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BACKGROUND: Intrauterine growth restriction (IUGR) is associated with cardiovascular remodeling persisting into adulthood. Mitochondrial bioenergetics, essential for embryonic development and cardiovascular function, are regulated by nuclear effectors as sirtuins. A rabbit model of IUGR and cardiovascular remodeling was generated, in which heart mitochondrial alterations were observed by microscopic and transcriptomic analysis. We aimed to evaluate if such alterations are translated at a functional mitochondrial level to establish the etiopathology and potential therapeutic targets for this obstetric complication. METHODS: Hearts and placentas from 16 IUGR-offspring and 14 controls were included to characterize mitochondrial function. RESULTS: Enzymatic activities of complexes II, IV and IIâ¯+â¯III in IUGR-hearts (-11.96⯱â¯3.16%; -15.58⯱â¯5.32%; -14.73⯱â¯4.37%; pâ¯<â¯0.05) and II and IIâ¯+â¯III in IUGR-placentas (-17.22⯱â¯3.46%; pâ¯<â¯0.005 and -29.64⯱â¯4.43%; pâ¯<â¯0.001) significantly decreased. This was accompanied by a not significant reduction in CI-stimulated oxygen consumption and significantly decreased complex II SDHB subunit expression in placenta (-44.12⯱â¯5.88%; pâ¯<â¯0.001). Levels of mitochondrial content, Coenzyme Q and cellular ATP were conserved. Lipid peroxidation significantly decreased in IUGR-hearts (-39.02⯱â¯4.35%; pâ¯<â¯0.001), but not significantly increased in IUGR-placentas. Sirtuin3 protein expression significantly increased in IUGR-hearts (84.21⯱â¯31.58%; pâ¯<â¯0.05) despite conserved anti-oxidant SOD2 protein expression and activity in both tissues. CONCLUSIONS: IUGR is associated with cardiac and placental mitochondrial CII dysfunction. Up-regulated expression of Sirtuin3 may explain attenuation of cardiac oxidative damage and preserved ATP levels under CII deficiency. GENERAL SIGNIFICANCE: These findings may allow the design of dietary interventions to modulate Sirtuin3 expression and consequent regulation of mitochondrial imbalance associated with IUGR and derived cardiovascular remodeling.
Assuntos
Retardo do Crescimento Fetal/metabolismo , Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/biossíntese , Placenta/metabolismo , Sirtuína 3/biossíntese , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/patologia , Mitocôndrias Cardíacas/patologia , Placenta/patologia , Gravidez , CoelhosRESUMO
The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706AâG, m.3197TâC, and m.3010GâA polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.
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Antibacterianos/toxicidade , Ciclo-Oxigenase 2/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Linezolida/toxicidade , Mitocôndrias/efeitos dos fármacos , Fibras Nervosas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/toxicidade , Canais de Ânion Dependentes de Voltagem/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Proteínas Mitocondriais/metabolismo , Polimorfismo de Nucleotídeo Único/genética , RNA Ribossômico/genética , RNA Ribossômico 16S/genética , Pele/citologia , Pele/inervaçãoRESUMO
OBJECTIVES: Ex vivo analysis of mitochondrial function may reveal HIV progression and the impact of ART. We propose a mitochondrial and apoptotic in vitro model using Jurkat T cells incubated with plasma. The objectives of this study were to evaluate mitochondrial and apoptotic lesions in this model in relation to HIV progression, and to assess the effect of >1 year of standard non-thymidine-containing therapy. METHODS: This was a cross-sectional comparison among three age- and gender-matched groups (nâ=â19â×â3): healthy non-HIV-infected participants, HIV-infected long-term non-progressors (LTNPs) and standard antiretroviral-naive chronically infected patients [standard progressors (Sps)], longitudinally evaluated before (Sp1) and after (Sp2) >1 year of efavirenzâ+âtenofovirâ+âemtricitabine therapy. We analysed mitochondrial DNA content by RT-PCR, mitochondrial function by spectrophotometry, mitochondrial protein synthesis by western blot analysis, mitochondrial dynamics by western blot analysis (MFN2), apoptotic transition pore formation by western blot analysis (VDAC-1) and mitochondrial membrane potential and annexin V/propidium iodide fluorescence by flow cytometry. RESULTS: There was a decreasing non-significant trend towards lower mitochondrial parameters for HIV-infected values with respect to uninfected control reference values. HIV progression (LTNP versus Sp1) was associated with decreased mitochondrial genetic, functional and translational parameters, which partially recovered after treatment intervention (Sp2). Mitochondrial fusion showed a trend to decrease non-significantly in Sp patients compared with LTNP patients, especially after therapy. All apoptotic parameters showed a trend to increase in Sp1 with respect to LTNP, followed by recovery in Sp2. CONCLUSIONS: We proposed an in vitro model for mitochondrial and apoptotic assessment to test the effects of HIV infection and its therapy, resembling in vivo conditions. This model could be useful for clinical research purposes.
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Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , Apoptose , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Mitocôndrias/efeitos dos fármacos , Adulto , Estudos Transversais , Progressão da Doença , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Células Jurkat , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mitocôndrias/fisiologiaRESUMO
The best oxygen therapy for acute carbon monoxide poisoning (ACOP) remains unestablished. Reported mitochondrial complex IV (mtCIV) inhibition, together with carboxyhaemoglobin (COHb)-induced hypoxia, may influence acute clinical symptoms and outcome. To "mitochondrially" evaluate treatment efficacy, we correlated intoxication severity and symptoms with mitochondrial function (mtCIV activity) and oxidative stress (lipid peroxidation) in 60 poisoned patients and determined ACOP recovery depending on either normobaric or hyperbaric oxygen therapy along a 3-month follow-up. In the present article we positively evaluate mtCIV as a good marker of ACOP recovery, treatment effectiveness, and late neurological syndrome development, which advocates for hyperbaric oxygen therapy as the treatment of choice. However, we discourage its usefulness as a severity marker because of its excessive sensitivity. We additionally evaluate oxidative stress role and prognostic factors for neurological sequelae development.
Assuntos
Poluentes Atmosféricos/toxicidade , Intoxicação por Monóxido de Carbono/terapia , Monóxido de Carbono/toxicidade , Mitocôndrias/efeitos dos fármacos , Oxigenoterapia , Doença Aguda , Adolescente , Adulto , Biomarcadores/metabolismo , Intoxicação por Monóxido de Carbono/diagnóstico , Intoxicação por Monóxido de Carbono/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo , Resultado do Tratamento , Adulto JovemRESUMO
The significant and progressive reduction in the number of permanent teachers in medical schools (professor, associate professor and assistant professor) is a reason for concern for the National Conference of Deans. This reduction will intensify in the coming decade (2017-2026). Forty-three percent of the permanent faculty will retire, as will 55% of the faculty linked to clinical areas, 34% of the faculty not linked to clinical areas and 32% of the faculty of basic areas. This deficit is significant now, and, in a few years, the situation will be unsustainable, especially in the clinical areas. This report reveals the pressing need to adopt urgent measures to alleviate the present situation and prevent a greater problem. The training of future physicians, immediately responsible for the health of our society, depends largely on the theoretical and practical training taught in medical schools, with the essential collaboration of healthcare institutions. Paradoxically, while the number of teachers decreases substantially, there is an exponential increase in the number of medical schools and students who are admitted every year without academic or healthcare justification.
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Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.
Assuntos
Cromossomos Humanos Par 4/genética , DNA Mitocondrial/genética , Deleção de Sequência , Síndrome de Wolfram/genética , Adulto , Sequência de Bases , Núcleo Celular/metabolismo , Mapeamento Cromossômico , Deficiência de Citocromo-c Oxidase , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Genes Recessivos , Ligação Genética , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Dados de Sequência Molecular , NADH Desidrogenase/deficiência , NADH Desidrogenase/genética , Linhagem , Succinato Citocromo c Oxirredutase/deficiência , Succinato Citocromo c Oxirredutase/genética , Síndrome de Wolfram/metabolismoRESUMO
OBJECTIVE: To determine potential mitochondrial and oxidative alterations in colon biopsies from idiopathic REM sleep behavior disorder (iRBD) and Parkinson's disease (PD) subjects. METHODS: Colonic biopsies from 7 iRBD subjects, 9 subjects with clinically diagnosed PD, and 9 healthy controls were homogenized in 5% w/v mannitol. Citrate synthase (CS) and complex I (CI) were analyzed spectrophotometrically. Oxidative damage was assessed either by lipid peroxidation, through malondialdehyde and hydroxyalkenal content by spectrophotometry, or through antioxidant enzyme levels of superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (Gpx1), and catalase (CAT) by western blot. The presence of mitochondrial DNA (mtDNA) deletions was assessed by long PCR and electrophoresis. RESULTS: Nonsignificant trends to CI decrease in both iRBD (45.69 ± 18.15; 23% decrease) and PD patients (37.57 ± 12.41; 37% decrease) were found compared to controls (59.51 ± 12.52, p: NS). Lipid peroxidation was maintained among groups (iRBD: 27.46 ± 3.04, PD: 37.2 ± 3.92, and controls: 31.71 ± 3.94; p: NS). Antioxidant enzymes SOD2 (iRBD: 2.30 ± 0.92, PD: 1.48 ± 0.39, and controls: 1.09 ± 0.318) and Gpx1 (iRBD 0.29 ± 0.12, PD: 0.56 ± 0.33, and controls: 0.38 ± 0.16) did not show significant differences between groups. CAT was only detected in 2 controls and 1 iRBD subject. One iRBD patient presented a single mtDNA deletion.
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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.
Assuntos
Envelhecimento/metabolismo , Peroxidação de Lipídeos , Mitocôndrias Cardíacas/enzimologia , Miocárdio/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Membrana Celular/metabolismo , Criança , Transporte de Elétrons , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/metabolismo , Proibitinas , Espectrofotometria , Superóxido Dismutase/análiseRESUMO
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.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Metabolismo Energético , Mitocôndrias Cardíacas/enzimologia , Adulto , Análise de Variância , Cardiomiopatia Dilatada/etiologia , Estudos de Casos e Controles , Citrato (si)-Sintase/análise , Grupo dos Citocromos b/genética , Transporte de Elétrons , Complexo I de Transporte de Elétrons , Complexo II de Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons/análise , Complexo IV da Cadeia de Transporte de Elétrons/análise , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/análise , Isquemia Miocárdica/complicações , Isquemia Miocárdica/metabolismo , NADH NADPH Oxirredutases/análise , Fosforilação Oxidativa , Oxirredutases/análise , Análise de Sequência de DNA , Espectrofotometria , Succinato Desidrogenase/análiseRESUMO
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.
Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Lipodistrofia/induzido quimicamente , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Adulto , Idoso , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Feminino , Deleção de Genes , Infecções por HIV/complicações , HIV-1 , Humanos , Lipodistrofia/metabolismo , Lipodistrofia/patologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestruturaRESUMO
Different abnormalities in mitochondrial electron transport chain activity have been demonstrated in muscle and other tissues of patients with idiopathic Parkinson's disease (PD). We studied eight Spanish patients with PD to evaluate the functional activity of the electron transport chain in muscle mitochondria from patients of this country. We found lower complex I activity (nmol.min-1.mg-1) in patients (245.8 +/- 42.8) than in controls (331.6 +/- 60.1) (p = 0.004) and lower complex IV activity in patients (46.1 +/- 9) than in controls (144.1 +/- 42.3) (p = 0.00001). Complex V activity was also decreased in two patients and complex II and III activities were normal in all of them. Although these results strongly suggest an alteration in mitochondrial DNA in PD, the various electron transport chain defects in different tissues seem to be nonspecific.
Assuntos
Mitocôndrias Musculares/metabolismo , Doença de Parkinson/metabolismo , Idoso , Transporte de Elétrons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/patologia , Fosforilação Oxidativa , Doença de Parkinson/patologia , EspanhaRESUMO
The contribution of the mitochondrial genetic system in the degenerative processes of senescence remains unclear. This study deals with age-related changes in brain mtDNA expression in humans. Brain tissue from the frontal lobe cortex was obtained from autopsy of 13 humans aged between 21 and 84 years. No structural changes were detected in mtDNA, increased mtDNA content and reduced steady-state level of mitochondrial transcripts and transcription ratio (mtRNA/mtDNA) were associated with aging. These findings suggest that the increase of the mtDNA levels could be considered as an inefficient compensatory mechanism to maintain the normal levels of mtRNA transcripts. This unbalanced mitochondrial condition could play a role in the process of senescence in human brain.
Assuntos
Envelhecimento/metabolismo , DNA Mitocondrial/metabolismo , Lobo Frontal/metabolismo , RNA/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Mitocondrial/análise , DNA Ribossômico/metabolismo , Lobo Frontal/crescimento & desenvolvimento , Humanos , Pessoa de Meia-Idade , RNA Mitocondrial , RNA Ribossômico 18S/genética , Valores de Referência , Análise de Regressão , Transcrição GênicaRESUMO
Considerable interest has recently focused on the possible role of alterations in mitochondrial activity and mutations in the mitochondrial genome for the development of non-insulin-dependent diabetes. Our study aimed at investigating the normal mitochondrial respiratory chain activity of nonpurified and purified islet cells to further explore whether some diabetic states are associated with alterations of mitochondrial oxidative processes. For this purpose, pancreatic islets were isolated from Wistar rats. Unpurified islet cells were obtained in the presence of trypsin and DNAse, and purified beta and non-beta cells were prepared by autofluorescence-activated sorting using a flowcytometer. Intact cell respiration and substrate oxidation in digitonin-permeabilized cells were measured polarographically with a Clark oxygen electrode in a micro-water-jacketed cell. Specific activity of the individual complexes of the respiratory chain was determined spectrophotometrically in unpurified islet cells. The relative amount of mitochondrial (mtDNA) and nuclear (nDNA) DNA in all three cell populations and in rat brain and skeletal muscle was estimated by dot blotting. The intact cell respiration of unpurified islet cells corresponds to the mean of values obtained for beta and non-beta islet cells. Oxidation rates of different substrates by permeabilized beta cells were lower than those for unpurified and non-beta cells. The amount of mtDNA relative to nDNA was similar in all three groups of cells, and was also similar to that obtained from brain and skeletal muscle. In summary, we have described mitochondrial respiratory chain activity in unpurified, beta, and non-beta islet cells. Our results represent an initial step in investigating the potential pathogenic role that alterations in oxidative phosphorylation could play in some diabetic states.
Assuntos
DNA Mitocondrial/metabolismo , Transporte de Elétrons/fisiologia , Ilhotas Pancreáticas/metabolismo , Animais , Separação Celular , Citometria de Fluxo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/enzimologia , Masculino , Polarografia , Ratos , Ratos WistarRESUMO
Determination of cytochrome c oxidase (COX; EC 1.9.3.1) activity in human mitochondria presents several technical difficulties which result in a large intra- and interlaboratory variability, especially when a single wavelength spectrophotometer (SWS) is used, as is generally done in most laboratories in the context of screening procedures for the detection of respiratory chain deficiencies. We studied the experimental conditions of COX assay in human skeletal muscle mitochondria using a SWS in order to define the optimal conditions for the assay and compared these results with those obtained using a double wavelength spectrophotometer (DWS). We demonstrate that a low intra-individual variability of COX assay can be obtained with SWS by: (1) using manual stirrers to avoid the formation of bubbles in the mixture; (2) preincubating mitochondria and laurylmaltoside before the addition of cytochrome c, which prevents light scattering secondary to mitochondrial swelling; and (3) using low amounts (1-2 microg) of mitochondrial protein to extend and linearize the reaction rate. Under these experimental conditions, the concordance between SWS and DWS was very good (R=0.975).
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Complexo IV da Cadeia de Transporte de Elétrons/análise , Músculo Esquelético/enzimologia , Espectrofotometria/métodos , Transporte de Elétrons/fisiologia , Humanos , Mitocôndrias Musculares/enzimologia , Transtornos Respiratórios/diagnóstico , Espectrofotometria/instrumentaçãoRESUMO
Electron transport chain (ETC) dysfunction has been claimed to contribute to the expression of neurodegenerative disorders. We have investigated the effects of the treatment with rivastigmine, a commonly used cholinesterase inhibitor, on lymphocyte mitochondria of patients with Alzheimer's disease (AD). Increased enzymatic activities of diverse complexes and oxidative capacity of the ETC were found. Enhanced mitochondrial ETC function may contribute to the beneficial effects of rivastigmine on clinical manifestations of AD.
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Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Carbamatos/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Linfócitos/metabolismo , Mitocôndrias/metabolismo , Fenilcarbamatos , Idoso , Transporte de Elétrons/efeitos dos fármacos , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Valores de Referência , RivastigminaRESUMO
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.
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Intoxicação por Monóxido de Carbono/etiologia , Linfócitos/efeitos dos fármacos , Doença Aguda , Adulto , Idoso , Intoxicação por Monóxido de Carbono/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Inibidores de Ciclo-Oxigenase/intoxicação , Transporte de Elétrons/efeitos dos fármacos , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de OxigênioRESUMO
The incidence and causes of iatrogenic illness in a department of internal medicine were studied prospectively in 1,176 patients admitted from 1 January 1986 to 31 December 1986. A total of 295 patients (25.1%) developed 367 episodes of iatrogenic illness. Phlebitis occurred most frequently (75.2% of all iatrogenic events), followed by drug reactions (10.7%), contusion (4.6%), and urinary tract infections (1.4%). Nineteen patients developed life-threatening events (in 2 it was the cause of death). Etiologic agents included intravenous catheter (79% of all adverse reactions), drugs (9.5%), falls from bed (5.4%), diagnostic procedures (3.3%), and urinary catheterization (1.6%). Risk factors associated with iatrogenic illness were hospital stay longer than 12 days, female sex, poor general medical status on admission, intravenous catheterization, and intravenously administered antibiotics and anticoagulants. We conclude that in our hospital (a) 25% of the inpatient admissions to the general medicine service resulted in iatrogenic illness, (b) most iatrogenic illnesses were not severe (phlebitis), but 2 of 19 patients with life-threatening events died, and (c) the probability of developing iatrogenic illness generally depended on long hospital stay, poor general status at admission, and the use of both intravenous catheters and medication. In our patients, a reduction of hospital stay and a rational limitation of these procedures may diminish the rate of complications.
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Departamentos Hospitalares , Doença Iatrogênica/epidemiologia , Medicina Interna , Idoso , Análise de Variância , Cateteres de Demora/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Doença Iatrogênica/prevenção & controle , Incidência , Masculino , Pessoa de Meia-Idade , Flebite/etiologia , Estudos Prospectivos , Fatores de Risco , EspanhaRESUMO
Chronic fatigue syndrome represents a poorly defined disease with protean clinical manifestations, the majority of them expressed as a muscle fatigue or as inability to maintain the expected muscle strength. In the present work we studied muscle function and muscle histopathology in 20 patients fulfilling the proposed criteria for chronic fatigue syndrome. Special interest is directed towards the immunoreactive expression of class I MHC molecules comparing some inflammatory and virus-related myopathies with muscles from chronic fatigue syndrome. Only minor morphological changes were detected in 9 out of 20 patients of the series. The nonspecific morphological changes in muscle tissue and the lack of class I MHC expression does not support the viral etiology of muscle fatigue in chronic fatigue syndrome. In contrast with the reported clinical improvement with high doses of essential fatty acids, our patients' clinical condition did not improve after three months of L-carnitine therapy.
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Síndrome de Fadiga Crônica/patologia , Músculos/patologia , Adolescente , Adulto , Biópsia , Carnitina/uso terapêutico , Dermatomiosite/patologia , Diagnóstico Diferencial , Síndrome de Fadiga Crônica/tratamento farmacológico , Feminino , Infecções por HIV/patologia , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Polimiosite/patologia , Rabdomiólise/patologiaRESUMO
The case histories of 1200 patients admitted to our hospital over a 20 month period were reviewed to determine the degree, frequency and cause of dissociated cholestasis as a biological syndrome. Patients were divided into two groups: group I with 80 cases, included all patients whose gamma-GT levels were more than 30 mU/ml and serum-bilirubin less than 1.2 mg/ml, with alkaline phosphatase levels between 90-180 mU/ml. Group II included those with alkaline phosphatase levels higher than 180 mU/ml (57 cases). All over incidence of dissociated cholestasis was 13.82%. Main causes in group I were infectious diseases, mainly pneumonias and urinary infections and congestive cardiac failure. In group II, neoplasias such as Hodgkin's disease and epithelial metastases and obstructions of the biliary tract such as vesicular or choledocal litiasis were the main causes. Transaminase levels underwent variable increases according to the different entities, without there being any difference between the two groups. The physiopathology as well as the anatomopathological aspects which could originate the syndrome are discussed.
Assuntos
Colestase/classificação , Fosfatase Alcalina/sangue , Bilirrubina/sangue , Colestase/sangue , Colestase/enzimologia , Colestase/etiologia , Humanos , gama-Glutamiltransferase/sangueRESUMO
The authors describe a case of chronic endocarditis by Q fever, in a patient who had been operated for coarctation of the aorta twelve years previously and at the same time was carrier of a congenital bivalve aorta. The clinical picture was suggestive of subacute endocarditis, but the blood culture was negative repeatedly. There was also a prolonged and relapsing febrile syndrome over a period of one-year-and-a-half. The following data are also worthy of note: the coexistence of a liver disorder and a focal and segmentary glomerulonephritis. Based on some recent publications (one by the same group) the authors feel that Coxiellosis burnetti must be more frequent in their environment than is suspected.