RESUMO
OBJECTIVES: The objective of this study was to determine the optimal scan delay quantitatively and qualitatively in cerebral CT angiography (CTA) with a test injection method at the circle of Willis (cW). METHODS: 66 consecutive patients suspected of having unruptured intracranial aneurysms underwent CTA using 40 ml of 370 mg iodine ml(-1) contrast material (CM). After the time until CM arrival at the cW (T(cW)) was calculated, scan delay was divided into three groups according to T(cW) and scan duration (SD) between the second cervical vertebra and cW as follows: [(T(cW)+6)-SD] in 21 patients (Group A); [(T(cW)+8)-SD] in 23 patients (Group B); and [(T(cW)+10)-SD] in 22 patients (Group C). Arterial and venous attenuation in the intracranial vessels was measured. Mean attenuation values were compared quantitatively. The arterial enhancement and venous overlap at the cW and above the cW were qualitatively compared among the three groups. RESULTS: Mean arterial attenuation in Groups B and C was significantly higher than that in Group A. Mean venous attenuation in Group C was significantly higher than those in Groups A and B. Arterial enhancement above the cW showed a significant difference between Groups A and C, and at the cW between Groups A and B, and Groups A and C. There was a significant difference in venous overlap among the three groups, except for that at the cW between Groups B and C. CONCLUSIONS: Setting scan delay as [(T(cW)+8)-SD] s can produce the best performance both quantitatively and qualitatively.
Assuntos
Angiografia Cerebral/métodos , Meios de Contraste/administração & dosagem , Aneurisma Intracraniano/diagnóstico por imagem , Intensificação de Imagem Radiográfica/métodos , Tomografia Computadorizada por Raios X/métodos , Ácidos Tri-Iodobenzoicos/administração & dosagem , Adulto , Idoso , Algoritmos , Círculo Arterial do Cérebro/diagnóstico por imagem , Feminino , Humanos , Júpiter , Masculino , Pessoa de Meia-Idade , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , UltrassonografiaRESUMO
OBJECTIVES: The aim of this study was to examine attenuation values in the central vein and perivenous artefacts at the subclavian vein in cervical CT angiography (CTA) when using 40 ml contrast material (CM) followed by different volumes (25 ml vs 40 ml) of saline flush (SF). METHODS: 61 patients underwent CTA between the aortic arch (AA) and distal to the circle of Willis (cW). After calculating test-bolus time to peak enhancement at the cW (Tc), scanning delay was represented as [(Tc + 4) - scan duration between AA and cW] s. 28 patients (Group A) received 40 ml of 370 mg iodine (I) ml(-1) CM followed by 25 ml of SF, and 33 patients (Group B) received the same CM followed by 40 ml of SF, both administered through the right antecubital vein. Arterial attenuation was measured at seven points in the aorto-carotid artery and at three points in the vertebrobasilar artery. Venous attenuation in the central vein was measured at four points. Mean attenuation values were analysed quantitatively. Axial and post-processing three-dimensional images were assessed qualitatively. RESULTS: When Groups A and B were compared, there were no differences in the mean attenuation values in either the aorto-carotid artery (p=0.78) or the vertebrobasilar artery (p=0.82). Mean venous attenuation values were lower (p=0.002) in Group B than in Group A. Although the qualitative assessment of arterial images showed no differences between the two groups overall, perivenous artefacts at the subclavian vein were assessed as less prominent (p<0.01) in Group B. CONCLUSIONS: When compared with CTA followed by 25 ml of SF, CTA followed by 40 ml of SF can reduce venous attenuation values and perivenous artefacts at the subclavian vein.
Assuntos
Artefatos , Meios de Contraste , Cloreto de Sódio/administração & dosagem , Veia Subclávia/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Although fast acquisition of multidetector-row computed tomography (MDCT) can make it possible to acquire sufficient early vascular enhancement using small volumes and high concentrations of contrast material (CM), there are still some problems with nephrotoxicity and costs related to CM. PURPOSE: To compare the qualitative and quantitative performance in cervicocranial CT angiography (CTA) using two different iodine volumes and concentrations of CM. MATERIAL AND METHODS: CTA ranging from the aortic arch (AA) to distal to the circle of Willis (cW) was performed on a 32-MDCT system. Fifty-eight patients were randomly divided into two groups: group A (29 patients) received 60 ml of 300 mg I/ml CM, and group B (the other 29 patients) received 40 ml of 370 mg I/ml CM. Time to peak arterial enhancement at cW (T(c)) was calculated. As scan speed was 96.9 mm/s and injection rate was 4.0 ml/s, scanning delay was individually decided according to T(c) and scan duration between AA and cW. Arterial attenuation along the z-axis at eight points in the carotid-cerebral artery and venous attenuation of the internal jugular vein (IJV) at carotid bifurcation were measured. Mean attenuation values were then quantitatively analyzed. Postprocessing images were qualitatively assessed. RESULTS: Arterial attenuation profiles revealed maximum attenuation at the distal common carotid artery in both groups. Although there were no significant differences in mean arterial attenuation in group A versus group B (402+/-70 HU vs. 407+/-67 HU; P=0.78), venous attenuation of the IJV was lower in group B than in group A (114+/-57 HU vs. 224+/-81 HU; P<0.001). Although arterial images demonstrated no difference qualitatively between the two groups, the venous contamination of IVC was less prominent in group B. CONCLUSION: Although a different amount of CM was administered in both groups, quantitative and qualitative arterial images did not show significant differences between the two groups.
Assuntos
Angiografia/métodos , Artérias Carótidas/diagnóstico por imagem , Meios de Contraste , Iodo , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Arteriosclerose Intracraniana/diagnóstico por imagem , Masculino , Pessoa de Meia-IdadeRESUMO
Overproduction of proinflammatory cytokines is characteristic of hemophagocytic syndrome (HPS), a highly lethal inflammatory disease. Peripheral blood monocytes include two distinct subpopulations according to surface antigen expression: a major type, CD14(+)/CD16(-) (classical monocytes), and a minor type, CD14(+)/CD16(bright) (proinflammatory monocytes). Among peripheral blood monocytes from HPS patients, CD14(+)/CD16(bright) cells were increased, together with lipopolysaccharide-induced production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. By three-color immunofluorescence, CD14(+)/CD16(bright) monocytes exhibited more intense human leukocytic antigen DR than CD14(+)/CD16(-) monocytes, consistent with greater maturity. Serum IL-6, TNF-alpha, and IL-8 were increased in HPS patients. A sensitive inflammatory marker, neutrophil CD64 expression, also was significantly elevated in HPS patients. In conclusion, expansion of proinflammatory monocytes and increased expression of neutrophil CD64 appeared to be important in the pathophysiology of HPS. Expansion of CD14(+)/CD16(bright) monocytes and neutrophil CD64 expression could serve as indicators of the inflammatory state in HPS.
Assuntos
Antígenos CD/sangue , Inflamação/sangue , Receptores de Lipopolissacarídeos/sangue , Linfo-Histiocitose Hemofagocítica/sangue , Monócitos/classificação , Receptores de IgG/sangue , Adulto , Idoso , Antígenos CD/imunologia , Biomarcadores , Estudos de Casos e Controles , Feminino , Proteínas Ligadas por GPI , Humanos , Receptores de Lipopolissacarídeos/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Neutrófilos/classificação , Receptores de IgG/imunologiaRESUMO
Colorectal cancer incidence in relation to body size, smoking, and alcohol consumption was studied in a cohort of 29 051 city residents of Japan. In 1992, each participant completed a self-administered questionnaire on sociodemographic characteristics, drinking, cigarette smoking, diet, exercise, and reproductive and medical histories. The response rate was 92%. From 1993 to 2000, 161 men and 134 women were diagnosed with colorectal cancer at two major hospitals in the city. Relative risks and 95% confidence intervals were calculated by using Cox proportional hazard models. A positive relation between height and colorectal cancer was seen in both sexes, controlling for age, body mass index (BMI), smoking and drinking habits, and years of education. The findings were statistically significant only for men (relative risk 2.13 for the tallest compared with the shortest height tertile; 95% confidence interval=1.26-3.58). Body mass index was also associated positively with colon cancer risk for men, whereas the pattern for women was not clear. There was a positive association between pack-years of cigarette smoking and the risk of rectal cancer in men. A positive dose-response relation between alcohol consumption and colon cancer risk was observed for men and women.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Estatura , Peso Corporal , Neoplasias Colorretais/etiologia , Adulto , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fumar/efeitos adversosRESUMO
We investigated the role of the mitochondrial inner membrane permeability transition and subsequent release of cytochrome c into the cytosol during oxidative stress-evoked apoptosis. Sublethal oxidative stress was applied by treating L929 cells with 0.5 mM H2O2 for 90 min. Then the cellular localization of cytochrome c was examined by immunofluorescent staining and Western blotting. H2O2 treatment caused the permeability transition and pore formation, resulting in membrane depolarization and translocation of cytochrome c from the mitochondria into the cytosol. Pretreatment with cyclosporin A and aristolochic acid (to inhibit pore formation) significantly attenuated a reduction of the mitochondrial membrane potential, as well as signs of apoptosis such as DNA fragmentation, increased plasma membrane permeability, and chromatin condensation. Therefore, exposure to H2O2 caused the opening of permeability transition pores in the inner mitochondrial membrane. An essential role of cytosolic cytochrome c in the execution of apoptosis was demonstrated by its direct microinjection into the cytosol, thus bypassing the need for cytochrome c release from the mitochondrial intermembrane space. Microinjection of cytochrome c caused caspase-dependent apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Grupo dos Citocromos c/fisiologia , Peróxido de Hidrogênio/farmacologia , Membranas Intracelulares/metabolismo , Mitocôndrias/metabolismo , Animais , Grupo dos Citocromos c/metabolismo , Grupo dos Citocromos c/farmacologia , Citosol/metabolismo , Membranas Intracelulares/efeitos dos fármacos , Camundongos , Microinjeções , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Permeabilidade/efeitos dos fármacos , Transporte Proteico , Células Tumorais CultivadasRESUMO
Islet antigen (IA)-2 is a novel autoantigen of insulin-dependent diabetes mellitus (IDDM), and belongs to a new class within the receptor-type protein tyrosine phosphatase (PTP) family characterized by lack of PTP enzymatic activity with conventional substrates. Its expression is restricted primarily to the pancreas, pituitary, and brain with the highest level in the brain. IA-2 mRNA expressions in the brain, pituitary and pancreas of 1-, 4-, and 8-week-old mice were examined. In situ hybridization of the brain revealed that IA-2 mRNA was expressed in the cerebral cortex, hippocampus, thalamus, choroid plexus, hypothalamus, Purkinje cells, and granular layer of the cerebellum. In the pituitary, IA-2 mRNA was located in the anterior and posterior pituitary by in situ hybridization. The pattern of IA-2 mRNA expression in normal male mouse brain at 1, 4, and 8 weeks of age by the Northern blot analysis was similar to that in the pituitary by RT-PCR analysis. The expression level was higher at 4 weeks and lower at 1 week of age. In the pancreas, IA-2 mRNA expressions detected by RT-PCR were highest at 8 weeks of age. These results indicated that the amount of mRNA expression increased in accordance to development in brain, pituitary, and pancreas.
Assuntos
Encéfalo/crescimento & desenvolvimento , Proteínas de Membrana/biossíntese , Hipófise/crescimento & desenvolvimento , Proteínas Tirosina Fosfatases/biossíntese , Animais , Autoantígenos , Encéfalo/metabolismo , Hibridização In Situ , Cinética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Pâncreas/crescimento & desenvolvimento , Pâncreas/metabolismo , Hipófise/metabolismo , Proteínas Tirosina Fosfatases/genética , RNA Mensageiro/biossíntese , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores , Distribuição Tecidual , Transcrição GênicaRESUMO
We report a very rare case of anterior dislocation of the subtalar joint. Forceful supination of the foot and dorsiflexion of the ankle was considered the cause of the injury in this case. Closed reduction was successful for the talocalcaneal component of subtalar joint, although surgery was subsequently performed because of the residual subluxation of the midtarsal joint including the talonavicular component of subtalar joint and the associated fracture of the lateral process of the talus. Satisfactory results were shown at three-year follow-up.
Assuntos
Luxações Articulares/terapia , Articulação Talocalcânea/lesões , Acidentes de Trânsito , Adulto , Fraturas Ósseas/cirurgia , Humanos , Luxações Articulares/cirurgia , Masculino , Tálus/lesõesRESUMO
PURPOSE: The purpose of this study was to assess the relationship between risk of colorectal adenoma and dietary intake of nutrients and foods. METHODS: In 1992, diet was assessed by a semiquantitative food-frequency questionnaire in a cohort of the Takayama Study in Japan. Patients were 181 male and 98 female cohort members who were newly histologically proved to have colorectal adenoma at colonoscopic examination between January 1, 1993, and December 31, 1995. Controls were 12,607 males and 15,754 females who had no history of colorectal polyp, adenoma, and cancer at baseline (1992) and were not diagnosed to have these diseases during the follow-up period. RESULTS: In males, the risk of adenoma was significantly associated with intake of animal protein and vitamin A (relative risk, 1.42; 95 percent confidence interval, 1.00-2.04; and relative risk, 1.51; 95 percent confidence interval, 1.04-2.20, for the highest vs. lowest tertiles, respectively; P for trend = 0.048 and 0.03, respectively) after controlling for age, years of smoking, and alcohol intake. A significantly inverse association was observed for carbohydrate intake after controlling for the covariates (relative risk, 0.52; 95 percent confidence interval, 0.32-0.82, for the highest vs. lowest tertiles; P for trend = 0.02). Intakes of animal fat and cholesterol were marginally associated with risk of adenoma. CONCLUSION: Some dietary components such as animal protein and carbohydrate, which have been associated with risk of colorectal adenoma or cancer in western populations, were also associated with risk of colorectal adenoma in the Japanese population.
Assuntos
Adenoma/etiologia , Neoplasias Colorretais/etiologia , Dieta/efeitos adversos , Adenoma/patologia , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/patologia , Feminino , Alimentos/efeitos adversos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Fatores de Risco , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Treatment with the nitric oxide-(NO)-generating compound S-nitroso-N-acetylpenicillamine protected cul-tured L929 cells from apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) plus actinomycin D, as determined by the detection of DNA fragmentation and morphological changes. NO also prevented an enhancement of the production of reactive oxygen intermediates by TNF-alpha plus actinomycin D, as assessed by the oxidation of dihydrorhodamine 123 and hydroethidine. Because the inhibition of mitochondrial respiration by rotenone or antimycin A suppressed the increased oxidation of both dihydrorhodamine 123 and hydroethidine, it was suggested that TNF-alpha accelerated the leakage of reactive oxygen intermediates from the mitochondrial electron transport system. Polarography showed that NO reversibly inhibited mitochondrial respiration at either complexes I-III, II-III, or IV, thus suggesting the inhibition of cytochrome oxidase. Taken together, these findings indicate that the decreased mitochondrial formation of reactive oxygen intermediates in the presence of NO might have a protective effect against TNF-alpha plus actinomycin D-induced apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Dactinomicina/farmacologia , Fibroblastos/efeitos dos fármacos , Óxido Nítrico/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Antimicina A/farmacologia , Citoproteção , Fibroblastos/fisiologia , Camundongos , Mitocôndrias/fisiologia , Penicilamina/análogos & derivados , Penicilamina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologiaRESUMO
Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N(G)-monomethyl-l-arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2, 2'-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.
Assuntos
Apoptose , Encefalopatia Hepática/tratamento farmacológico , Óxido Nítrico/fisiologia , Aminoquinolinas/farmacologia , Animais , Fragmentação do DNA/efeitos dos fármacos , Dactinomicina , Dibutiril GMP Cíclico/farmacologia , Encefalopatia Hepática/sangue , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/patologia , Hidroxilamina/farmacologia , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Mutantes , Microscopia Confocal , Nitratos/sangue , Nitritos/sangue , Compostos Nitrosos/farmacologia , ômega-N-Metilarginina/farmacologiaRESUMO
PURPOSE: The aim of this study was to examine the relationships between smoking and alcohol use and risk of colorectal adenoma. METHODS: Information about smoking, alcohol use, and other lifestyle variables were obtained prospectively from 14,427 male and 17,125 female residents in a city of Gifu Prefecture, Japan, by a self-administered questionnaire in September, 1992. Colorectal adenomas were newly diagnosed in 181 men and 78 women in this cohort between January, 1993 and December, 1995 by colonoscopic examination at two major hospitals of the city. Gender-specific and site-specific relative risks and 95 percent confidence intervals adjusted for age and for age plus other potential confounding factors were calculated by using logistic regression models. RESULTS: Thirty or more years of smoking was significantly associated with risk of adenoma in general compared with never having smoked in both men and women (relative risk, 1.60; 95 percent confidence interval, 1.02-2.62 and relative risk, 4.54; 95 percent confidence interval, 2.04-9.08, respectively). Effect of smoking was stronger in the proximal colon. After adjusting for age and carbohydrate intake, total alcohol intake was not associated with risk of adenoma in any site in the colon in men. Sake drinkers were at significantly increased risk of adenoma in general, but the dose-response relationship was not statistically significant. Risk of adenoma in the rectum was not significantly increased for those who consumed >30.3 g/day of ethanol (relative risk, 5.7). CONCLUSION: These data suggest that smoking is a risk factor of adenoma in Japanese men and women. The role of alcohol, however, is less clear.
Assuntos
Adenoma/epidemiologia , Consumo de Bebidas Alcoólicas , Neoplasias Colorretais/epidemiologia , Fumar , Causalidade , Fatores de Confusão Epidemiológicos , Dieta , Feminino , Humanos , Japão/epidemiologia , Estilo de Vida , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
OBJECT: The mechanism of arterial vasoconstriction caused by oxyhemoglobin production after subarachnoid hemorrhage was investigated. METHODS: Using a fluorescent Ca++ indicator (fura-2 acetoxymethyl ester), the change in the cytosolic intracellular Ca++ concentration, [Ca++]i. was measured in cultured rat vascular smooth-muscle cells exposed to oxyhemoglobin and other substances. Oxyhemoglobin induced transient elevation of smooth-muscle cell [Ca++]i in either the presence or absence of ethyleneglycol-bis (beta-aminoethylether)-N,N'-tetraacetic acid, indicating that Ca++ released by oxyhemoglobin was derived from [Ca++]i stores. In contrast, methemoglobin had no effect on the smooth-muscle cells. Exposure of the cells to reactive oxygen species generated by xanthine plus xanthine oxidase yielded the same results as with oxyhemoglobin, that is, transient elevation of smooth-muscle cell [Ca++]i. Procaine (a Ca++ channel blocker) failed to inhibit the oxyhemoglobin-induced elevation of [Ca++]i. Ryanodine (a Ca++ channel opener) plus oxyhemoglobin caused markedly greater elevation of [Ca++]i than ryanodine alone, whereas thapsigargin (an adenosine triphosphate [ATP]-dependent Ca++ pump inhibitor) plus oxyhemoglobin had no additional effect when compared with thapsigargin alone. The oxyhemoglobin-induced elevation of [Ca++]i could be blocked by an Fe++ chelator (ferene), but not by an Fe chelator (deferoxamine mesylate). Treatment with either dithiothreitol or glutathione monoethyl ester markedly inhibited the oxyhemoglobin-induced elevation of [Ca++]i. CONCLUSIONS: These results indicate that Fe++-catalyzed hydroxyl radicals generated from oxyhemoglobin-derived free radicals induce the elevation of [Ca++]i by inhibiting the ATP-dependent Ca++ pump rather than the Ca++ channels in the sarcoplasmic reticulum and that thiols may prevent Ca++ pump inactivation by inhibiting the oxidation of membrane sulfhydryl groups.
Assuntos
Cálcio/metabolismo , Citosol/metabolismo , Glutationa/análogos & derivados , Músculo Liso Vascular/metabolismo , Oxiemoglobinas/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Combinação de Medicamentos , Inibidores Enzimáticos/farmacologia , Compostos Ferrosos/farmacologia , Glutationa/farmacologia , Músculo Liso Vascular/citologia , Concentração Osmolar , Oxiemoglobinas/antagonistas & inibidores , Ratos , Espécies Reativas de Oxigênio/fisiologia , Rianodina/farmacologia , Tapsigargina/farmacologiaAssuntos
Adjuvantes Imunológicos/farmacologia , Cimetidina/farmacologia , Imunidade Celular/efeitos dos fármacos , Interleucina-12/imunologia , Adjuvantes Imunológicos/uso terapêutico , Cimetidina/uso terapêutico , Cuidados Críticos , Feminino , Humanos , Imunidade Celular/imunologia , Interleucina-12/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Reduction of mitochondrial membrane potential (Psim) and release of cytochrome c from mitochondria appear to be key events during apoptosis. Apoptosis was induced in IC.DP premast cells by the withdrawal of interleukin-3 (IL-3). Psim decreased by 12 hours and cytochrome c was detected in the cytosol at 18 hours. Despite these changes in the mitochondria after 18 hours of IL-3 deprivation, clonogenicity was unaffected when IL-3 was replenished at 18 hours. Activation of v-Abl tyrosine kinase (v-Abl TK) in IC.DP cells before IL-3 depletion led to increased levels of Bcl-XL, prevented reduction of Psim and the release of mitochondrial cytochrome c, and suppressed apoptosis. Activation of v-Abl TK 18 hours after withdrawal of IL-3 when =10% of the cells had died restored Psim in the remaining cells. More than 40% of cells thus rescued by v-Abl TK between 18 and 42 hours could subsequently form colonies in the presence of IL-3. These data suggest that reduction in Psim precedes loss of mitochondrial cytochrome c in IC.DP cells; that v-Abl TK activation, probably via upregulation of Bcl-XL, prevents loss of Psim and blocks the release of cytochrome c from mitochondria; and that neither of these mitochondrial events is sufficient for commitment to apoptosis.
Assuntos
Apoptose , Células Sanguíneas/metabolismo , Grupo dos Citocromos c/metabolismo , Mitocôndrias/fisiologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ensaio de Unidades Formadoras de Colônias , Citosol/metabolismo , Ativação Enzimática/efeitos dos fármacos , Interleucina-3/farmacologia , Interleucina-3/fisiologia , Mastócitos/citologia , Mastócitos/metabolismo , Potenciais da Membrana/fisiologia , Camundongos , Mitocôndrias/metabolismo , Proteínas Oncogênicas v-abl/metabolismo , Temperatura , Fatores de TempoRESUMO
Anoxia/reoxygenation injury of isolated rat liver mitochondria was investigated. During anoxia of up to 60 min, the membrane potential was largely preserved and mitochondrial swelling was not observed. Reoxygenation of anoxic mitochondria rapidly caused swelling, cyclosporin A-sensitive Ca2+ efflux, [14C]sucrose trapping, and loss of the membrane potential along with increased generation of reactive oxygen intermediates (ROI). Although pretreatment with catalase and superoxide dismutase completely abolished reoxygenation-induced generation of ROI, mitochondrial damage was not prevented, as indicated by swelling, loss of the membrane potential, a decrease of the ATP content, and cyclosporin A-sensitive Ca2+ efflux. However, addition of the immunosuppressant cyclosporin A or addition of ADP completely prevented the mitochondrial damage induced by reoxygenation. The same protective effect was noted when Ca2+ cycling was prevented, either by chelating Ca2+ with EGTA or by inhibiting Ca2+ reuptake with ruthenium red. These findings indicate that mitochondrial anoxia/reoxygenation injury is caused by the cyclosporin A-sensitive and Ca2+-dependent membrane permeability transition. In contrast, reoxygenation injury does not appear to be triggered by the enhanced production of ROI.
Assuntos
Cálcio/fisiologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Membranas Intracelulares/metabolismo , Mitocôndrias Hepáticas/metabolismo , Oxigênio/toxicidade , Trifosfato de Adenosina/análise , Animais , Cálcio/metabolismo , Radioisótopos de Carbono , Ciclosporina/farmacologia , Ácido Egtázico/farmacologia , Membranas Intracelulares/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Rutênio Vermelho/farmacologia , Sacarose/metabolismoRESUMO
1. The influence of hyperammonemia (produced by the continuous intraperitoneal infusion of ammonium acetate for 6 days) on stress-induced gastric ulcer formation was investigated in conscious rats. 2. Continuous ammonium acetate infusion significantly reduced stress-induced gastric ulceration concomitant with an increase in gastric blood flow, as determined using radioactive microspheres. The serum levels of L-arginine as well as nitrite and nitrate (oxidative byproducts of nitric oxide) were increased by ammonium acetate infusion. 3. Prior administration of N omega-nitro-L-arginine methyl ester, a competitive nitric oxide synthase inhibitor, substantially attenuated the increase in gastric blood flow caused by ammonium acetate infusion and diminished the protective effect on gastric ulceration. 4. These findings suggest that the synthesis of endogenous nitric oxide from L-arginine is accelerated by continuous ammonium acetate infusion when the urea cycle remains intact and has a substantial cytoprotective effect on the stomach, probably through maintaining the gastric mucosal microcirculation.
Assuntos
Acetatos/uso terapêutico , Imersão/fisiopatologia , Óxido Nítrico/biossíntese , Úlcera Gástrica/tratamento farmacológico , Estresse Fisiológico/tratamento farmacológico , Acetatos/sangue , Animais , Inibidores Enzimáticos/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Nitratos/sangue , Óxido Nítrico Sintase/antagonistas & inibidores , Nitritos/sangue , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Restrição Física , Úlcera Gástrica/sangue , Úlcera Gástrica/psicologia , ÁguaRESUMO
Overproduction of reactive oxygen intermediates (ROI) may have an important role in the pathophysiology of lipopolysaccharide-mediated liver-injury. This study examined the role of cytosolic and mitochondrial glutathione in protecting hepatocytes from oxidative stress during exposure to lipopolysaccharide. In addition, the possible participation of changes of inner mitochondrial membrane permeability in lipopolysaccharide-induced hepatotoxicity was investigated. The changes of hepatic glutathione content following lipopolysaccharide challenge (2 mg/kg) were measured in mice by reverse-phase high-performance liquid chromatography. Glutathione depletion and a glutathione-rich state were produced by intraperitoneal administration of a specific inhibitor of gamma-glutamyl cysteine synthetase, buthionine sulfoximine (3 mmol/kg), and by administration of glutathione monoethyl ester (10 mmol/kg), respectively. Intracellular ROI generation and the mitochondrial membrane potential were quantified by flow cytometry. Changes of inner mitochondrial membrane permeability in hepatocytes were assessed by radioactive sucrose entrapment. There was increased production of ROI along with depletion of cellular and mitochondrial glutathione in the liver after lipopolysaccharide administration. There was also a change of inner mitochondrial membrane permeability in hepatocytes, with the loss of coupled functions. Buthionine sulfoximine decreased the hepatic antioxidant capacity, worsened mitochondrial function, and reduced the survival rate of the mice. In contrast, glutathione monoethyl ester improved all of these parameters. Glutathione may have an important role in cellular defenses against lipopolysaccharide-induced liver damage in mice, and excessive oxidative stress may precipitate the mitochondrial membrane permeability transition in hepatocytes and lead to cell death.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Glutationa/análogos & derivados , Glutationa/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/metabolismo , Mitocôndrias Hepáticas/patologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Butionina Sulfoximina/farmacologia , Citosol/metabolismo , Feminino , Glutationa/uso terapêutico , Cinética , L-Lactato Desidrogenase/sangue , Hepatopatias/metabolismo , Hepatopatias/patologia , Potenciais da Membrana , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/fisiologia , Tamanho do Órgão , Espécies Reativas de Oxigênio/metabolismo , Sacarose/metabolismoRESUMO
A healthy, nonepileptic 16-month-old child ingested a massive overdose (approximately 4000 mg) of valproic acid (VPA). Upon admission to the hospital, he was in a deep coma and had generalized hypotonicity and no response to pain. His serum and urinary concentrations of VPA were 1316.2 and 3289.5 micrograms/mL, respectively. Urinary concentrations of the beta-oxidation metabolites of VPA were low, whereas concentrations of omega- and omega 1-oxidation metabolites were high. Moreover, 4-en-valproate (a potential hepatotoxin) was detected in the urine. Gastric lavage and general supportive measures were undertaken, including intravenous infusion to increase urine output and oral L-carnitine to correct hypocarnitinemia. Subsequently, the beta-oxidation metabolites increased, the omega- and omega 1-oxidation metabolites decreased, and 4-en-valproate was no longer detected. The patient recovered completely and was discharged on the eighth hospital day without any sequelae. This case suggests that enhanced drug excretion and L-carnitine supplementation may prevent potentially fatal hepatic dysfunction after VPA overdose.
Assuntos
Anticonvulsivantes/intoxicação , Carnitina/uso terapêutico , Ácido Valproico/intoxicação , Doença Hepática Induzida por Substâncias e Drogas , Química Clínica , Overdose de Drogas , Humanos , Lactente , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/prevenção & controle , Masculino , Fatores de Tempo , Ácido Valproico/sangue , Ácido Valproico/urinaRESUMO
The effect of hyperammonemia on ex vivo platelet function and in vivo nitric oxide synthesis was evaluated in rats. In addition, mitochondrial energy production was assessed from the fluorescence intensity of tetramethylrhodamine ethyl ester (TMRE). Continuous ammonium acetate infusion significantly reduced ex vivo platelet aggregation concomitant with a decrease of the platelet cytoplasmic ATP level. The serum level of L-arginine, as well as the levels of nitrite and nitrate (oxidative by-products of nitric oxide), increased with ammonium infusion. Prior administration of N omega-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase, did not affect the ammonia-induced rise in L-arginine, but substantially attenuated the associated decrease of platelet ATP and TMRE fluorescence as well as diminishing the anti-aggregatory effect of ammonia infusion. These findings suggest that the synthesis of nitric oxide from L-arginine is accelerated by continuous ammonium infusion and inhibits ex vivo platelet aggregation in the rat, probably by reducing mitochondrial energy production.