Biomedical subjects

M Younes

Publications and source records attributed to M Younes.

At least 181 records · Page 10Linked to original sources

PubMed1987

Effects of expiratory resistive load on respiratory motor output in conscious humans.

We examined, in five conscious human subjects, the steady-state effects of expiratory resistive loading (ERL; R = 8 cmH2O.l-1.s) on the time course of inspiratory and postinspiratory muscle activities (IA and PIA, respectively) and ventilatory pattern during quiet breathing. Driving pressure (DP) was calculated by means of a respiratory neuromechanical model (J. Appl. Physiol. 51: 963-989, 1981) that permitted the derivation, from tidal volume and flow, of the occlusion pressure equivalent (at functional residual capacity) of respiratory neural output throughout the breath. ERL caused a prolongation of both neural inspiratory duration (12.2 +/- 6.9% SD) and expiratory duration (25.0 +/- 10.1%) and an increase in the amplitude of DP (16.5 +/- 10.2%) without any changes in the waveshape of IA and in end-expiratory level. The relative time course of PIA was not altered by ERL. Minute ventilation was depressed (-6.75 +/- 2.88%) during ERL with little change in alveolar PCO2. The results indicate that pulmonary gas exchange may be improved during ERL through increased tidal volume as well as delayed expiratory lung emptying secondary to sustained PIA.

Adult↗

PubMed1987

Lipid peroxidation is not a major factor involved in the edema formation in perfused lungs.

Perfusion of isolated rat lungs was previously found to induce edema formation, which was considered to be mediated by oxygen-free radicals as scavengers reduced the edema. In the present study we elaborated upon these findings by measuring products found by O2-radical generation. We measured reduced and oxidized glutathione as well as conjugated dienes as an estimate of lipid peroxidation. Amount of water was also measured. Perfusion with oxygenated dextran/Tyrode solution increased edema as compared to nonoxygenated dextran/Tyrode and to nonperfused control lungs. Induction of oxygen radical formation by addition of xanthine and xanthine oxidase to the nonoxygenated dextran/Tyrode perfusate significantly increased the amount of edema as measured by the percentage of water in the lung to 87.0% as compared to the control value of 78.2%. Addition of the radical scavenger superoxide dismutase and catalase to this perfusate prevented edema accumulation. Levels of conjugated dienes as well as those of reduced and oxidized glutathione in lung tissue were measured before the start of perfusion and after 5 and 30 min of perfusion. No significant changes were seen in any of these parameters, indicating that lipid peroxidation may not be a major factor contributing to the edema formation during perfusion of isolated lungs.

Animals↗

PubMed1987

Expiratory resistive loading in patients with severe chronic air-flow limitation. An evaluation of ventilatory mechanics and compensatory responses.

In order to estimate the extent of dynamic compression in patients with COPD who were flow-limited at rest, we measured tidal expiratory flows before and after application of small expiratory resistive loads (ERL). We sought also to evaluate the compensatory strategies available to such patients during ERL by measuring steady-state ventilatory responses. Nine patients with severe COPD (FEV1 +/- SE, 27 +/- 3% predicted) completed the study. Mean tidal flow-volume plots representing all breaths analyzed during 4 min of ERL (resistance, 8 cm H2O/L/s) and unloaded control (4 min) were compared at isoabsolute volume in each individual subject. In 6 subjects, ERL resulted in appreciable reduction of expiratory flows throughout the tidal volume (VT) when compared with volume-matched flows during control. In the remaining subjects, expiratory flows during loading and control coincided during part of the VT. In the group as a whole at 50, 30, and 10% of VT during ERL, when mouth pressure was increased by 3, 2.5, and 2 cm H2O, respectively, flow rates were significantly lower than volume-matched flows during control (delta V, = 0.10, 0.09 and 0.06 L/s, respectively). Minute ventilation was reduced significantly by ERL, but only small insignificant changes in breathing pattern parameters occurred. End-expiratory volume increased by 0.1 L +/- 0.02 (p less than 0.005). We conclude that the majority of patients with chronic air-flow limitation do not sustain significant dynamic compression at rest, and loading response to ERL in patients with COPD are attenuated when compared with those in normal subjects.

Adaptation, Physiological↗

PubMed1987

Effect of dynamic airway compression on breathing pattern and respiratory sensation in severe chronic obstructive pulmonary disease.

Patients with severe COPD are frequently flow-limited during expiration at rest. When expiratory flow is at its maximum, application of negative pressure at the mouth should accentuate dynamic compression downstream from the flow-limiting segment (FLS) without substantially affecting flow or pressure upstream. The purpose of this study was to determine the ventilatory response to such intervention and to determine its effect on respiratory sensation. Such responses should reflect the effect of airway receptors downstream from the FLS. Nine patients with severe COPD (FEV1 +/- SE = 27 +/- 3% predicted) breathed into a closed-circuit apparatus that incorporated a rolling-seal spirometer. The spirometer was fitted with a linear actuator that caused mouth pressure to become negative in proportion to expiratory flow (expiratory assistance, EA). Ventilatory responses were measured during 4 min of EA (-9.7 cm H2O/L/s) and were compared with those during control periods (4 min each) before and after this (C1 and C2). Sense of breathing effort was assessed at 1-min intervals by asking the subject to point to a category scale of 1 to 5, with 1 being minimal effort and 5 indicating that breathing was very difficult. There were small but significant (p less than 0.05) decreases in TI (mean +/- SE, -0.2 +/- 0.05 s) and TE (-0.3 +/- 0.07 s), with increases in breathing frequency (+2.25 +/- 0.7) and ventilation (+1.5 +/- 0.6 L/min). No significant changes were observed in tidal volume or end-expiratory volume. The EA caused a highly significant (p less than 0.001) increase in the sense of breathing effort.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1987

Alcohol-induced hepatotoxicity: a role for oxygen free radicals.

Perfusion of isolated rat livers with ethanol at a concentration of 2 g/l (%o) resulted in a release of glutamate-pyruvate-transaminase (GPT) and sorbitol dehydrogenase (SDH) into the perfusate as markers of toxicity. Inhibition of alcohol dehydrogenase by 4-methylpyrazole or of aldehyde dehydrogenase by cyanamide totally abolished ethanol hepatotoxicity despite of a severalfold increase in acetaldehyde concentration in the perfusate. Addition of superoxide dismutase or catalase clearly suppressed the ethanol-induced release of GPT and SDH, suggesting that .O2- and H2O2 are involved in this process. Also, chelation of iron ions by means of desferrioxamine displayed a clear inhibitory action, suggesting the involvement of an iron-catalyzed Haber-Weiss-reaction leading to the formation of .OH radicals in the hepatotoxic response to ethanol. Our data suggest that during the metabolism of acetaldehyde primary reactive oxygen species (.O2-, H2O2) are produced which may interact to yield hydroxyl or .OH-like radicals, which possibly represent the hepatotoxic principle of ethanol.

Alanine Transaminase↗

PubMed1986

Cell-mediated cytotoxicity by natural killer and killer cells, lipid peroxidation and glutathione.

In the course of spontaneous cell-mediated cytotoxicity (SCMC) and antibody-dependent cell-mediated cytotoxicity (ADCC) with human peripheral lymphocytes as effector cells, no lipid peroxidation occurred as measured by the production of ethane and thiobarbituric acid-reactive material. Furthermore, impairment of major cellular defense systems of target cells (K562 cells for SCMC, Chang liver cells for ADCC), by decreasing their glutathione content, had no effect on either lipid peroxidation or the cytotoxic response. These findings indicate that peroxidative damage is not a mechanism of NK and K cell-mediated cytotoxicity.

Adult↗

PubMed1986

Hepatoprotection by malotilate against carbon tetrachloride-alcohol-induced liver fibrosis.

Subchronic treatment of male rats with carbon tetrachloride (CCl4, twice weekly 0.2 ml/kg p.o.) and feeding a 5% alcohol solution instead of drinking water led to a nearly complete liver cirrhosis in all animals within 4 weeks. This was also documented by a three fold increase in hepatic total hydroxyproline content. Steatosis was quantified by enhanced liver triglyceride concentrations and acute necroses by increments of serum enzyme activities (GPT, SDH). Daily oral treatment with malotilate (100 mg/kg) totally prevented the development of liver cirrhosis, hepatic hydroxyproline accumulation and increases in serum enzyme activities induced by CCl4-alcohol. In cianidanol-treated rats (100 mg/kg p.o.) only portoseptal fibrosis was seen, however hydroxyproline and triglyceride accumulation as well as enhanced serum enzyme activities were not suppressed. D-penicillamine (300 mg/kg p.o.) and colchicine (50 micrograms/kg i.p.) failed to protect rats against CCl4-alcohol induced fibrosis, necrosis and steatosis in this model.

Animals↗

PubMed1986

Hepatotoxicity of metals in glutathione-depleted mice.

Sublethal doses of cadmium chloride (CdCl2; 3 mg/kg i.v.), mercuric chloride (HgCl2; 2 mg/kg i.v.) and sodium vanadate (6 mg/kg i.v.) were administered to normal and glutathione (GSH)-depleted mice (phorone, 250 mg/kg i.p.). In normal mice serum sorbitol dehydrogenase (SDH) activity as a measure of hepatotoxicity was elevated 24 h after treatment with CdCl2 and HgCl2. Following GSH depletion more pronounced increments of SDH activities were observed only after CdCl2 treatment. No difference was seen in the exhalation of ethane by normal and GSH-depleted animals, neither in metal-treated nor in control mice, indicating that lipid peroxidation is not involved in their hepatotoxicity.

Animals↗

PubMed1986

Influence of extracellular calcium on allyl alcohol-induced hepatotoxicity.

The role of calcium in allyl alcohol-induced hepatotoxicity was investigated in the isolated haemoglobin-free perfused rat liver. At a Ca++ concentration of 2.5 mmol/l in the perfusate, allyl alcohol (initial concentration 1.17 mmol/l) produced an enhanced release of GPT and SDH from the liver, an increase in the lactate/pyruvate ratio of the perfusate, a decrease in hepatic oxygen consumption and an increase of both hepatic calcium and malondialdehyde content. In the absence of Ca++ in the perfusate, no hepatic calcium accumulation occurred with allyl alcohol, but all other signs of hepatic damage were as severe as with 2.5 mmol/l Ca++. On the other hand, high extracellular Ca++ (5 mmol/l) alone led to a threefold increase of liver calcium but produced only marginal hepatotoxicity and only slightly enhanced the hepatotoxic effects of allyl alcohol. The concentrations of allyl alcohol in the perfusate were not altered at different Ca++ concentrations. In conclusion, the primary allyl alcohol-induced hepatotoxic injury does not appear to depend upon an influx of extracellular calcium.

1-Propanol↗

PubMed1986

Steady-state response of normal subjects to inspiratory resistive load.

Tidal volume (VT) is usually preserved when conscious humans are made to breathe against an inspiratory resistance. To identify the neural changes responsible for VT compensation we calculated the respiratory driving pressure waveform during steady-state unloaded and loaded breathing (delta R = 8.5 cmH2O X 1(-1) X s) in eight conscious normal subjects. Driving pressure (DP) was calculated according to the method of Younes et al. (J. Appl. Physiol. 51: 963-989, 1981), which provides the equivalent of occlusion pressure at functional residual capacity throughout the breath. VT during resistance breathing was 108% of unloaded VT, as opposed to a predicted value of 82% of control in the absence of neural compensation. Compensation was accomplished through three changes in the DP waveform: 1) peak amplitude increased (+/- 23%), 2) the duration of the rising phase increased (+42%); and 3) the rising phase became more concave to the time axis. There were no changes in the relative decay rate of inspiratory pressure during expiration, in the shape of the declining phase of DP, or in end-expiratory lung volume.

Adult↗

PubMed1986

Steady-state response of quadriplegic subjects to inspiratory resistive load.

Normal subjects preserve tidal volume (VT) in the face of added inspiratory resistance by increasing maximal amplitude and duration of the rising phase of respiratory driving pressure (DP) and by changing the shape of this phase to one that is more concave to the time axis. To explore the possible role of chest wall afferents in mediating these responses, we determined averaged DP in eight quadriplegic subjects during steady-state unloaded breathing and while breathing through an inspiratory resistance (8.5 cmH2O X 1(-1) X s). As with normal subjects, quadriplegics preserved VT (loaded VT = 106% control) by utilizing all three mechanisms. However, prolongation of the inspiratory duration derived from the DP waveform (+22% vs. +42%) and shape response were significantly less in the quadriplegic subjects. Shape response was completely absent in subjects with C4 lesions. The results provide strong evidence that respiratory muscle spindles are responsible for shape response and that changes in afferent feedback from the chest wall play an important role in mediating inspiratory prolongation.

Adult↗

PubMed1986

Breathing pattern during and after maximal exercise in patients with chronic obstructive lung disease, interstitial lung disease, and cardiac disease, and in normal subjects.

Inspiratory muscle fatigue and pulmonary edema are both known to cause rapid shallow breathing. It has been suggested that exercise tolerance in patients with pulmonary disease and cardiac disease may be limited by the development of inspiratory muscle fatigue and pulmonary edema, respectively, at maximal exercise. If these hypotheses are correct, breathing pattern during recovery from maximal exercise in these patients should be rapid and shallow compared with that during exercise. This study was performed to test these hypotheses. Seven patients with chronic obstructive pulmonary disease (COPD), 8 patients with interstitial lung disease (ILD), 7 patients with cardiac disease (CD) (mitral valve disease or left ventricular dysfunction) and 8 normal (NR) subjects each performed maximal incremental exercise on a cycle ergometer. Exercise breathing pattern was compared with that during recovery by calculating the mean difference in tidal volume (at the same levels of minute ventilation) between exercise and recovery for each subject. Recovery breathing pattern was similar to that during exercise for the COPD, ILD, and NR subjects. In contrast, breathing pattern during recovery was rapid and shallow compared with that during exercise for the CD patients; recovery tidal volume was less than that during exercise for the same level of minute ventilation. The fact that rapid shallow breathing does not develop during recovery from maximal exercise in patients with COPD or ILD suggests that inspiratory muscle fatigue does not limit their exercise tolerance. The relative rapid shallow breathing during recovery from maximal exercise in patients with CD is probably due to the development of pulmonary edema at maximal exercise, but further studies are needed to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Glutathione depletion by phorone organ specificity and effect on hepatic microsomal mixed-function oxidase system.

Phorone (diisopropylidene acetone) led to a strong depletion of cellular glutathione in liver, kidney and heart but not in lung or brain upon administration to mice or rats. Its efficacy in lowering hepatic glutathione levels was comparable to that of diethylmaleate. Unlike this agent, however, phorone did not affect the microsomal mixed-function oxidase system at all. Our findings favor the use of phorone when studying the effect of a decreased glutathione content on detoxication, bioactivation or drug metabolism mechanisms, as it merely interacts with glutathione itself.

Animals↗

PubMed1986

Ferrous ion supported in vivo lipid peroxidation induced by paracetamol--its relation to hepatotoxicity.

Treatment of mice with 400 mg/kg paracetamol or 20 mg/kg Fe2+ did not evoke in vivo lipid peroxidation as evidenced by the rate of ethane exhalation. The combined treatment with both, however, led to a more than ninefold enhancement of lipid peroxidation. In glutathione-depleted mice treatment by either agent alone almost doubled the rate of ethane exhalation as compared to the respective control group. Here, again, treatment with both led to an even 26-fold increase in in vivo-lipid peroxidation. These results indicate that iron ions are needed to initiate lipid peroxidation by a redox-cycling metabolite of paracetamol. Marked hepatotoxicity was seen in both groups of mice treated with both Fe2+ and paracetamol as well as in glutathione-depleted mice treated with paracetamol only, the degree of liver damage being identical in all three groups despite of the different rates of lipid peroxidation. This dissociation of hepatotoxic response from ethane exhalation indicates that lipid peroxidation is at least not the sole mechanism by which paracetamol exerts its toxicity towards liver cells.

Acetaminophen↗

PubMed1985

Involvement of reactive oxygen species in the microsomal S-oxidation of thiobenzamide.

Superoxide dismutase, catalase and methional proved capable of inhibiting the microsomal oxidation of thiobenzamide, which is most probably catalyzed by the flavin-containing monooxygenase. This indicates that excited oxygen species (e.g. X O-2,H2O2, X OH) are involved in the catalytic cycle of this enzymatic reaction. CO, which inhibits the cytochrome P-450-dependent oxygen radical formation, had no effect on the oxidation reaction, suggesting that the source of the reactive oxygen species is not the microsomal mixed-function oxidase.

Aldehydes↗

PubMed1985

Effect of phorone-induced glutathione depletion on the metabolism and hepatotoxicity of carbon tetrachloride and vinylidene chloride in rats.

Although the depletion of hepatic glutathione in male rats following treatment with phorone (diisopropylidene acetone) did not affect the xenobiotic-metabolizing microsomal enzyme system, the metabolic elimination of vinylidene chloride (VDC) from the atmosphere of a closed exposure system was inhibited. However, the hepatotoxicity of VDC was enhanced after GSH-depletion, although no enhancement of VDC-induced in vivo lipid peroxidation was observed. In contrast, GSH depletion had no influence on the metabolic elimination of carbon tetrachloride, but augmented both the hepatotoxic response to and the in vivo lipid peroxidation induced by CCl4. In the case of VDC GSH-depletion hepatoxicity was increased because of a change in the metabolic pathway, resulting in production of intermediates of greater toxicity: lack of GSH in CCl4 treated rats renders membrane phospholipids more susceptible to peroxidative damage.

Animals↗

PubMed1985

Effect of subchronic cholestasis on microsomal mixed-function oxidases and the glutathione-conjugating enzyme system in rat liver.

Bile duct ligation in male rats for two weeks led to a marked increase in both serum sorbitol dehydrogenase activity and serum bile acid concentration indicating cholestatic liver injury. Furthermore, a rise in the hepatic hydroxyproline level indicating collagen accumulation was observed. As a consequence of these alterations, the hepatic microsomal mixed-function oxidase system was impaired as evidenced by a decrease in cytochrome P-450 content and in the activities of NADPH-cytochrome c reductase and aminopyrine-demethylase. While the hepatic glutathione content remained unaffected, the cytosolic GSH S-transferase activity was clearly suppressed due to subchronic cholestasis.

Animals↗

PubMed1985

Effect of malotilate on paracetamol-induced hepatotoxicity.

Malotilate (diisopropyl-1,3-dithiol-2-ylidenemalonate) prevented liver damage induced by paracetamol in male mice only when given 1 h prior to the hepatotoxic agent. Furthermore, it partially inhibited paracetamol-induced glutathione depletion in mouse liver, indicating that the antihepatotoxic activity of malotilate is related to an interaction with the bioactivation of paracetamol.

Acetaminophen↗