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Biomedical subjects

P Chariot

Publications and source records attributed to P Chariot.

At least 37 records · Page 2Linked to original sources
PubMed1996

Cytochrome c oxidase deficiencies in the muscle of patients with inflammatory myopathies.

We studied mitochondrial function in inflammatory myopathies, using cytochrome c oxidase (COX) reaction on muscle biopsy samples from 30 patients (15 with dermatomyositis, 12 with polymyositis, and 3 with inclusion body myositis) and 30 age-matched controls. We also performed immunocytochemistry for COX II and COX IV subunits in 7 of these patients who had COX deficiency. COX-deficient fibers were a constant finding in patients or controls older than 65 years and the percentage of COX-deficient fibers correlated with age in both patients and controls. Focal COX deficiency was found in 24 patients (13 of 15 with dermatomyositis, 8 of 12 with polymyositis, and 3 of 3 with inclusion body myositis) and 18 controls. The percentages of COX-deficient fibers were higher in patients with inflammatory myopathies (range: 0-4.7%; mean: 1.2%) than in age-matched controls (range: 0-1.9%; mean: 0.4%) (P < 0.01). In the subgroup of patients under age 65, COX-deficient fibers were more frequent in dermatomyositis than in polymyositis (mean: 0.8% vs 0.2%, P = 0.02). In patients with dermatomyositis, capillary loss correlated positively with COX deficiency (P < 0.02). Immunocytochemistry for COX II and IV showed that 82% of COX-negative fibers were COX II-negative and 26% were COX IV-negative, suggesting that proteins encoded by mitochondrial DNA are predominantly, but not exclusively, involved in COX deficiency. We conclude that mitochondrial dysfunction and COX deficiency can occur in inflammatory myopathies. Such a mitochondrial dysfunction is not solely related to the aging process. We suggest that muscle ischemia contributes to mitochondrial dysfunction in dermatomyositis.

Adult↗
PubMed1996

Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio.

1. Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction. 2. This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio. 3. Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels > 6.0 mmol l-1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects. 4. Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P < 0.05 and P < 0.001). The difference was not significant between fibratetreated patients and untreated patients. 5. Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l-1 +/- 0.04) than in untreated hypercholesterolaemic patients (0.95 mg l-1 +/- 0.09; P < 0.05). 6. We conclude that statin therapy can be associated with high blood lactate/ pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.

Adult↗
PubMed1995

Structural and functional analysis of the metal-binding sites of Clostridium thermocellum endoglucanase CelD.

Crystallographic analysis indicated that Clostridium thermocellum endoglucanase CelD contained three Ca(2+)-binding sites, termed A, B, and C, and one Zn(2+)-binding site. The protein contributed five, six, and three of the coordinating oxygen atoms present at sites A, B, and C, respectively. Proteins altered by mutation in site A (CelDD246A), B (CelDD361A), or C (CelDD523A) were compared with wild type CelD. The Ca(2+)-binding isotherm of wild type CelD was compatible with two high affinity sites (Ka = 2 x 10(6) M-1) and one low affinity site (Ka < 10(5) M-1). The Ca(2+)-binding isotherms of the mutated proteins showed that sites A and B were the two high affinity sites and that site C was the low affinity site. Atomic absorption spectrometry confirmed the presence of one tightly bound Zn2+ atom per CelD molecule. The inactivation rate of CelD at 75 degrees C was decreased 1.9-fold upon increasing the Ca2+ concentration from 2 x 10(-5) to 10(-3) M. The Km of CelD was decreased 1.8-fold upon increasing the Ca2+ concentration from 5 x 10(-6) to 10(-4) M. Over similar ranges of concentration, Ca2+ did not affect the thermostability nor the kinetic properties of CelDD523A. These findings suggest that Ca2+ binding to site C stabilizes the active conformation of CelD in agreement with the close vicinity of site C to the catalytic center.

Binding Sites↗
PubMed1995

Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene.

We report on a new maternally-inherited syndrome characterized by a combination of sensorineural hearing loss, ataxia and myoclonus in a large kindred from Sicily. Hearing loss was the most widespread and sometimes the only symptom found in family members. Sequence analysis of the mitochondrial DNA regions encompassing the tRNA genes revealed the presence of a heteroplasmic insertion at nucleotide position 7472. The insertion adds a seventh cytosine to a six-cytosine run that is part of the mitochondrial tRNASer(UCN) gene. Conformational analysis showed that this mutation is likely to alter the structure of the T psi C loop in the tRNASer(UCN) clover leaf secondary structure. Moreover, the degree of heteroplasmy in blood and muscle was correlated with the clinical phenotype, and homoplasmic mutant hybrids showed decreased complex I activity, low oxygen consumption and high lactic acid output, indicating faulty oxidative phosphorylation. Finally, mutation was absent in 381 unrelated maternal lineages, suggesting specific segregation with the disease. We propose that the C7472 insertion-mutation is pathogenic, and etiologically related to hearing loss and other symptoms that define a novel maternally-inherited clinical entity.

Ataxia↗
PubMed1995

Myopathy and HIV infection.

Skeletal muscle involvement may occur at all stages of HIV infection. The most simple classification of muscular disorders in HIV-infected patients is 1) HIV-associated myopathies, 2) zidovudine myopathy, 3) HIV wasting syndrome, and 4) opportunistic infections and tumoral infiltrations of muscle. Immunohistology for major histocompatibility complex class I antigen and histochemical reaction for cytochrome c oxidase are helpful in correctly classifying a myopathy as HIV polymyositis or zidovudine myopathy. Studies of cytokine expression in HIV-infected patients and of supplementation with compounds such as carnitine or micronutrients such as selenium might yield new insights into the pathogenesis and treatment of the various AIDS-associated muscular disorders.

AIDS-Related Opportunistic Infections↗
PubMed1995

Cytochrome c oxidase deficiency in zidovudine myopathy affects perifascicular muscle fibres and arterial smooth muscle cells.

In order to assess the pathogenesis of myopathological alterations induced by zidovudine, we studied muscle samples from 21 patients infected by human immunodeficiency virus with zidovudine myopathy. Cytochrome c oxidase histoenzymatic reaction was evaluated in skeletal muscle fibres and arterial smooth muscle cells. Other investigations included immunocytochemistry for membrane attack complex and endomysial capillary counts. All patients had partial cytochrome c oxidase deficiency. A perifascicular distribution of cytochrome c oxidase-deficient fibres was found in 14 of 21 patients. Cytochrome c oxidase-deficient fibres were significantly more frequent in perifascicular areas than in the complete muscle sections (28% vs 12%, P < 0.001). Cytochrome c oxidase-deficient arteries were found in 11 patients, of whom 10 also had a perifascicular deficiency. Mononuclear microvascular inflammation was observed in four patients and membrane attack complex deposition in capillary walls in two patients. The capillary counts were not significantly different in the patients and in the controls. These results suggest that, in addition to a direct action of zidovudine on mitochondrial DNA, chronic muscle ischaemia related to zidovudine-induced vascular dysfunction might be implicated at the inception of muscle damage in zidovudine myopathy.

Adult↗
PubMed1995

Fenoverine-induced rhabdomyolysis.

Fenoverine is a spasmolytic drug that inhibits calcium channel currents. We describe the clinicopathologic findings in two patients with fenoverine-induced rhabdomyolysis, of whom one died. A transient left-bundle-branch block was observed in both patients. In one case, pre-existing hepatic dysfunction may have induced accumulation of the drug. Concurrent treatment by fibrates, as observed in the second patient, may have been a predisposing factor for fenoverine-induced rhabdomyolysis. The incidence of muscular complications of fenoverine therapy could be reduced by avoidance of prescription of the drug in patients with hepatopathy or those being treated with cholesterol-lowering agents. Physicians should be aware of life-threatening adverse effects of apparently innocuous drugs.

Aged↗
PubMed1995

[Muscular involvement in HIV infection].

Skeletal muscle involvement may occur at all stages of HIV-infection and represents the first manifestation of the disease in some patients. We usually classify muscle involvement in HIV-infected patients in one of the following categories: (1) HIV-associated myopathy, a myopathy that meets the criteria for polymyositis in a majority of patients, and those for acquired nemaline myopathy in some; (2) zidovudine myopathy, a reversible mitochondrial myopathy; (3) the HIV-wasting syndrome and other AIDS-associated cachexias; (4) opportunistic infections and tumoral infiltrations of the skeletal muscle; (5) vasculitic processes and iron pigment deposits; (6) HIV-associated myasthenia gravis and (7) rhabdomyolysis. Immunohistology for major histocompatibility complex class I antigen and histochemical reaction for cytochrome c oxidase are helpful in correct classification of a myopathy as HIV polymyositis or zidovudine myopathy.

HIV Infections↗
PubMed1994

Determination of fenoverine in tissue samples by high-performance liquid chromatography.

Fenoverine is a spasmolytic, non-anticholinergic phenothiazine derivative that inhibits calcium channel currents. We describe a high-performance liquid chromatographic method for the determination of fenoverine in striated muscle, smooth muscle, myocardium, and liver tissue. Reversed-phase liquid chromatography was performed on a 5 microns Nucleosil C18 column with acetonitrile-0.015 M phosphate buffer (28:72, v/v) as a mobile phase and detection with ultraviolet at 214 nm. The limit of quantitation of fenoverine in tissue samples was 25 ng injected. This method is well suited for the determination of fenoverine in various organs in animal experiments.

Animals↗
PubMed1994

Determination of the blood lactate:pyruvate ratio as a noninvasive test for the diagnosis of zidovudine myopathy.

OBJECTIVE: To evaluate the use of the lactate: pyruvate ratio as a test for the detection of zidovudine myopathy. METHODS: Twenty consecutive human immunodeficiency virus-infected patients with muscle involvement and 20 without muscle involvement were studied prospectively. Blood lactate and pyruvate levels and serum creatine kinase levels were tested, muscle involvement was assessed both clinically and electrophysiologically, and muscle biopsy was performed in patients with myopathy. RESULTS: Nine patients had biopsy-proven zidovudine myopathy. All 9 had a high lactate:pyruvate ratio, with elevations on 2 of 2 determinations in 6 patients and on 1 of 2 in 3 patients. Two of 11 patients with other myopathies and 2 of 20 patients without myopathy had a high lactate:pyruvate ratio on 1 of 2 determinations. CONCLUSION: The lactate:pyruvate ratio, when determined repeatedly, is a sensitive test for detecting mitochondrial muscular toxicity of zidovudine.

Adult↗
PubMed1994

Muscle weakness in intensive care patients: initial manifestation of vitamin D deficiency.

A 72-year-old woman was referred to hospital for obnubilation with general muscle weakness and hypotonia. Biology showed hypocalcemia, hypophosphatemia, increased serum creatine kinase and alkaline phosphatase levels. Brain CT scan, cerebrospinal fluid examination, and electromyogram were normal. Clinical status and electroencephalogram were consistent with non-convulsive generalized status epilepticus. The treatment included clonazepam and CaCl2 and consciousness returned to normal. A treatment with multivitamin infusion containing vitamin D2 was given for 3 weeks. Muscle weakness improved partially. Serum vitamin D3 level was low and osteomalacic myopathy was diagnosed. A treatment was given with 25OH vitamin D3, 50 micrograms per day. Two months later, serum vitamin D3 and creatine kinase levels were normal and the patient could walk without help. We conclude that vitamin D status should be monitored in elderly patients with muscle symptoms and abnormal calcium status. Osteomalacic myopathy should be considered in critically ill patients with muscle symptoms of an unclear cause.

Aged↗
PubMed1994

Expression of cytochrome c oxidase subunits encoded by mitochondrial or nuclear DNA in the muscle of patients with zidovudine myopathy.

The present study was carried out to determine whether a selective decrease of mitochondrial (mt) DNA-encoded cytochrome c oxidase (CCO) subunits occurs in zidovudine myopathy, as expected with a compound known to induce selective mtDNA depletion. Fourteen HIV-infected patients with zidovudine myopathy were studied. Thirteen had partial CCO deficiency assessed by histochemistry. Western blot analysis of CCO subunits (II/III, IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, and VIIc) was performed on muscle biopsy samples. We evaluated the mtDNA-encoded subunits to nuclear DNA-encoded subunits ratio with the II/III to IV ratio. Patients had either a selective decrease of mtDNA-encoded CCO subunits (3 patients), or an overall decrease affecting both mtDNA-and nuclear DNA-encoded subunits (5 patients), or a normal expression of CCO subunits (6 patients). Positive correlations could not be established between the pattern of expression of CCO subunits and total zidovudine intake, degree of inflammation, and percentages of ragged-red fibers or CCO-deficient fibers. The finding of a decrease of both mtDNA- and nuclear DNA-encoded CCO subunits suggests that a factor additional to zidovudine could be implicated in the pathogenesis of the myopathy, at least in some patients. New insights into the pathogenesis of zidovudine myopathy might come from the use of more sensitive methods, including evaluation of CCO subunits in single fibers.

Adult↗
PubMed1994

Acute rhabdomyolysis in patients infected by human immunodeficiency virus.

To delineate the spectrum of rhabdomyolysis associated with human immunodeficiency virus (HIV) infection, we reviewed the clinical and pathologic data from nine HIV-infected individuals with acute rhabdomyolysis, and pooled data with those of 11 previously reported cases. Patients with rhabdomyolysis were at all stages of HIV infection and could be classified into three groups: (1) HIV-associated rhabdomyolysis (7 of 20), including rhabdomyolysis in primary HIV infection, recurrent rhabdomyolysis, and isolated rhabdomyolysis; (2) rhabdomyolysis induced by drugs (6 of 20), including didanosine; and (3) rhabdomyolysis at the end stage of acquired immunodeficiency syndrome (7 of 20), including opportunistic infections of muscle and rhabdomyolysis without a definite cause. Because prognosis, in part, depends on the cause of rhabdomyolysis, recognition of drug-induced or opportunistic infectious muscle disorders is required.

Acute Disease↗
PubMed1994

Optimal handling of blood samples for routine measurement of lactate and pyruvate.

Blood lactate and pyruvate are of critical importance for the diagnosis of mitochondrial diseases. To determine guidelines for adequate blood pyruvate and lactate determinations, intraindividual studies were carried out on 10 subjects, and the influences of venostasis, delay before deproteinization, and pH in the pyruvate assay were analyzed. Delays of 1 hour or more before deproteinization of samples induced major elevations of lactate-pyruvate ratios. The lactate-pyruvate ratio correlated positively with pH in the pyruvate assay, and inadequate pH appeared as a largely underestimated cause of misleading results, while venostasis was a minor source of errors.

Adult↗