillus efflux pumps. Conclusion: Benzohydrazones and INH-acylhydrazones may be considered scaffolds for the development of new anti- Mtb drugs.

A flattened or decreasing O 2 pulse trajectory during incremental CPET is commonly found in patents with low exercise stroke volume but not in those with severely impaired muscle O 2 utilisation. This finding should prompt additional cardiovascular work-up. http://bit.ly/2HRE739., Competing Interests: Conflict of interest: L.H. Degani-Costa has nothing to disclose. Conflict of interest: L.E. Nery has nothing to disclose. Conflict of interest: M.T. Rodrigues has nothing to disclose. Conflict of interest: A.C. Gimenes has nothing to disclose. Conflict of interest: E.V. Ferreira has nothing to disclose. Conflict of interest: J.S. Ota-Arakaki has nothing to disclose. Conflict of interest: R.P. Ramos has nothing to disclose. Conflict of interest: J.A. Neder has nothing to disclose.

Interval exercise delays critical mechanical-ventilatory constraints with positive consequences on Dyspnoea and exercise tolerance in COPD. We hypothesized that those advantages of interval exercise would be partially off-set in patients showing excessive ventilation (V˙E) to metabolic demand (V˙CO 2 ). Sixteen men (FEV 1  = 42.3 ± 8.9%) performed, on different days, 30 s and 60 s bouts at 100% peak (on) interspersed by moderate exercise at 40% (off). Nine patients did not sustain exercise for 30 min irrespective of on duration. They presented with higher V˙E/V˙CO 2 nadir (35 ± 3 vs. 30 ± 5) and dead space/tidal volume (0.39 ± 0.05 vs. 0.34 ± 0.06) compared to their counterparts (p < 0.05). [Lactate], operating lung volumes and symptom burden (dyspnoea and leg effort) were also higher (p < 0.05). Unloading off decreased the metabolic-ventilatory demands, thereby allowing 7/9 patients to exercise for 30 min. Increased wasted ventilation accelerates the rate at which critical mechanical constraints and limiting dyspnoea are reached during interval exercise in patients with COPD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: It was hypothesized that patients with chronic obstructive pulmonary disease (COPD) would exhibit a slow muscle deoxygenation (HHb) recovery time when compared with sedentary controls., Methods: Neuromuscular electrical stimulation (NMES 40 and 50 mA, 50 Hz, 400 µs) was employed to induce isometric contraction of the quadriceps. Microvascular oxygen extraction (µO2EF) and HHb were estimated by near-infrared spectroscopy (NIRS). Recovery kinetic was characterized by measuring the time constant Tau (HHb-τ). Torque and work were measured by isokinetic dynamometry in 13 non-hypoxaemic patients with moderate-to-severe COPD [SpO2 = 94.1 ± 1.6 %; FEV1 (% predict) 48.0 ± 9.6; GOLD II-III] and 13 age- and sex-matched sedentary controls., Results: There was no desaturation in either group during NMES. Torque and work were reduced in COPD versus control for 40 and 50 mA [torque (Nm) 50 mA = 28.9 ± 6.9 vs 46.1 ± 14.2; work (J) 50 mA = 437.2 ± 130.0 vs. 608.3 ± 136.8; P < 0.05 for all]. High µO2EF values were observed in the COPD group at both NMES intensities (corrected by muscle mass 50 mA = 6.18 ± 1.1 vs. 4.68 ± 1.0 %/kg; corrected by work 50 mA = 0.12 ± 0.05 vs. 0.07 ± 0.02 %/J; P < 0.05 for all). Absolute values of HHb-τ (50 mA = 31.11 ± 9.27 vs. 18.08 ± 10.70 s), corrected for muscle mass (50 mA 3.80 ± 1.28 vs. 2.05 ± 1.45 s/kg) and corrected for work (50 mA = 0.08 ± 0.04 vs. 0.03 ± 0.02 s/J) were reduced in COPD (P < 0.05 for all). The variables behaviour for 40 mA was similar to those of 50 mA., Conclusions: COPD patients exhibited a slower muscle deoxygenation recovery time after NMES. The absence of desaturation, low torque and work, high µO2EF and high values for recovery time corrected by muscle mass and work suggest that intrinsic muscle dysfunction has an impact on muscle recovery capacity.

Background: The use of evaluation tools such as the manovacuometer and respirometer is frequent and disinfection is usually limited to the external surfaces, which is insufficient and raises concerns because of the potential spread of infectious diseases. Hydrophobic heat and moisture exchangers (HME) are used in mechanical ventilation and have microbiological filters, which can possibly reduce contamination, increasing the safety of related procedures. It is unknown, however, if the addition of an exchanger affects the measurements obtained. Aim of this study was to verify if the use of an HME interferes in maximal inspiratory and expiratory pressures assessed using the manovacuometer and vital capacity evaluated using the respirometer in healthy adults., Methods: A controlled transversal trial was carried out. Twenty healthy young adults were included in the study. Vital capacity by respirometer and, maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were assessed with and without the use of HME., Results: No significant difference was found between the values pre and post HME use in vital capacity measurements: (3878.8 ± 202.2 mL vs. 3925.5 ± 206.0 mL, p = 0.116) and the respiratory muscle strength measurements: MIP (-99.0 ± 8.9 vs -95.5 ± 9.0 cm H2O, p = 0.149) and MEP (92.5 ± 7.5 vs 92.5 ± 7.7 cm H2O, p = 1.0) respectively., Conclusion: We conclude that the use of HME does not modify the lung volumes or respiratory muscle strength, and can be used in order to reduce the occurrence of pulmonary infection.

Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption ( V ˙ O 2 ) at CWR exercise, both at isotime (1151±115 vs 1049±104 mL/min) and at Tlim (1223±114 vs 1060±108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO.

Background: Ataxia telangiectasia (AT) is a genetic syndrome caused by a mutation of chromosome 11. The clinical features are cerebellar ataxia, telangiectasia, and progressive loss of muscular coordination, including an inefficient cough secondary to progression of neurological disease., Objective: To evaluate the effects of inspiratory muscle training (IMT) on ventilation, lung volume, dyspnoea, respiratory muscle strength, and quality of life in patients with AT., Methods: A longitudinal study was conducted with 11 AT patients and nine healthy volunteers. Ventilometry, subjective sensation of dyspnoea, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and quality of life were assessed before and after a 24-week IMT program. The IMT load used was set at 60% of the MIP, and the training was performed for 20 min daily., Results: Patients with AT had lower height and weight and also had lower respiratory muscle strength and lung volume compared with healthy volunteers. Furthermore, patients with AT showed a significant improvement when pre- and post-IMT were compared for ventilatory pattern: Vt (476.5 ± 135 ml vs. 583.3 ± 66 ml, P = 0.015) and f (23.3 ± 6 rpm vs. 20.4 ± 4 rpm, P = 0.018), and VC (1,664 ± 463 ml/kg vs. 2,145 ± 750 ml/kg, P = 0.002). IMT also significantly improved the sensation of dyspnoea (median 0.5; minimum 0; maximum 1.0; P = 0.022) and respiratory muscle strength: MIP (-22.2 ± 2 cmH2O vs. -38 ± 9 cmH2O, P < 0.001) and MEP (29 ± 7 cmH2O vs. 40 ± 8 cmH2O, P = 0.001). The health and vitality domains of the SF-36 also showed significant improvement (P = 0.009 and P = 0.014, respectively) post-IMT., Conclusion: IMT was effective in improving ventilatory pattern, lung volume, respiratory muscle strength, and the health and vitality domains for quality of life in patients with AT. IMT may be an effective adjunct therapy to drug treatment for patients with AT., (© 2013 Wiley Periodicals, Inc.)

This study addressed whether O(2) delivery during recovery from high-intensity, supra-gas exchange threshold exercise would be matched to O(2) utilization at the microvascular level in patients with mitochondrial myopathy (MM). Off-exercise kinetics of (1) pulmonary O(2) uptake VO(2P) (2) an index of fractional O(2) extraction by near-infrared spectroscopy (Δ[deoxy-Hb + Mb]) in the vastus lateralis and (3) cardiac output (Q'(T)) by impedance cardiography were assessed in 12 patients with biopsy-proven MM (chronic progressive external ophthalmoplegia) and 12 age- and gender-matched controls. Kinetics of VO(2P) were significantly slower in patients than controls (τ = 53.8 ± 16.5 vs. 38.8 ± 7.6 s, respectively; p < 0.05). Q'(T), however, declined at similar rates (τ = 64.7 ± 18.8 vs. 73.0 ± 21.6 s; p > 0.05) being typically slower than [Formula: see text] in both groups. Importantly, Δ[deoxy-Hb + Mb] dynamics (MRT) were equal to, or faster than, τVO(2P) in patients and controls, respectively. In fact, there were no between-group differences in τVO(2P)MRTΔ[deoxy-Hb + Mb] (1.1 ± 0.4 vs. 1.0 ± 0.2, p > 0.05) thereby indicating similar rates of microvascular O(2) delivery. These data indicate that the slower rate of recovery of muscle metabolism after high-intensity exercise is not related to impaired microvascular O(2) delivery in patients with MM. This phenomenon, therefore, seems to reflect the intra-myocyte abnormalities that characterize this patient population.

We determined the response characteristics and functional correlates of the dynamic relationship between the rate (Δ) of oxygen consumption (VO(2)) and the applied power output (work rate = WR) during ramp-incremental exercise in patients with mitochondrial myopathy (MM). Fourteen patients (7 males, age 35.4 ± 10.8 years) with biopsy-proven MM and 10 sedentary controls (6 males, age 29.0 ± 7.8 years) took a ramp-incremental cycle ergometer test for the determination of the VO(2) on-exercise mean response time (MRT) and the gas exchange threshold (GET). The ΔVO(2)/ΔWR slope was calculated up to GET (S(1)), above GET (S(2)) and over the entire linear portion of the response (S(T)). Knee muscle endurance was measured by isokinetic dynamometry. As expected, peak VO(2) and muscle performance were lower in patients than controls (P < 0.05). Patients had significantly lower ΔVO(2)/ΔWR than controls, especially the S(2) component (6.8 ± 1.5 vs 10.3 ± 0.6 mL·min(-1)·W(-1), respectively; P < 0.001). There were significant relationships between ΔVO(2)/ΔWR (S(T)) and muscle endurance, MRT-VO(2), GET and peak VO(2) in MM patients (P < 0.05). In fact, all patients with ΔVO(2)/ΔWR below 8 mL·min(-1)·W(-1) had severely reduced peak VO(2) values (<60% predicted). Moreover, patients with higher cardiopulmonary stresses during exercise (e.g., higher Δ ventilation/carbon dioxide output and Δ heart rate/ΔVO(2)) had lower ΔVO(2)/ΔWR (P < 0.05). In conclusion, a readily available, effort-independent index of aerobic dysfunction during dynamic exercise (ΔVO(2)/ΔWR) is typically reduced in patients with MM, being related to increased functional impairment and higher cardiopulmonary stress.

Background: High-frequency neuromuscular electrical stimulation increases exercise tolerance in patients with advanced chronic obstructive pulmonary disease (COPD patients). However, it is conceivable that its benefits are more prominent in patients with better-preserved peripheral muscle function and structure., Objective: To investigate the effects of high-frequency neuromuscular electrical stimulation in COPD patients with better-preserved peripheral muscle function., Design: Prospective and cross-over study., Methods: Thirty COPD patients were randomly assigned to either home-based, high-frequency neuromuscular electrical stimulation or sham stimulation for six weeks. The training intensity was adjusted according to each subject's tolerance. Fat-free mass, isometric strength, six-minute walking distance and time to exercise intolerance (Tlim) were assessed., Results: Thirteen (46.4%) patients responded to high-frequency neuromuscular electrical stimulation; that is, they had a post/pre Δ Tlim >10% after stimulation (unimproved after sham stimulation). Responders had a higher baseline fat-free mass and six-minute walking distance than their seventeen (53.6%) non-responding counterparts. Responders trained at higher stimulation intensities; their mean amplitude of stimulation during training was significantly related to their fat-free mass (r = 0.65; p<0.01). Logistic regression revealed that fat-free mass was the single independent predictor of Tlim improvement (odds ratio [95% CI] = 1.15 [1.04-1.26]; p<0.05)., Conclusions: We conclude that high-frequency neuromuscular electrical stimulation improved the exercise capacity of COPD patients with better-preserved fat-free mass because they tolerated higher training stimulus levels. These data suggest that early training with high-frequency neuromuscular electrical stimulation before tissue wasting begins might enhance exercise tolerance in patients with less advanced COPD.

Patients with chronic obstructive pulmonary disease (COPD) have slowed pulmonary O(2) uptake (Vo(2)(p)) kinetics during exercise, which may stem from inadequate muscle O(2) delivery. However, it is currently unknown how COPD impacts the dynamic relationship between systemic and microvascular O(2) delivery to uptake during exercise. We tested the hypothesis that, along with slowed Vo(2)(p) kinetics, COPD patients have faster dynamics of muscle deoxygenation, but slower kinetics of cardiac output (Qt) following the onset of heavy-intensity exercise. We measured Vo(2)(p), Qt (impedance cardiography), and muscle deoxygenation (near-infrared spectroscopy) during heavy-intensity exercise performed to the limit of tolerance by 10 patients with moderate-to-severe COPD and 11 age-matched sedentary controls. Variables were analyzed by standard nonlinear regression equations. Time to exercise intolerance was significantly (P < 0.05) lower in patients and related to the kinetics of Vo(2)(p) (r = -0.70; P < 0.05). Compared with controls, COPD patients displayed slower kinetics of Vo(2)(p) (42 +/- 13 vs. 73 +/- 24 s) and Qt (67 +/- 11 vs. 96 +/- 32 s), and faster overall kinetics of muscle deoxy-Hb (19.9 +/- 2.4 vs. 16.5 +/- 3.4 s). Consequently, the time constant ratio of O(2) uptake to mean response time of deoxy-Hb concentration was significantly greater in patients, suggesting a slower kinetics of microvascular O(2) delivery. In conclusion, our data show that patients with moderate-to-severe COPD have impaired central and peripheral cardiovascular adjustments following the onset of heavy-intensity exercise. These cardiocirculatory disturbances negatively impact the dynamic matching of O(2) delivery and utilization and may contribute to the slower Vo(2)(p) kinetics compared with age-matched controls.

Study Objective: To determine the structural and functional consequences of high-frequency neuromuscular electrical stimulation (hf-NMES) in a group of moderately impaired outpatients with chronic obstructive pulmonary disease (COPD)., Design: A prospective, cross-over randomized trial., Setting: An university-based, tertiary center., Patients and Materials: Seventeen patients (FEV(1)=49.6+/-13.4% predicted, Medical Research Council dyspnoea grades II-III) underwent 6-weeks hf-NMES (50Hz) and sham stimulation of the quadriceps femoris in a randomized, cross-over design. Knee strength was measured by isokinetic dynamometry (peak torque) and leg muscle mass (LMM) by DEXA; in addition, median cross-sectional area (CSA) of type I and II fibres and capillary-fibre ratio were evaluated in the vastus lateralis. The 6-min walking distance (6MWD) was also determined., Results: At baseline, patients presented with well-preserved functional capacity, muscle strength and mass: there was a significant relationship between strength and type II CSA (P<0.05). NMES was not associated with significant changes in peak torque, LMM or 6MWD as compared to sham (P>0.05). At micro-structural level, however, electrical stimulation increased type II, but decreased type I, CSA; no change, however, was found in the relative fibre distribution or capillary:fibre ratio (P<0.05). There was no significant association between individual changes in structure and function with training (P>0.05). Post-NMES increase in type II CSA was inversely related to baseline mass and strength (P<0.05)., Conclusion: NMES may promote a modest degree of type II muscle fibre hypertrophy in COPD patients with well-preserved functional status. These micro-structural changes, however, were not translated into increased volitional strength in this sub-population.