Biomedical subjects
Publications and source records attributed to M Levitt.
Simple models are presented that describe the rules for almost all the packing that occurs between and among alpha-helices and pleated sheets. These packing rules, together with the primary and secondary structures, are the major determinants of the three-dimensional structure of proteins.
Diethyldithiocarbamate (DEDTC) prevented dimethylnitrosamine (DMN)-induced strand breaks in liver DNA and liver cell necrosis in male Wistar rats. In contrast, DEDTC did not inhibit the fragmentation of liver DNA caused by several other chemical carcinogens (N-hydroxy-2-acetylaminofluorene, 3-hydroxyxanthine, aflatoxin B1, N-acetoxy-2-acetylaminofluorene, methyl methanesulfonate, methylnitrosourea, and methylazoxy-methanol acetate), whether or not they required metabolic activation. Aminoacetonitrile exerted an action similar to that of DEDTC. The inhibitory effect was transitory, lasting at least for 4 hours, and protection for longer than 4 hours required multiple administrations of DEDTC. DEDTC also inhibited the serum clearance of DMN, methylation of liver DNA, and oxidative demethylation of DMN in the in vitro hepatic microsomal system prepared from either male Wistar rats or from hamsters. Interference of the metabolism of DMN appeared to be the mechanism by which DEDTC arrested DMN-induced biochemical and biologic effects.
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Previous studies have suggested that the activity of erythrocyte catechol-O-methyltransferase (COMT) may be reduced in women with bipolar and particularly unipolar affective illness. More recently, increased COMT activity in both men and women with affective disorder was reported. The activity of COMT in erythrocytes was determined in 184 outpatients with primary affective disorder at the Lithium Clinic of the New York State Psychiatric Institute. COMT activity was determined by a modification of the Axelrod and Cohn method with dopamine as substrate. This change resulted in an apparent threefold increase in the values for COMT activity; however, when both methods were compared, the results correlated (r = 0.97, p less than 0.001, N = 37). We found that the values for women were not significantly lower than those for men. In addition, there was no difference between patients with affective disorder and controls. Further, no difference was demonstrated between patients diagnosed as bipolar or uni-polar. Parameters such as mood, medication, and inpatient or outpatient status had no effect on COMT activity. The results of previous studies are discussed in an attempt to reconcile the different results.
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A simple diagrammatic representation has been used to show the arrangement of alpha helices and beta sheets in 31 globular proteins, which are classified into four clearly separated classes. The observed arrangements are significantly non-random in that pieces of secondary structure adjacent in sequence along the polypeptide chain are also often in contact in three dimensions.
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Plasma dopamine beta hydroxylase (DBH) activity was measured in patients with affective disorders and in their relatives. The groups studied had wide distributions of values for plasma DBH activity. No significant difference of plasma DBH activity was found between unipolar and bipolar patients, nor between patients given lithium or placebo. Exercise on a treadmill at 40 degrees or 10 degrees C elicited a different pattern of response for plasma DBH activity in three patients as compared to control subjects. In familial studies we found the values of plasma DBH activity to be almost identical in monozygotic twin pairs and quite similar in dizygotic twin pairs. All pairs, however, were discordant for affective illness. There was also a marked similarity of plasma DBH activity in 15 pairs of the same sex sibs discordant for affective illness. These studies suggest that the resting level of plasma DBH activity is not related to affective illness but is genetically determined.
A rapid procedure to estimate tritiated norepinephrine (levarterenol) in a single mouse heart is described. The method is based upon oxidation of the tritium in the tissue to tritiated water, which is then determined by liquid scintillation spectroscopy. Large numbers of samples can be assayed with great facility. The effects of standard compounds that modify the uptake and release of 3H-norepinephrine in heart tissue were determined with this system, and a procedure for studying their interactions is described.
Catechol-O-Methyltransferase (COMT) activity was studied in three groups of institutionalized children: (1) a group of schizophrenic children; (2) a heterogeneous group of chronic psychotic children characterized by severe symptomatology and onset before 5 years of age; (3) a group of acting-out but nonpsychotic children. Erythrocyte COMT activity was found to be significantly lower among the schizophrenic subjects in contrast to the greater activity in both the other groups--the nonpsychotic and chronic psychotic children. The difference in COMT activity between psychotic groups appeared to be related to diagnosis and age of onset of disorder. Generality of findings is limited by the small sample size (N = 42) and by the difficulties inherent in the diagnosis of severe mental disorder in children. However, this preliminary study suggests that enzymatic activity may be associated with the development of schizophrenia in children.
Two hundred and fifty-eight patients with small cell carcinoma and 185 patients with adenocarcinoma were centrally randomized to receive either cyclophosphamide (1000 mg/m2 every 3 weeks) iv or cyclophosphamide (700 mg/m2 every 3 weeks) iv plus CCNU (70 mg/m2 every 6 weeks) orally. Those patients who were initially treated with the single agent were then treated with CCNU (130 mg/m2 every 6 weeks) at the time of cyclophosphamide failure. Objective tumor regression occurred more frequently with the combination regimen in patients with small cell carcinoma (43% vs 22%, P = 0.002), but no difference in response rates was apparent in patients with adenocarcinoma. In both cell types patients survived somewhat longer following treatment with the combination. The overall incidence of severe toxicity was equal for the two regimens in both cell types; however, the therapeutic index of the combination was superior to that of the single agent in small cell carcinoma. Severe drug toxicity was more frequent in small cell carcinoma patients with extensive disease, and survival was reduced in both cell types with extensive disease. Survival was better for ambulatory patients in both cell types and women survived longer than men. In women with small cell carcinoma, ambulatory status also was associated with a higher incidence of tumor regression. In patients with small cell carcinoma those who had prior lung surgery survived longer than those without prior surgery. Previous radiation therapy was associated with a reduced incidence of objective regression in men with small cell carcinoma. In both cell types patients with tumor regression lived longer than nonresponders; however, objective disease stability was associated with improved survival only in patients with adenocarcinoma. Stratification in future studies should consider extent of disease, performance status, sex, and prior therapy.
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A new and very simple representation of protein conformations has been used together with energy minimisation and thermalisation to simulate protein folding. Under certain conditions, the method succeeds in "renaturing" bovine pancreatic trypsin inhibitor from an open-chain conformation into a folded conformation close to that of the native molecule.
Seventeen patients with Stage III or IV reticulum cell sarcoma were treated with three cycles of a 5-drug regimen between February, 1969 and December, 1970. Of the 17 patients, 9 attained a complete remission and 6 had a parital remission; 2 were considered unevaluable. Recently, the original biopsies from these patients were reclassified according to the criteria of rappaport et al. The results were: diffuse histiocytic--8; nodular histiocytic--2; diffuse mixed--2; nodular mixed--3; diffuse lymphocytic poorly differentiated--1; nodular lymphocytic poorly differentiated--1. Of the 8 patients with diffuse histiocytic lymphoma 6 attained complete remission, 1 had a partial remission, and 1 was unevaluable. One of the 6 with complete remission relapsed at 7 months and died 2 months later. However, the other 5 are alive and in continued unmaintained remission for 55 to 65 months.
Hypercalcemia is very uncommon in small cell (oat cell) carcinoma of the lung. Two cases of this neoplasm associated with symptomatic hypercalcemia are described. Despite normal skeletal roentgenograms, metastatic bone disease was demonstrated by abnormal bone scans and bone biopsies in both patients. The combination of conventional antihypercalcemia therapy, cytotoxic cancer chemotherapy, and synthetic salmon calcitonin corrected the hypercalcemia despite progression of the small cell carcinoma. One patient with elevated serum immunoreactive parathyroid hormone (PTH) had a parathyroid adenoma at autopsy. This association emphasizes that in cases of bronchogenic small cell carcinoma with hypercalcemia, conincidental primary hyperparathyroidism should be considered.
A simple fluorometric method for the quantitation of 3-methoxy-4-hydroxyphenylalanine, either alone or in the presence of levodopa, is presented. Fluorescence is developed by reaction with fluorescamine. The interactions of this reagent with levodopa and a number of its derivatives under various experimental conditions were studied. Negligible fluorescence was obtained with levodopa, dopamine, levodopa benzyl ester, and 6-hydroxydopamine.