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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.

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.

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.