Memory one month after acute carbon monoxide intoxication: a prospective study.

BACKGROUND: Serious delayed neuropsychological sequelae may complicate carbon monoxide intoxication. The existence of minor manifestations, especially memory disturbances, is not well documented. AIMS: To study several memory functions after carbon monoxide intoxication. METHODS: In a prospective study, 32 poisoned patients without risk factors for cognitive disturbances were compared to 32 paired control subjects one month after acute carbon monoxide intoxication (blood carbon monoxide concentration at least 1.0 mmol/l), who had been treated with standard conventional therapy. Psychometric tests included Buschke's verbal memory testing, verbal digit span, Corsi's visuospatial span, reaction times, Stroop's colours decoding test, and verbal fluency test. RESULTS: (1) Memory functions in poisoned subjects were not worse than in the control group and were even better in some areas: learning, word recall, and quality of learning by Buschke's verbal memory testing. Attention was also better in the patients, in whom visual reaction time was shorter than in controls. (2) Results of several memory functions-quality of learning and immediate visual memory-were positively correlated with the initial carbon monoxide level. CONCLUSIONS: In a highly selected subset of patients devoid of risk factors for memory impairment, memory, objectively evaluated by psychometric testing, was not worse one month after carbon monoxide intoxication in patients undergoing standard treatment than in paired control subjects.

Cognitive functions in workers exposed to toluene: evaluation at least 48 hours after removal from exposure.

OBJECTIVES: Long-term exposure to toluene may result in subtle impairment of cognitive functions. However, it is not clear whether this impairment is due to the presence of the solvent in the body or if it persists after its elimination from blood. The aim of this study is to compare cognitive functions between toluene-exposed workers (at least 48 h after removal from exposure) and non-exposed workers. METHODS: Seventy-two workers exposed for at least 5 years to toluene (9 to 467 ppm) completed a questionnaire and psychometric tests. The results were compared with those of 61 non-exposed workers. An alveolar air sample was taken just before the tests to ensure the absence of toluene. RESULTS: Results of the vocabulary test were slightly better in exposed (correct words: 21 +/- 0.6) than in non-exposed workers (19 +/- 0.8) (P < 0.05). No differences were found for simple reaction time, digit symbol, digit span, continuous tracking test, color word and switching attention test. CONCLUSIONS: The results of this study do not support the notion of the persistence of cognitive effects of toluene after elimination of the solvent from blood.

[Changes in the high-amplification electrocardiogram after myocardial revascularization. Comparison between coronary artery bypass and angioplasty]. / Evolution de l'électrocardiogramme haute amplification après revascularisation myocardique. Comparaison entre pontage aorto-coronarien et angioplastie coronaire.

The signal-averaged electrocardiogram (SA-ECG) was studied in 148 patients undergoing myocardial revascularisation either by coronary bypass surgery (CBS) (64 cases) or transluminal angioplasty (PTCA) (84 cases). The investigation was performed before the procedure, at day 7 (D7) and after 3 months (D120). No difference was observed in the SA-ECG between the two groups before revascularisation. The CBS population was older, more symptomatic and had more severe lesions than the PTCA population. One hundred and thirty-nine patients were followed up until the end of the study protocol (CBS = 63; PTCA = 76). Two criteria of the SA-ECG were significantly modified after CBS: QRS duration (p < 0.05) and Under 40 (p < 0.01). No significant changes were observed after PTCA. In the patients with late potentials (LP) before revascularisation, the mean value of these criteria (Under 40 and Last 40) were significantly modified after CBS (U40 = 54.3 +/- 16 to 35.4 +/- 15; p < 0.01) (L40 = 11.9 +/- 4.7 to 26.1 +/- 24.3; p < 0.01). No changes in these criteria were observed after PTCA. The value of negativation of the criteria of LP for patients with two criteria of positivity was 71.1% after CBS compared with 25% after PTCA (not significant). These observations support the hypothesis of a favourable modification of the arrhythmogenic substrate after myocardial revascularisation, especially by CBS.

Effects of female sex hormones on mitochondria: possible role in acute fatty liver of pregnancy.

Acute fatty liver of pregnancy occurs in some women. As other cases of microvesicular steatosis are due to impaired mitochondrial oxidation of fatty acids, we investigated the effects of female sex hormones on liver mitochondria in female mice. Three hours after administration of both estradiol (36 mumol/kg) and progesterone (150 mumol/kg), the in vitro beta-oxidation of [U-14C]palmitic acid and the activity of the tricarboxylic acid cycle decreased 49 and 54%, whereas the in vivo oxidation of [U-14C]palmitic acid decreased 38%. One week of treatment with both sex hormones produced ultrastructural lesions of mitochondria, decreased the recovery of mitochondrial proteins by 34%, increased state 4 respiration by 54-77%, and decreased the activities per gram of liver of several enzymes involved in the activation, mitochondrial uptake, and oxidation of fatty acids by 34-54%. We conclude that female sex hormones have deleterious effects on liver mitochondria and suggest that these effects, together with other factors, may contribute to the development of acute fatty liver of pregnancy in some women.

Inhibition by nilutamide of the mitochondrial respiratory chain and ATP formation. Possible contribution to the adverse effects of this antiandrogen.

The effects of nilutamide on the mitochondrial respiratory chain were investigated in rats. In isolated mitochondria, nilutamide (100 microM) inhibited respiration that was supported by substrates feeding electrons into complex I of the respiratory chain but did not inhibit respiration that was supported by substrates donating electrons to complexes II, III or IV. Inhibition of complex I occurred without any lag time. In submitochondrial particles, nilutamide (100 microM) decreased both oxygen consumption mediated by NADH and the oxidation of NADH; addition of superoxide dismutase and catalase did not alleviate inhibition. There was no electron spin resonance evidence for detectable mitochondrial formation of the nilutamide nitro anion free radical by submitochondrial particles or for the formation of iron-nitrosyl complexes with mitochondrial Fe-S clusters in isolated hepatocytes. Severe inhibition of complex I by nilutamide (500 microM) led to upstream inhibition of fatty acid beta-oxidation. Nilutamide (100 microM) decreased the mitochondrial membrane potential and ATP formation in mitochondria energized by malate plus glutamate. In hepatocytes incubated without glucose, nilutamide (500 microM) led to an early (2 hr) drop in cellular ATP and early (4 hr) toxicity. With 5 mM glucose, however, ATP was not decreased and toxicity was mild at these early times. It was concluded that nilutamide itself inhibited the mitochondrial respiratory chain at the level of complex I and decreased ATP in hepatocytes incubated without glucose, which resulted in early toxicity. In the presence of glucose, ATP was not depleted at early times and delayed toxicity was probably the result of an oxidative stress (as previously reported).

Persistent asthma after inhalation of a mixture of sodium hypochlorite and hydrochloric acid.

Chlorine gas inhalation can lead to temporary mucous membrane irritation, pulmonary edema, and transient bronchospasm. Existence of respiratory sequelae is debated. We report a case of asthma, persisting 2 years after the inhalation of a mixture of sodium hypochlorite and hydrochloric acid. Bronchial histologic findings and transmission electron microscopy examinations showed uncommon abnormalities supporting irritation for cause of this nonimmunologic asthma.

Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions.

In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, we determined the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial beta-oxidation of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 hr to 25 mumol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 mumol/L perhexiline did not modify ATP and viability but decreased the beta-oxidation of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 hr of culture. We conclude that perhexiline is concentrated inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial beta-oxidation of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.

Evaluation of human blood lymphocytes as a model to study the effects of drugs on human mitochondria. Effects of low concentrations of amiodarone on fatty acid oxidation, ATP levels and cell survival.

Human lymphocytes were assessed as a cellular model for determining the effects of drugs on human mitochondria. Formation of total oxidized 14C-products was maximal with 1 mM [U-14C]palmitic acid, was linear for 90 min, linear with the number of lymphocytes, and decreased by 95% and 77% in the presence of 30 microM rotenone and 2 mM KCN. Seven drugs were tested which had previously been shown to inhibit beta-oxidation in animals; all decreased formation of total oxidized 14C-products by human lymphocytes, but with different IC50 values: 35 microM with amiodarone, 2.75 mM with tetracycline and amineptine, 3.75 mM with tianeptine, and more than 10 mM for valproic acid and the ibuprofen enantiomers. Formation of [14C]CO2 either increased or decreased, in relation to the various effects of these drugs on coupling, beta-oxidation, and the tricarboxylic acid cycle. There was a general trend for some relationship between inhibition of fatty acid oxidation and loss of cellular ATP. Those compounds, however, which uncoupled oxidative phosphorylation (2,4-dinitrophenol, amiodarone, ibuprofen) and/or inhibited the mitochondrial respiratory chain (amiodarone, rotenone, KCN) resulted in comparatively higher ATP depletion. Amiodarone, a drug which produces several effects (uncoupling, inhibition of beta-oxidation, of the tricarboxylic acid cycle and of the respiratory chain), caused a dramatic decrease in cellular ATP and cell viability at low concentrations (20-100 microM). Both these effects were prevented by the addition of 5 mM glucose, a substrate for anaerobic glycolysis. We conclude that human lymphocytes may be a useful model for assessing the effects of drugs on human mitochondrial function. IC50 values determined with this model may not necessarily apply, however, to other cells.

Evoked potentials in workers occupationally exposed to organic solvents.

Somatosensory, Brainstem Auditory and Pattern Reversal Evoked Potentials (SEPs, BAEPs, PREPs) are recorded in workers occupationally exposed to mixtures of organic solvents, in order to specify the levels of the nervous system affected by a long term exposure to solvents, and to analyze the effects of age and gender. The most significant differences are found for SEPs; they objectivate peripheral impairments magnifying the differential effects of age observed in the control subjects, and show the higher sensitivity of women. The central impairment is pointed out by the latency delay of P22 component mainly, whose age-related increase is amplified by solvent exposure.

Evoked potentials and cerebral blood flow in solvent induced psycho-organic syndrome.

Epidemiological studies have provided evidence that neuropsychiatric symptoms are induced by long term exposure to solvents; individual diagnosis with psychometric tests, however, is not always possible (for example, when the patient has linguistic difficulties). Therefore evoked potentials and cerebral blood flow were studied in 50 patients occupationally exposed to solvents who were referred to our department and for whom a solvent induced psycho-organic syndrome was suspected. Degree of exposure was evaluated by its duration (mean 13.9, range 1 to 37 years) and its intensity (from an interview). At the group level, P22 and N35 latencies and amplitude N20-P22 of somatosensory evoked potentials were higher in cases than in controls (p < 0.05), whereas there was no difference for brainstem and visual evoked potentials, nor for hemispheric cerebral blood flow (but a higher distribution in the left occipital region was seen in patients, p < 0.05). Some parameters were linked to degree of exposure (amplitude N20-P22 of somatosensory evoked potentials, interpeak latency I-V of brainstem evoked potentials, distribution of cerebral blood flow in the internal frontal left region). At the individual level, these examinations were not of diagnostic value because sensitivity was low.

Inhibition by salicylic acid of the activation and thus oxidation of long chain fatty acids. Possible role in the development of Reye's syndrome.

Administration of either aspirin or salicylic acid (3 mmol.kg-1 b.wt. i.p.) decreased by 50 and 65%, respectively, the in vivo oxidation of [U-14C]palmitic acid to [14C]CO2 in mice; after salicylic acid administration, exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 87, 33 and 38%, respectively. Inhibition lasted 9 hr. It was associated with markedly decreased blood glucose concentrations and increased plasma ketone bodies. Repeated administration of salicylic acid (2 mmol.kg-1 i.p. every 8 hr) tripled hepatic triglycerides and produced mild microvesicular steatosis of the liver at 22 hr in fasted mice. In vitro, salicylic acid (1.5 mM) had no or little effect on the formation of beta-oxidation products from [1-14C]octanoic or [1-14C]palmitoyl-L-carnitine, in the presence of ATP, carnitine (40 microM) and coenzyme A (40 microM), but decreased by 51% that from [1-14C]palmitic acid. In the latter system, increasing the concentrations of coenzyme A and carnitine to 200 microM suppressed the inhibitory effect of salicylic acid. Salicylic acid (1.5 mM) decreased by 80% the in vitro mitochondrial formation of palmitoyl-coenzyme A from [1-14C]palmitic acid and 10 microM coenzyme A; again, increasing the concentration of coenzyme A prevented inhibition. We conclude that salicylic acid decreases the mitochondrial activation and thus beta-oxidation of long chain fatty acids, presumably by sequestering extramitochondrial coenzyme A and possibly carnitine.

Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from [U-14C]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of [14C]CO2 from [U-14C]palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of [U-14C]palmitic acid. One hour after 100 mg.kg-1, the exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of [14C]CO2 from [1-14C]palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

Toxicity of ethylene oxide on the lens and on leukocytes: an epidemiological study in hospital sterilisation installations.

An epidemiological study was conducted in 55 subjects (mean age: 41) in hospitals to determine the prevalence of lens opacities and cataracts in workers exposed to ethylene oxide in six sterilisation units. The 21 exposed subjects over 45 were then compared with 16 non-exposed subjects, matched for age and sex. The relation between occupational exposure to ethylene oxide and white blood cell concentrations was also investigated. Lens opacities (independently of visual acuity) were observed in 19 of the 55 exposed. Among both exposed and non-exposed aged over 45, there were no significant differences with regard to the characteristics of lens opacities--prevalence (19 in the 21 exposed; 10 in the 16 non-exposed), distribution of the location, and importance and type (opalescence or discontinuous opacities). No link was found between the characteristics of the lens opacities and the characteristics of exposure: habitual exposure, measured between 0.06 and 39 ppm (cumulated in ppm-number of weekly hours-years) and accidental over-exposures (regular and irregular). For cataracts, defined by the association of lens opacities and a visual acuity less than 20/25 (this loss not being attributable to another cause), their prevalence differed significantly (p less than 0.05) between the exposed (six of 21) and the non-exposed (0 of 16); there was no relation between their existence and overexposures (the analysis for habitual exposure was not possible because of the small size of the sample). The risk of lens opacifications by ethylene oxide in cases of massive exposures as previously described could also exist during chronic exposure to low concentrations. It could be explained by saturation of protective mechanisms against alkylating action of this product. Linear relations were found between the logarithms of blood concentrations of polymorphoneutrophils (R=-0.54; p<0.005) and of lymphocytes (R=-0.45;p<0.05).

[Toxicity of ethylene oxide on the crystalline lense in an occupational milieu. Difficulty of epidemiologic surveys of cataract]. / Etude en milieu professionnel de la toxicité de l'oxyde d'éthylène sur le cristallin. Difficulté des enquêtes épidémiologiques sur la cataracte.

Ethylene oxide is a sterilizing gas for heat-sensitive materials. Eight cases of subcapsular cataract were attributed to this compound from 1982 to 1985. This epidemiological study was conducted in 55 persons to determine the prevalence of lens opacities and cataracts in workers exposed to this gas. The 21 persons of more than 45 years of age were then compared to 16 non-exposed persons matched for age and gender. Lens opacities (independently of visual acuity) were observed in 19 of the 55 exposed. Among exposed and non-exposed persons of more than 45 years of age, there were no significantly differences with regard to the following characteristics of lens opacities: prevalence (13 in the 21 exposed; 10 in the 16 non-exposed), distribution of the localisations, morphology and importance of the cortical opacities. No link was found between the characteristics of the lens opacities and the characteristics of the exposure: habitual exposure and accidental overexposures. For cataracts, defined by the association of lens opacities and a visual acuity less than 20/25 (this loss not being attributable to another cause), their prevalence differed significantly (p less than 0.05) between the exposed (6 of 21) and the non-exposed (0 of 16). There was no relation between their existence and accidental overexposures. The risk of lens opacification by ethylene oxide, established in cases of massive exposures as previously described, could also exist during chronic exposure to low concentrations, but is to be confirmed by other studies. It could be explained by saturation of the protective mechanisms against alkylating action of this product. This study prompted us to discuss the epidemiological difficulties in studies of cataracts.

[Carotid sinus hypersensitivity. Medium and long-term development in patients treated by ventricular pacing]. / Hypersensibilité sino-carotidienne. Evolution à moyen et à long terme des patients traités par stimulation ventriculaire.

The problem of pacing patients with carotid sinus hypersensitivity (CSH) is the choice and criteria of selection of the pacing mode. The authors studied 29 patients with CSH treated by VVI pacing over a period of 10 years. The average follow-up was 34 months (range 6 to 96 months). Three of the 27 patients (11%) who were asymptomatic at the outset continued to have symptoms. The nature of the CSH was well-defined in 25 patients; 19 of the 20 cases of cardio-inhibitory CSH and 4 of the 5 cases of mixed CSH were asymptomatic. These two poor clinical results were analysed: the patient with the cardio-inhibitory CSH (one recurrence in 84 months) had a drop of 40 mmHg in systolic blood pressure which fulfilled criteria of the cardio-inhibitory form of CSH (a drop of 30 to 50 mmHg). The second case was a complete therapeutic failure with 3 recurrent syncopal episodes. The patient had a mixed form of CSH (B.P. drop of 65 mmHg) associated with a "pace maker syndrome" (drop of 50 mmHg in systolic blood pressure at the onset of VVI pacing without any sino carotid massage). The authors conclude that the cases of CSH which, during their investigation, are best corrected by dual-chamber pacing or which are associated with a significant pacemaker effect or present retrograde ventriculo-atrial conduction, should receive dual-chamber pacemakers.

Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice.

Tianeptine is a new tricyclic antidepressant which is metabolized mainly by beta-oxidation of its heptanoic side chain. We determined the effects of tianeptine on the mitochondrial oxidation of natural fatty acids in mice. In vitro, tianeptine (0.5 mM) inhibited by only 32% the formation of beta-oxidation products from [1-14C]palmitic acid by hepatic mitochondria, but inhibited by 71% that from [1-14C]octanoic acid and by 51% that from [1-14C]butyric acid. The activity of the tricarboxylic acid cycle, assessed as the in vitro formation of [14C]CO2 from [1-14C]acetylcoenzyme A was decreased by 51% in the presence of tianeptine (0.5 mM). The inhibition of both beta-oxidation and the tricarboxylic acid cycle appeared reversible in mitochondria from mice exposed to tianeptine in vivo but incubated in vitro without tianeptine. In vivo, administration of tianeptine (0.0625 mmol/kg i.p.), decreased by 53 and 58%, respectively, the formation of [14C]CO2 from [1-14C]octanoic acid and [1-14C]butyric acid, but did not significantly decrease that from [1-14C]palmitic acid. After administration of high doses of tianeptine, however, formation of [14C]CO2 from [1-14C]palmitic acid became inhibited as well, transiently after 0.25 mmol/kg and durably (greater than 24 hr) after 0.75 mmol/kg i.p. Hepatic triglycerides were increased 24 hr after administration of 0.75 mmol/kg i.p. of tianeptine, but not after 0.25 mmol/kg i.p. Microvesicular steatosis of the liver was observed in some mice after 0.75 mmol/kg i.p., but not after 0.5 mmol/kg i.p. We conclude that tianeptine inhibits the oxidation of medium- and short-chain fatty acids in mice. Microvesicular steatosis, however, requires very large doses in mice (0.75 mmol/kg i.p., i.e. 600-times the oral dose in humans), and is therefore unlikely to occur in humans.