A mechanism of toxicity of isovaleric acid in rat liver mitochondria.
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Biomedical subjects
Publications and source records attributed to R Haas.
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Wild caught African lungfish, Protopterus amphibius, were found to reject most first-set cutaneous allografts more slowly than comparable allograft rejection in teleost fishes at a temperature of 24.0 +/- 0.5 C. Second-set allografts made 68 days after first sets were rejected more rapidly, indicating the immunological basis for rejection in this primitive fish. Wide variation in survival times of scale transplants with some surviving in excess of 131 days suggest moderate histoincompatibility systems and substantial sharing of histocompatibility antigens.
Polarographic assays of oxidative phosphorylation in muscle mitochondria indicated abnormal pyruvate-malate metabolism in Friedreich ataxia (FA). Pursuing this clue, more specific assays were performed. Mitochondrial malic enzyme (MEm; malate: NADP+ oxidoreductase) specific activity was 10% of controls in fibroblasts from eight FA patients (p less than 0.0001). Cytosolic malic enzyme was modestly increased in FA fibroblasts. Mitochondrial and cytosolic malate dehydrogenase and aspartate aminotransferase, and malate transport on the dicarboxylate and alpha-ketoglutarate carriers were normal in fibroblasts or leukocytes. MEm activity is normally highest in the nervous system and heart is important in regulating carbohydrate metabolism. MEm deficiency could cause FA; further studies are required to substantiate this hypothesis.
There is uncertainty as to whether the clinical behavior of nasopharyngeal lymphoepithelioma differs from that of squamous cell carcinoma of the nasopharynx. To determine if significant differences existed, we have studied 39 patients with nasopharyngeal lymphoepithelioma and compared their data with 50 nasopharyngeal squamous cell carcinoma patients. In contrast to squamous cell carcinoma, lymphoepithelioma occurred at a younger age, presented as smaller primary tumors, and manifested more extensive cervical lymph node involvement. When analyzed by T stage, N stage, or overall stage groups, the 5-year actuarial survivals were better in the lymphoepithelioa patients. Late tumor recurrences (beyond 4 years) were seen in the lymphoepithelioma patients, whereas all of the recurrences in the squamous cell carcinoma group occurred within 4 years. Tumor recurrences were more common in the cervical lymph nodes in the lymphoepithelioma group and in the primary site of the squamous cell carcinoma group.
Until now, the possibility of radiotherapeutic treatment after a failure of chemotherapy has not been systematically investigated. Eight cases with primary failure of chemotherapy or recurrence after chemotherapy could be evaluated. The patients were submitted to curative irradiation; six of them achieved a total remission, four had recurrences. Thus two patients remain to give an example that radiotherapy can bring about long-term total remissions after primary failure of chemotherapy or recurrence after chemotherapy. When the data were evaluated, the total remission times of the two patients were 12 and 18 months, respectively. The toxicity of radiotherapy was justifiable. It was increased especially in regions that had already been irradiated or if a ABVD therapy was applied a short time before or after the radiotherapy. There are only few communications in literature about the success of a radiotherapy after failure of chemotherapy. Most of the patients mentioned had "remissions" (total/partial remissions?). In most of the cases, there are no indications about the further development. On the whole, the data show that there may be some special indications for radiotherapy in case of a failure of chemotherapy.
Fibrinopeptide A (FPA), which is considered to be a quantitative indicator for the thrombin activity in vivo, was measured in 136 patients treated with phenprocoumon in order to obtain information on the effectiveness of the inhibition of the coagulation system. The results show a decrease of the FPA concentration in relation to the efficacy of the anticoagulant therapy as measured by the thrombotest coagulation method (p less than 0.01). However, elevated FPA was observed even under an effective oral anticoagulation. These data indicate that an increased thrombin activity cannot be completely prevented by oral anticoagulants in every patient. Combined measurement of FPA and the thrombotest coagulation methods might be used to detect patients with an elevated risk of recurrent thromboembolism despite treatment with phenprocoumon.
All children with leukaemia or malignant tumour receiving cytostatic agents were followed by virological tests over three years. Serological tests or virus isolation in 200 children demonstrated 238 instances of viral infection. Only those of the herpes group led to severe symptoms which, however, responded to treatment. The course of infections induced by respiratory viruses was no different from that in children not receiving immunosuppressive agents. It was possible, by using a "virus risk register", to give early protection to infected children by the appropriate prophylactic means. In addition to the virus infections there were seven cases of Pneumocystis carinii pneumonia which ended fatally in two. Since the prophylactic use of cotrimoxazole there have been no further cases.
Seventeen patients with relapsed, acute leukemia were grafted with bone marrow from HLA-identical siblings by the 'Munich Cooperative Group for Bone Marrow Transplantation' during the period from August 1975 to June 1980. The antileukemic and immunosuppressive conditioning treatment consisted of high doses of bischlorethyl nitrosourea, Cytosine-Arabinoside and Cyclophosphamide, as well as, total body irradiation of about 9 Gy (midline body dose) from dual 60Cobalt sources. Methotrexate was given to all patients for prophylaxis of graft-versus-host disease (GvHD). Nine patients received marrow that was treated with anti-T-cell globulin (ATCG) "in vitro".--Crossreacting antibodies against hemopoietic stem cells were removed by absorption. Two of 5 evaluable patients given untreated marrow developed chronic GvHD, while patients given ATCG-treated marrow did not show unequivocal symptoms of GvHD. Six patients are in complete remission one to 33 months following bone marrow transplantation (b.m.t.) Five patients died with relapses of leukemia between 3 1/2 and 24 months following b.m.t., 3 patients died with interstitial pneumonia within 3 months of b.m.t. and 3 patients died with insufficient graft function within 4 weeks of b.m.t. Four of thirteen patients that were grafted more than 6 months ago are presently alive and in continuous complete remission at 11, 14, 29 and 33 months following b.m.t. Our results confirm that longterm remissions can be obtained with b.m.t. in patients with acute leukemia in advanced stage.
Severe immunosuppression with prednisone and cyclophosphamide failed to prevent neurological progression in a patient with adrenoleukodystrophy.
In leukemia patients with extremely high leukocytosis the great number of poorly deformable lymphoblasts compared to normally deformable red cells greatly influences the flow properties of leukemic blood. The increased blood viscosity implies a great risk of disturbance of the microcirculation by leukostasis and bleeding. Removal of large amounts of leukemic cells by exchange transfusion with fresh blood diminished leukemic cell burden and reduced the initial elevated leukocyte counts by more than 50% in 3 patients. In addition, anemia and thrombocytopenia improved and the disturbed plasma coagulation returned to normal. One of the patients with additional risk factors treated by exchange transfusion died 8 months after diagnosis in hematologic release. The two other patients perform well without relapse six and nine months after diagnosis, respectively. Exchange transfusion with 150 ml/kg of fresh blood is considered to be of value to avoid severe early complications as e.g. massive intracerebral hemorrhage observed in 3 other patients and to correct hematological and rheological abnormalities in childhood leukemia with extreme leukocytosis. Possible favourable effects as to long term prognosis have to be awaited.
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Sodium valproate (VP) inhibited oxidative phosphorylation in isolated rat liver mitochondria. State 3 rates of oxygen consumption with glutamate as substrate were 80% of control values at a low VP concentration (24 microM). At 240 microM, there was more than 50% inhibition of glutamate and alpha-ketoglutarate state 3 rates. Succinate state 3 rates were 80% of control values, and uncoupling was noted at 2400 microM VP. These VP effects were similar to those of propionate and isovalerate, suggesting a common mechanism of toxicity. Inhibition of mitochondrial oxidative phosphorylation may explain why VP intoxication causes a hepatocerebral disorder that resembles Reye syndrome.
Mitochondria were isolated from oat primary leaves via mesophyll protoplasts and subjected to phospholipid analysis. In mesophyll cells mitochondria account for only small proportions of cellular phospholipids (in the order of 5%) and proteins (in the order of 2%). Contamination by lipids from other membranes was insignificant as indicated by the absence or very low levels of chlorophyll, galactolipids and steryl glycosides. The absence of 3-trans-hexadecenoic acid in phosphatidylglycerol from mitochondria of green cells serves an an additional criterion of purity. The phospholipid mixture extracted from these mitochondria resembles phospholipids in mitochondria from non-green tissues regarding composition as well as fatty acid profiles. Therefore, mitochondria maintain a rather constant lipid profile and in contrast to plastids do not respond at this level to differences in the physiological status of their housing cell. Palmitic acid in mitochondrial phosphatidylcholine and phosphatidylethanolamine is primarily localized at the C-1 position of the glycerol moiety. Two enzymatic activities so far not described in mitochondria, formation of acylgalactosyl diacylglycerol and hydrolysis of acyl-CoA, were found in the purified mitochondrial fraction.
A rare instance of renal cell carcinoma metastatic to the prostate gland is described. The prostatic metastases caused acute urinary retention and were clinically thought to represent benign prostatic hypertrophy. Histologic examination of the transurethral resection specimen demonstrated the true nature of the tumor.
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A carboxypeptidase from rat liver mitochondria was partially purified by discontinuous sucrose gradient centrifugation, washes with NaCl/KBr/Tris buffer, and solubilization with 2 M NaCl in the presence of soybean trypsin inhibitor bound to CM-cellulose. By means of dodecylsulfate/polyacrylamide gel electrophoresis a molecular weight of 34,500 was determined; a value of 38,000 was estimated by Sephadex G-100 gel filtration. The carboxypeptidase was completely inhibited by 3 mM Hg2+. In the presence of 3 mM Cu2+ 50% of the catalytic activity was inhibited. Among several peptides tested Cbz-Ala-Phe, Cbz-Leu-Phe, Cbz-Phe-Leu, and Cbz-Phe-Phe, were good substrates. The enzyme activity exhibited a pH optimum of around 9 with Cbz-Ala-Phe as a substrate. After submitochondrial fractionation it was found that the carboxypeptidase is located in the inner mitochondrial membrane.