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J Casademont

Publications and source records attributed to J Casademont.

At least 19 recordsLinked to original sources
PubMed2001

Mitochondrial involvement in antiretroviral therapy-related lipodystrophy.

OBJECTIVES: The management of HIV infection has greatly improved during recent years essentially because of the appearance of new antiretroviral drugs. Highly active antiretroviral therapy (HAART) has achieved important reductions of viraemia and significant recoveries of CD4(+) cell counts in HIV-infected patients. Nonetheless, cases of HIV-infected individuals experiencing lipodystrophy (LD) are being increasingly reported. The purpose of this work was to analyse whether the presence of mitochondrial abnormalities is a frequent feature in LD, since we previously detected mitochondrial abnormalities in an HIV-patient. The second main objective was to study whether LD could be associated with a specific drug. DESIGN: Seven HIV patients presenting LD and five HIV non-LD controls participated in the study. LD patients met the following criteria: (1) LD was their only clinical abnormality, (2) LD was clinically relevant, (3) compliance with antiretroviral treatment was higher than 90% and (4) patients did not have personal or familial history suggestive of mitochondrial disease or neuromuscular disorder. METHODS: Histological stainings, histo-enzymatic reactions, enzymatic and respiratory activities of mitochondrial respiratory chain complexes, and mitochondrial DNA (mtDNA) depletion and rearrangements were examined on muscle mitochondria. RESULTS: Structural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients. CONCLUSIONS: The mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy.

Adult↗
PubMed2001

Is mitochondrial DNA depletion involved in Alzheimer's disease?

Several studies have suggested that mitochondrial metabolism disturbances and mitochondrial DNA (mtDNA) abnormalities may contribute to the progression of the pathology of Alzheimer's disease (AD). In this study we have investigated whether the amount of mtDNA is modified in different brain regions (cerebellum, hippocampus and frontal cortex) of confirmed AD necropsies and in blood of living AD patients. We used a real-time PCR method to analyse the mtDNA relative abundance in brain regions from 12 AD and seven controls and from a group of blood samples (17 living AD patients and 11 controls). MtDNA from blood samples together with hippocampus and cerebellum brain areas did not show differences between controls and AD. However, AD patients showed a 28% decrease in the amount of mtDNA in the frontal cortex when compared to controls for this specific area. Since frontal cortex is a severely affected region in AD, our results support the hypothesis that mitochondrial defects may play a role in the pathogenesis of AD.

Aged↗
PubMed2001

Muscle angiogenic growth factor gene responses to exercise in chronic renal failure.

Patients with chronic renal failure (CRF) have impaired exercise capacity even after erythropoietin treatment. We recently showed that although this is explained in part by reduced convective O(2) delivery to muscles, there is also an impairment of O(2) transport from muscle capillaries to the mitochondria. Given the importance of the capillary surface area for capillary mitochondrial O(2) transport and reports of reduced capillarity in CRF, we hypothesized that the angiogenic gene response to exercise is impaired in such patients. Six patients with CRF and six control subjects matched for age, size, and sedentary lifestyle exercised on a single occasion for 1 h at similar work intensities averaging 50% of maximal capacity. Exercise was confined to the knee extensors of a single leg by means of a specially designed leg-kick ergometer. A percutaneous biopsy of the quadriceps was taken within 30 min of cessation of exercise and compared with a similar biopsy done at different times without any prior exercise for 24 h. Conventional Northern blots were prepared and probed for vascular endothelial growth factor (VEGF; the major putative angiogenic growth factor for muscle), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-beta(1). Data during both rest and exercise were successfully obtained in four subjects of each group. We also assessed muscle capillarity and mitochondrial oxidative capacity to relate to these changes. Mitochondrial oxidative capacity was normal, whereas capillary number per fiber was 12% lower than in normal subjects. VEGF mRNA abundance was increased after exercise by about one order of magnitude, with no reduction in response in CRF. For bFGF and TGF-beta(1), exercise elicited no response in either group. Reduced muscle capillarity in CRF does not, therefore, stem from reduced transcription of VEGF. To the extent that VEGF is important to exercise-induced angiogenesis in muscle, we suspect a posttranscriptional aberration in this response occurs in CRF to explain reduced capillarity.

Adolescent↗
PubMed2000

Aging is associated with increased lipid peroxidation in human hearts, but not with mitochondrial respiratory chain enzyme defects.

BACKGROUND: Aging is associated with increased oxidative damage at multiple cellular and tissular levels. A decrease in mitochondrial function has repeatedly been advocated as a primary key event, especially on the basis of analysis of skeletal muscle mitochondria. However, some doubts on this issue have arisen when confounding variables (such as physical activity or smoking habit) have been taken into account in the analysis of mitochondrial respiratory chain (MRC) enzyme activities or when additional analytical parameters such as enzyme ratios have been considered. OBJECTIVE: To determine whether oxidative damage and enzyme activities of the MRC are influenced by the aging process in human hearts. PATIENTS AND METHODS: We studied cardiac muscle obtained from 59 organ donors (age: 56+/-12 years, 75% men). Oxidative membrane damage was evaluated through the assessment of lipid peroxidation. Absolute and relative enzyme activities (AEA and REA, respectively) of complex I, II, III and IV of the MRC were spectrophotometrically measured. Stoichiometric relationships among MRC complexes were also assessed through calculating MRC ratios. Linear regression analyses were employed to disclose any potential correlation between mitochondrial dysfunction and aging. RESULTS: We found a progressive, significant increase of heart membrane lipid peroxidation with aging (P<0.05). Conversely, neither AEA nor REA decreased with age (P=n.s. for all complexes). Similarly to observations in other tissues, we found that stoichiometry of the MRC enzymes is maintained within a narrow range in human hearts. When the effects of aging on MRC ratios were explored, we failed again in demonstrating any subtle disarray. CONCLUSION: MRC enzymes remain preserved in heart with aging, and thus they cannot be considered the main cause of the increased oxidative damage associated with aging.

Adolescent↗
PubMed2000

Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy.

OBJECTIVE: To study the mitochondrial respiratory chain enzyme activities in patients with idiopathic dilated cardiomyopathy (IDC). METHODS: Mitochondrial respiratory chain enzyme activities were assessed spectrophotometrically in left ventricular tissue of 17 patients with IDC undergoing cardiac transplantation, as well as in two groups of controls: a group of six patients suffering from ischemic dilated cardiomyopathy (IC) also undergoing cardiac transplantation, and a group of 17 organ donors considered normal from a cardiac point of view. Cytochrome b gene from three IDC patients whose complex III activity was particularly low and from three controls was also sequenced. RESULTS: We found that complex III enzymatic activity was lower not only in IDC but also in IC patients when compared with normal controls. When analysing cytochrome b gene we only found neutral polymorphisms previously described. CONCLUSIONS: In view of such results, we believe that the decrease of respiratory chain complex III activity found in some cases of IDC is a secondary phenomenon, and not due to a primary mitochondrial disease.

Adult↗
PubMed2000

Heart mitochondrial respiratory chain complexes are functionally unaffected in heavy ethanol drinkers without cardiomyopathy.

BACKGROUND: Harmful effects of chronic ethanol intake on liver mitochondria have been clearly demonstrated; however, mitochondria from skeletal muscle are preserved, and the effect of ethanol on heart mitochondria remains controversial. We assessed individual enzyme activity of mitochondrial respiratory chain (MRC) complexes and membrane oxidative damage of heart mitochondria in active ethanol drinkers before the development of dilated cardiomyopathy. PATIENTS AND METHODS: Heart samples were obtained from otherwise healthy organ donor individuals with a sudden death of traumatic or neurological cause in whom hearts could not be used because of absence of matched receptors or size inadequacy. Detailed history of alcohol intake was achieved from the relatives. Citrate synthase activity was spectrophotometrically assayed, as well as absolute (nmol x min(-1) x mg protein(-1)) and relative (corrected by citrate synthase) activities of complex I, II, III, and IV of the MRC. Oxidative damage of myocardium membranes was assessed measuring the degree of lipid peroxidation by fluorescence using cis-parinaric acid as probe. RESULTS: We included 10 ethanol drinkers (age 53 +/- 13 years, 100% males, mean lifetime intake of 15.6 +/- 7.9 kg ethanol kg body weight(-1)) and 12 controls (age 60 +/- 10 years, 75% males). Mitochondrial content did not differ between the two groups. Absolute enzyme activities for ethanol drinkers and controls were, respectively, 145 +/- 75 and 130 +/- 50 for complex I (p = NS); 399 +/- 193 and 376 +/- 100 for complex II (p = NS); 719 +/- 288 and 714 +/- 308 for complex III (p = NS); and 475 +/- 139 and 570 +/- 160 for complex IV (p = NS). After correcting such activities by citrate synthase activity, we failed again to demonstrate differences between ethanol drinkers and controls. Lipid peroxidation of myocardium membranes was similar in both groups. CONCLUSIONS: Chronic ethanol drinkers without cardiomyopathy exhibit normal MRC activity in the heart and do not show increased oxidative damage in myocardial membranes.

Adult↗
PubMed1999

Oxidative damage on lymphocyte membranes is increased in patients suffering from acute carbon monoxide poisoning.

Increased oxidative damage seems to be a relevant mechanism in the pathophysiology of patients with an acute carbon monoxide (CO) poisoning. We have investigated the degree of membrane oxidative damage through the assessment of lipid peroxidation in circulating lymphocytes from five patients acutely intoxicated by CO. Since mitochondria are a major source of reactive oxygen species and mitochondrial cytochrome c oxidase (COX) has been reported to be inhibited after acute CO poisoning, we have also assessed the lymphocyte COX activity and its relationship with the degree of lipid peroxidation. Data were compared with those from 32 non-smoker healthy controls comparable in terms of age, gender and physical activity. In intoxicated patients, we have found a significant increase of lipid peroxidation compared to control individuals (P < 0.05), as well as a marked COX inhibition (P < 0.001). Both parameters showed a positive, nearly significant correlation (r = 0.81, P = 0.09). We conclude that oxidative damage of lymphocyte membranes is increased after acute CO poisoning, and suggest that such increase could be partially mediated by mitochondrial COX inhibition caused by CO.

Acute Disease↗
PubMed1999

[Clinical course of idiopathic inflammatory myopathies: complications, survival and prognostic factors].

OBJECTIVES: To describe the clinical and epidemiological characteristics, complications, survival and prognostic factors of a series of patients with idiopathic inflammatory myopathy (IIM) diagnosed with homogeneous criteria in the same center. PATIENTS AND METHODS: Patients with the diagnosis of IIM during an inclusion period of 20 years were studied. They were classified following the criteria of Bohan and Peter, and Dalakas. Epidemiological, clinical and therapeutical data were obtained in all cases. Evolution and survival were analyzed with the Kaplan-Meier and Cox multiple regression models. RESULTS: One-hundred thirty-five patients with IIM were included in the study: 32 polymyositis (PM), 90 dermatomyositis (DM) and 13 inclusion body myositis (IBM). Forty-six percent presented some complications attributed to the disease or treatment, and 10 with PM, 29 with DM and 3 with IBM died during the follow-up. The probabilities of survival were 86% the first year, 80% the second year, 71% the fifth year, and 57% the tenth year. Infections and cancer were the main death causes. While survival analyses did not show independent risk factors for PM, advanced age, presence of associated neoplasm, raised erythrocyte sedimentation rate (ESR) and muscle relapse were identified as a poor prognostic indicators for DM, whereas raised ESR and long lasting symptoms prior to diagnosis of the myopathy were for IBM. CONCLUSION: In spite of the therapeutic advances, IIM are still diseases with high mortality and morbidity.

Adult↗
PubMed1999

[An analysis of 6 Leber mutations in 31 individuals with optic atrophy. A study of its transmission in 5 families].

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder that represents the most frequent cause of visual loss among otherwise healthy young men. PATIENTS AND METHODS: We have screened for the most important LHON mutations (primary mutations) and several other previously described mutations (secondary mutations) in 31 Spanish patients suffering from optic atrophy. These individuals fulfilled the clinical criteria for LHON. We have compared the mutation frequencies obtained with those reported in several other countries. We have also followed the segregation of the disease and its associated LHON mutations in five families. The screening has been performed by PCR followed by restriction enzyme digestions and electrophoretic separation. RESULTS: 67.75% of the patients did not harbour any of the studied mutations, whereas 16.13% showed one mutation and the remaining 16.13% carried two Leber mutations in their mitochondrial DNA. The three primary mutations as well as G15257A were the changes most frequently detected (30% each of them). There were no significant differences among the compared populations in terms of frequencies of the primary mutations. In contrast, our patients showed a significantly higher rate of 15257 mutation. CONCLUSIONS: The incidence of primary LHON mutations among the Spanish patients is not statistically different from those observed in other Caucasian populations. Transmission of the mutation to the progeny is not necessarily linked to the transmission of the disease. This fact complicates genetic counselling and makes prenatal diagnosis almost impossible for this disease.

Base Sequence↗
PubMed1999

Interferon-alpha may exacerbate cryoblobulinemia-related ischemic manifestations: an adverse effect potentially related to its anti-angiogenic activity.

The discovery of the strong association between hepatitis C virus (HCV) infection and the development of mixed cryoglobulinemia has motivated active testing of antiviral-directed alternative therapies. Several trials have demonstrated that classic cryoglobulinemia-associated manifestations improve with interferon-alpha (IFNalpha) treatment. Herein we report on 3 HCV-infected patients with severe cryoglobulinemia-related ischemic manifestations who were closely followed up during IFNalpha therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryocrit determinations were serially performed. In addition to prednisone and immunosuppressive agents, the patients received IFNalpha at 3 x 10(6) units, 3 times per week for 2 months, 3 months, and 4 months, respectively. In all 3 patients, systemic features improved, liver function results returned to normal, and cryocrit values decreased. However, ischemic lesions became less vascularized and ischemia progressed, leading to transmetatarsal and subcondylar amputation, respectively, in 2 of the patients and fingertip necrosis and ulcer enlargement in the third. Skin biopsies performed before IFNalpha therapy and after 2 months of IFNalpha therapy in the third patient showed a significant decrease in subepidermal microvessels. When IFNalpha was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemic lesions may worsen during IFNalpha treatment, presumably through a decrease in inflammation-induced angiogenesis. The anti-angiogenic activity of IFNalpha may delay the appropriate healing of ischemic lesions.

Cryoglobulinemia↗
PubMed1999

Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle.

BACKGROUND: General anaesthetics inhibit mitochondrial function in animal models. However, very few studies have been performed in humans, and the results have not been conclusive. METHODS: We prospectively studied the oxygen consumption and the individual enzyme activity of each complex of the mitochondrial respiratory chain of skeletal muscle mitochondria in 54 healthy individuals who underwent general anaesthesia for orthopaedic surgery. The control group (n = 54) was made up of individuals submitted to the same orthopaedic procedure under regional anaesthesia (n = 31), and patients who underwent muscle biopsies for diagnostic purposes by local anaesthesia (n = 23). RESULTS: We found a significant decrease in the oxidation of glutamate (-36%), succinate (-25%) and ascorbate (-29%) in the general anaesthetic group compared with the controls (P < 0.001 for all substrates). The level of such inhibition was similar for volatile anaesthetics with strong (halothane) or weak (isoflurane) negative inotropic effect. By contrast, the enzymatic activity of all individual complexes and the coupling of oxidative phosphorylation did not differ between the two groups. CONCLUSION: We conclude that during general anaesthetic procedures there is an extensive inhibition of substrate oxidation in human muscle mitochondria, and that it is not caused by a direct effect on complexes of the mitochondrial respiratory chain or through uncoupling oxidative phosphorylation.

Anesthesia, Conduction↗