Search PubMed⌕ Search

Biomedical subjects

M Younes

Publications and source records attributed to M Younes.

At least 145 records · Page 8Linked to original sources

Effect of pressure assist on ventilation and respiratory mechanics in heavy exercise.

To assess the effect of the normal respiratory resistive load on ventilation (VE) and respiratory motor output during exercise, we studied the effect of flow-proportional pressure assist (PA) (2.2 cmH2O.l-1.s) on various ventilatory parameters during progressive exercise to maximum in six healthy young men. We also measured dynamic lung compliance (Cdyn) and lung resistance (RL) and calculated the time course of respiratory muscle pressure (Pmus) during the breath in the assisted and unassisted states at a sustained exercise level corresponding to 70-80% of the subject's maximum O2 consumption. Unlike helium breathing, resistive PA had no effect on VE or any of its subdivisions partly as the result of an offsetting increase in RL (0.78 cmH2O.1-1.s) and partly to a reduction in Pmus. These results indicate that the normal resistive load does not constrain ventilation during heavy exercise. Furthermore, the increase in exercise ventilation observed with helium breathing, which is associated with much smaller degrees of resistive unloading (ca. -0.6 cmH2O.l-1.s), is likely the result of factors other than respiratory muscle unloading. The pattern of Pmus during exercise with and without unloading indicates that the use of P0.1 as an index of respiratory motor output under these conditions may result in misleading conclusions.

Adult↗

Effect of phase shifts in pressure-flow relationship on response to inspiratory resistance.

Inspiratory prolongation is an integral component of the response to added inspiratory resistance. To ascertain whether this response depends on the relation between inspiratory flow (V) and the pressure perturbation, we compared the responses when this relationship was made progressively less distinct by creating phase shifts between V and the resulting negative mouth pressure (Pm). This was done with an apparatus that altered Pm in proportion to V (J. Appl. Physiol. 62:2491-2499, 1987). V was passed through low-pass electronic filters of different frequency responses before serving as the command signal to the apparatus. In six normal subjects the average neural inspiratory duration (TI) response (delta TI) was sharply (P less than 0.01) reduced (0.32 +/- 0.07 to 0.12 +/- 0.07 s) when the filter's frequency response decreased from 7.5 to 3.0 Hz. The TI response was essentially flat between tube resistance (i.e., no lag, delta TI = 0.36 +/- 0.11 s) and the 7.5-Hz filter, and there was no further change in TI response with filters having a frequency response less than 3.0 Hz, with all TI responses in this range being not significant. Subjects could not consciously perceive a difference between various filter settings. We conclude that the TI response is critically influenced by the phase of the negative pressure wave relative to TI. Furthermore the TI responses are not deliberate, although consciousness is required for their elicitation.

Adult↗

Fodrin as a differentiation marker. Redistributions in colonic neoplasia.

Fodrin (nonerythroid spectrin) is a 475,000 molecular weight (MW) (apparent) heterodimeric actin-binding protein usually found in mature cells at the cytoplasmic face of the plasma membrane. While its precise role is uncertain, it may participate in the establishment and/or maintenance of cell polarity, shape, and specialized receptor domains. In polarized epithelial cells, an asymmetric distribution of fodrin appears to signal phenotypic maturity. Using immunohistochemical techniques, the distribution of fodrin in enterocytes during normal crypt-to-villus maturation, and in adenomas, adenocarcinomas, and cultured Madin-Darby Canine Kidney (MDCK) cells has been studied and its abundance quantitated by immunoblotting and digital immunofluorescent confocal microscopy. During normal maturation, fodrin was found to assemble at the apex of the enterocyte, presumably in the terminal web, only in those cells near the villus tip. Villin was found in an apical location in both crypt and surface enterocytes. In adenocarcinomas of the colon (n = 11), there were enhanced levels of fodrin at the apex, and an approximately threefold increase in the total amount of fodrin per cell relative to normal crypt enterocytes. An increased percentage of this protein was also found in the cytoplasm. Adenomas (n = 7), nonconfluent MDCK cells in culture, and two (of two) cases of ductal carcinoma of the breast also demonstrated enhanced cytoplasmic and total fodrin. Supranormal levels of fodrin at the apex of enterocytes were also observed in Crohn's disease samples and in the normal-appearing enterocytes adjacent to a tumor. It is hypothesized that increased apical fodrin may signal a reaction of the microvillar brush border to pathologic stress, while increased cytoplasmic and total pools of fodrin may mark neoplastic activity. These findings may be of diagnostic value, particularly in the evaluation of small biopsies or cytologic material.

Adenocarcinoma↗

Inhibition of halothane-induced lipid peroxidation by misoprostol without hepatoprotection.

In mice, the synthetic prostaglandin derivative misoprostol failed to protect against liver damage induced by acetaminophen, carbon terachloride,1,1-dichloroethylene or thioacetamide. In rats, misoprostol (20-100 micrograms/kg p.o.) markedly reduced early increments of plasma enzyme activities (glutamate-pyruvate-transaminase, GPT; sorbitol dehydrogenase, SDH) in a model of halothane-induced liver injury; the most effective dose in this respect (20 micrograms/kg) significantly depressed halothane-induced ethane exhalation indicating in vivo lipid peroxidation. Repeated treatment with misoprostol (20 micrograms/kg p.o.) still diminished halothane-induced elevations of enzyme activities over 48 h, but failed to prove hepatoprotection by histomorphological examinations. It is concluded that the antiperoxidative properties of misoprostol are not paralleled by an hepatoprotection, which was indicated by significant reductions of liver-specific plasma enzyme activities, but not confirmed by the morphological picture.

Acetaminophen↗

Dietary iron enhances the tumor rate in dimethylhydrazine-induced colon carcinogenesis in mice.

Treatment of male mice with 20 mg/kg dimethylhydrazine (DMH) s.c. for 10 weeks caused a mean tumour rate of 3.5 after 20 weeks. Dietary iron (3.5% Fefumarate for 10 weeks) enhanced the mean tumour rate to 13.9. All tumours detected were localized exclusively in the distal colon and rectum. The iron load caused a 6.5-fold increase in the mucosal Fe-concentration in the proximal as well as distal colon. DMH-demethylase activity was not influenced by iron and did not differ between proximal and distal segments. Cytosolic alcohol dehydrogenase (ADH) activity was also not altered by iron, but was 3.3-fold higher in the distal colon and rectum as compared to proximal segments; this might explain the DMH-induced tumorigenesis in the distal colon only. It is suggested that iron ions might evoke cocarcinogenic activity by a stimulation of cell proliferation.

Alcohol Dehydrogenase↗

Effect of deferrioxamine and diethyldithiocarbamate on paracetamol-induced hepato- and nephrotoxicity. The role of lipid peroxidation.

In mice subjected to glutathione depletion by pretreatment with phorone (diisopropylidene acetone, 200 mg/kg i.p. in 10 ml/kg olive oil) paracetamol (acetaminophen, 300 mg/kg p.o. in 10 ml/kg tylose 2 h later) led to a marked hepatotoxicity as evidenced by increased plasma activities of the liver-specific enzymes sorbitol dehydrogenase (SDH) and glutamate-pyruvate-transaminase (GPT) 3 and 24 h after treatment. Nephrotoxicity was also indicated at both timepoints by an increased creatinine concentration in plasma, while neither the urine volume nor its content in gamma-glutamyl transpeptitase over 20 h were affected. Hepato- and nephrotoxicity were also assessed histomorphologically. In vivo lipid peroxidation (LPO), as measured by ethane exhalation over 3 h, was clearly enhanced by paracetamol. Malondialdehyde content was increased and glutathione concentration diminished in the liver, but not in the kidney. Diethyldithiocarbamate (DTC, 200 mg/kg i.p.) or deferrioxamine (DFO, 500 mg/kg i.p.) both given 30 min before PA, inhibited in vivo LPO. However, only DTC was capable of antagonizing the hepato- and nephrotoxic effects of paracetamol, while DFO only delayed the onset of nephrotoxicity but left the hepatotoxicity unaffected. Both agents inhibited the rise in hepatic malondialdehyde-content, but only DTC prevented paracetamol-induced glutathione depletion. These results indicate that LPO is not mainly responsible for paracetamol toxicity towards liver or kidney.

Acetaminophen↗

Glutathione and GSH-dependent enzymes in the gastrointestinal mucosa of the rat.

The mucosal glutathione content of the gastrointestinal wall amounted to 50-60% of its concentration in the liver. GSH S-aryltransferase activity (CDNB) was very low in the glandular stomach, colon and rectum amounting to only 5% of liver enzyme activity. There was a marked postpyloric increase in GSH S-aryltransferase activity with an oral-aboral decline along the small intestine. GSH peroxidase was much lower in the mucosa of the small and large intestine as compared to the stomach or liver, whereas GSSG reductase was more than twice as high in the gastrointestinal mucosa as compared to the liver showing a gradual increase in activity from proximal to distal segments. The low GSH S-transferase activities found in the stomach, colon and rectum may account for the high and exclusive susceptibility of these segments to carcinogenesis and the deficient inducibility of these enzymes in the gastrointestinal wall may reflect an insufficient adaption towards higher exposure to toxic or even carcinogenic xenobiotics.

Animals↗

Inhibition of granulocyte-mediated release of oxygen free radicals following glutathione depletion.

Treatment of granulocytes freshly isolated from the blood of healthy human adult donors with phorone (diisopropylidene acetone) resulted in a clear depletion of intracellular glutathione without affecting cell viability. Upon stimulation of the phagocytes with phorbol myristate acetate (PMA), however, the release of .O2- and H2O2 by glutathione-depleted granulocytes was inhibited by 50 or 95% as compared to control cells, respectively. These findings may be of toxicological importance, as many xenobiotics are known to interact with glutathione (GSH)-dependent cellular defense mechanisms and may thus influence the phagocytic activity of granulocytes.

Adult↗

Biochemical assessment of acute and chronic treatment of Paget's bone disease with calcitonin and calcium with and without biphosphonate.

Response to acute and chronic administration of calcitonin and calcium and of biphosphonates (EHDP) was evaluated in 14 patients with Paget's bone disease who were grouped on the basis of homogeneous disease activity, as appraised by bone involvement and alkaline phosphatase and hydroxyproline levels. At first, 100 MRC U of calcitonin followed 4 hours later by 500 mg of elemental calcium were given for 10 days; a significant (p less than 0.001; paired and unpaired Student t test) reduction in alkaline phosphatase (-25%) and hydroproline (-55%) was observed. Subsequently, 5 mg/kg/day of EHDP was given for 20 days. Both parameters increased to levels similar to basal values. These increases were significant (p less than 0.001 for the paired and unpaired Student test) compared with those obtained after calcitonin administration; alkaline phosphatase rose +27% and hydroxproline +135%. After this, patients were divided into 2 groups (A and B). Group A was treated with calcitonin and calcium, at the dosage indicated above, for 10 days a month during 6 months. Group B continued with the same protocol with the addition of EHDP for the 20 days during which calcitonin and calcium were not given. The results of 6 months of treatment showed that calcitonin was more active and suggested that EHDP diminishes hormonal effects. These results also demonstrate a short-term absence of EHDP activity.

Aged↗

Antidotal effects of deferrioxamine in experimental liver injury--role of lipid peroxidation.

Pretreatment with deferrioxamine (DFO, 125-500 mg/kg i.p.) protected male mice against CCl4- or CBrCl3-induced hepatotoxicity which is closely related to an inhibition of iron-dependent lipid peroxidation monitored by ethane exhalation. For allyl alcohol, 1,1-dichloroethylene, dimethylnitrosamine, thioacetamide, bromobenzene and paracetamol no hepatoprotection was achieved with DFO indicating that lipid peroxidation is not involved as a primary mechanism of toxicity. In the case of bromobenzene a marked in vivo lipid peroxidation was observed, which was unaffected by DFO and appears therefore to be iron-dependent.

Animals↗

Enhanced in vivo-lipid peroxidation associated with halothane hepatotoxicity in rats.

To study the role of lipid peroxidation in halothane-induced hepatic damage, ethane exhalation by rats exposed to 1% halothane for 1 hour was determined under normoxic (21% O2) and hypoxic (6% O2) conditions. The effects of microsomal enzyme induction by phenobarbital and/or glutathione depletion on this parameter of in vivo lipid peroxidation were studied. To assess the degree of liver damage, serum activities of liver specific enzymes (glutamate-pyruvate-transaminase, GPT, and sorbitol dehydrogenase, SDH) were measured 3 hrs after the end of exposure. Besides, liver content of thiobarbituric acid-reactive material was estimated as a further parameter of lipid peroxidation. Enhanced rates of lipid peroxidation over basal levels were only seen under conditions leading to hepatic damage, i.e. phenobarbital induction and hypoxia. The highest rate of lipid peroxidation was observed after depletion of hepatic glutathione in addition to microsomal enzyme induction and hypoxia. Deferrioxamine, diethyldithiocarbamate and (+)-catechin inhibited in vivo lipid peroxidation, but only (+)-catechin suppressed halothane-hepatoxicity. These results indicate that halothane-induced hepatic damage is associated with an enhanced rate of lipid peroxidation, but this might not be the only mechanism of halothane toxicity.

Animals↗

Cyanide-induced injury to the isolated perfused rat liver.

In order to study the events that follow cyanide-induced inhibition of oxidative metabolism and produce cellular injury, isolated, haemoglobin-free perfused rat livers from fasted rats were exposed to KCN (100 mg/l). KCN reduced the oxygen consumption of the livers by about 80%. Hepatotoxicity was evident by a marked release of enzymes (LDH, SDH) and of glutathione (mainly GSSG) into the perfusate, by a depletion of hepatic glutathione and by an accumulation of calcium in the liver. Cyanide-induced hepatotoxicity could be prevented completely by feeding the rats before preparing the liver as well as by addition of fructose to the perfusate of fasted livers. Both treatments resulted in an increased energy supply from anaerobic glycolysis as evidenced by a large release of lactate + pyruvate into the perfusate. The toxic actions of cyanide were markedly attenuated by deferrioxamine as well as by allopurinol. These antitoxic actions occurred without changes in anaerobic glycolysis. Omission of calcium from the perfusate, however, did not influence cyanide toxicity. Thus, energy supply from anaerobic glycolysis seems to be sufficient for the basic functions of the liver to occur, when oxidative metabolism is inhibited by cyanide. The effects of deferrioxamine and allopurinol indicate the involvement of radical intermediates and/or Fe2+ in cyanide-induced cellular toxicity. An influx of calcium from the extracellular to the intracellular space is not involved in cyanide-induced hepatocellular injury.

Animals↗

Steady-state response of normal subjects to an inspiratory sinusoidal pressure load.

Inspiratory duration (TI) increases during inspiratory resistive loading in conscious humans. To ascertain whether this response is related to the temporal pattern of pressure perturbation (reaching a peak in early or midinspiration and declining subsequently) we compared the response of nine normal subjects to a usual resistor (narrow tube, RES) with their response when mouth pressure was reduced in a sinusoidal fashion during inspiration (SIN). Whereas the negative pressure pattern was similar with both loads (peak negative pressure near midinspiration), there was no relation between pressure and flow in the case of sinusoidal loading. Each experiment consisted of two loading periods, 4 min each, and three unloaded periods, also 4 min each, bracketing the periods of loading. The order of RES and SIN was randomized. TI during loading was compared with the average TI of the preceding and following unloaded periods. TI increased 0.74 +/- 0.12 and 0.27 +/- 0.05 (SE) s during RES and SIN, respectively (P less than 0.01). We conclude that the temporal pattern of pressure change during resistance breathing plays a small role in mediating the TI prolongation. Coupling between flow and the pressure perturbation appears to be an important determinant of TI prolongation.

Adult↗

Effect of tidal volume and PEEP on rate of edema formation in in situ perfused canine lobes.

The effects of raising tidal volume and positive end-expiratory pressure (PEEP) on rate of edema formation were studied in in situ canine left upper lobe preparations. Edema was induced by increasing blood flow to the left upper lobe (4-8 times normal). In the same animal, at equivalent flows and microvascular hydrostatic pressures, rate of edema formation observed with larger tidal volumes was significantly higher than that observed with smaller tidal volumes (0.73 +/- 0.29 vs. 0.58 +/- 0.30, P less than 0.001). Edema was also induced under static conditions (i.e., flow = 0) over a wide range of vascular pressures. Rate of edema formation was plotted against pressure and the best-fit linear regression was obtained. The slopes (g.min-1.mmHg-1.100 g-1) of the regression lines were significantly higher with larger tidal volumes compared with smaller tidal volumes [0.106 +/- 0.010 (SE) vs. 0.081 +/- 0.009, P less than 0.01]. The pressure intercepts were not different (16.1 +/- 1.6 vs. 15.7 +/- 1.8). When mean airway pressures were increased to levels equivalent to those obtained with larger tidal volumes, but by raising end-expiratory pressures, rate of edema formation dropped to levels below base line. We conclude that increasing the amplitude of cyclic changes in lung volume increases edema formation through mechanisms that are independent of changes in operating (i.e., mean) lung volume.

Animals↗

Effect of alveolar hypoxia on pulmonary fluid filtration in in situ dog lungs.

We have studied the effect of alveolar hypoxia on fluid filtration characteristics of the pulmonary microcirculation in an in situ left upper lobe preparation with near static flow conditions (20 ml/min). In six dogs (group 1), rate of edema formation (delta W/delta t, where W is weight and t is time) was assessed over a wide range of vascular pressures under two inspired O2 fraction (FIO2) conditions (0.95 and 0.0 with 5% CO2-balance N2 in both cases). delta W/delta t was plotted against vascular pressure, and the best-fit linear regression was obtained. There was no significant difference (paired t test) in either threshold pressure for edema formation [18.3 +/- 1.8 and 17.1 +/- 1.2 (SE) mmHg, respectively] or the slopes (0.067 +/- 0.008 and 0.073 +/- 0.017 g.min-1. mmHg-1.100g-1, respectively). In another seven dogs (group 2), delta W/delta t was obtained at a constant vascular pressure of 40 mmHg under four FIO2 conditions (0.95, 0.21, 0.05, and 0.0, with 5% CO2-balance N2). Delta W/delta t for the four conditions averaged 0.60 +/- 0.11, 0.61 +/- 0.11, 0.61 +/- 0.10, and 0.61 +/- 0.10 (SE) g.min-1.mmHg-1.100g-1, respectively. No significant differences (ANOVA for repeated measures) were noted. We conclude that alveolar hypoxia does not alter the threshold for edema formation or delta W/delta t at a given microvascular pressure.

Animals↗

External mechanical loading in conscious humans: role of upper airway mechanoreceptors.

To determine whether upper airway mechanoreceptors partly subserve the ventilatory response to external mechanical loading in conscious humans, we studied 11 laryngectomized subjects. The oropharynx (OP) or tracheostomy was selectively loaded (in random order) by attaching the mouth or tracheal tube to a special pressure-generating apparatus, and steady-state ventilatory responses were recorded. Phasic negative pressure changes generated at the OP to simulate inspiratory resistive loading, expiratory resistive unloading, and elastic loading resulted in trivial prolongation of inspiratory duration by 12, 9, and 4%, respectively; other ventilatory variables were not significantly altered. Phasic positive pressure changes at the OP that simulated inspiratory resistive unloading and expiratory resistive loading had little effect on breathing pattern. When the above loads were applied via the tracheostomy, using pressures of similar magnitude, ventilatory responses were qualitatively similar and quantitatively not significantly different from those of normal healthy controls. The results suggest that the OP does not make an important contribution to ventilatory responses during external mechanical loading in conscious humans. Loading responses to conventional mechanical loads are preserved in the absence of afferent information from the upper airways.

Aged↗

Lack of radiographic evidence of interstitial pulmonary edema after maximal exercise in normal subjects.

Recent physiologic studies have indirectly suggested that interstitial pulmonary edema may develop at maximal exercise in normal humans at sea level. Therefore, we compared chest radiographs taken before and immediately after incremental exercise to maximum in 5 healthy young subjects. We looked for evidence of redistribution of pulmonary blood flow, pulmonary venous distension, loss of sharp definition of pulmonary vascular markings, hilar blurring, Kerley's A, B, or C lines, peribronchial or perivascular cuffing, widening of fissures, pleural effusion, and diffuse opacity. We also quantitated radiographic density in 6 areas of the film in each subject. There was no radiographic change to suggest an increase in lung water in any lung zone in any of the subjects. Given the documented sensitivity of chest radiography in this respect, we conclude that any increase in extravascular lung water during exercise must be trivial.

Adult↗

Effect of continuous positive airway pressure on respiratory sensation in patients with chronic obstructive pulmonary disease during submaximal exercise.

We wished to evaluate the role of dynamic hyperinflation and dynamic airway compression as potential sources of exertional dyspnea in patients with chronic obstructive pulmonary disease (COPD). The rationale was that if such factors contribute importantly, then the administration of continuous positive airway pressure (CPAP), which serves to unload the inspiratory muscles and attenuate dynamic compression on expiration, should improve respiratory sensation. Further partitioning of CPAP into its continuous positive inspiratory pressure (CPIP) and continuous positive expiratory pressure (CPEP) components permitted an assessment of the relative importance of the above factors with respect to respiratory sensation. CPAP, CPIP, and CPEP (4 to 5 cm H2O each) were administered intermittently (for intervals of 40 to 60 s on each occasion) in random order during steady-state submaximal exercise in five patients with COPD (average FEV1, 40% predicted) and in five normal healthy subjects. Changes in the sense of breathing effort during the various pressure applications were assessed by asking the subjects to point to a category scale of -5 to +5, where -5 indicated that breathing was markedly easier and +5 indicated that breathing was markedly harder. CPAP, when administered to the COPD group, resulted in a highly significant (p less than 0.005) reduction in the sense of breathing effort. By contrast, CPAP significantly increased the sense of breathing effort in the normal group (p less than 0.01). CPIP facilitated breathing in both the COPD group and the normal group (p less than 0.05 and p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗