Biomedical subjects
Publications and source records attributed to W Welch.
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The lignans nordihydroguaiaretic acid (NDGA), heminordihydroguaiaretic acid (HNDGA) and norisoguaiacin were found to inhibit formyltetrahydrofolate synthetase (formate:tetrahydrofolate ligase (ADP-forming), EC 6.3.4.3) and carboxylesterase (carboxylic-ester hydrolase, EC 3.1.1.1) activity from a wide variety of sources. In all cases, NDGA was the most effective inhibitor. Synthetase activity was reduced by half at NDGA concentrations between 0.11 and 0.24 mM. Esterase activity consisted of NDGA-sensitive and NDGA-resistant forms. The sensitive class was half-inhibited by 2-4 microM NDGA. Irreversible inhibition of formyltetrahydrofolate synthetase by NDGA was observed both at low protein concentration (less than 0.2 mg/ml) and at high protein concentration where precipitation of protein was observed. Inhibition of formyltetrahydrofolate synthetase by NDGA arises from a decrease in Vmax and increase in Km for all substrates. In contrast, NDGA affects only the Vmax parameter of the esterase activity. It is suggested that the broad range of enzymes inhibited by NDGA may be a consequence of the amphipathic character of the molecule and the flexibility to accommodate to a variety of binding sites. It is also suggested that the previously reported ability of NDGA to inhibit phagocytosis may be due to the compound's ability to inhibit carboxylesterases.
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A familial presentation of torsade de pointes is described. The propositus had recurrent syncope, documented torsade de pointes, a normal Q-T, and close coupled premature ventricular beats initiating the paroxysmal arrhythmia. The mother had sporadic syncope without documented torsade de pointes, a normal Q-T, and closely coupled premature ventricular beats. Electrophysiological studies demonstrated reproducible inducible torsade de pointes tachycardia in both patients. Serial drug testing in both revealed suppression of induced torsade de pointes with oral propranolol. Chronic oral propranolol resulted in clinical cure in both patients.
A 40-year-old man presented with a solitary mediastinal (right paratracheal) mass which proved to be due to Mycobacterium tuberculosis. While the incidence of tuberculosis has diminished in our countries, such unusual manifestations of tuberculosis as the present case, are still encountered. Tuberculosis, the "perfect imitator", should be included in the differential diagnosis of a mediastinal mass. Excision for therapeutic, as well as histological and bacteriological diagnostic, purposes should be supplemented by appropriate antituberculous chemotherapy.
It has been previously established that formyltetrahydrofolate synthetase isolated from Clostridium cylindrosporum is reversibly dissociated and inactivated in the absence of certain monovalent cations. In the present paper, the reassociation of monomeric, inactive enzyme to form tetrameric, active enzyme was monitored by Rayleigh light scattering and enzymic activity. Light-scattering measurements confirmed that the active enzyme is composed of four subunits of equal weight. With the assumption that the results of analytical ultracentrifugation are correct--that monomers and tetramers are the only species ever present at appreciable levels--the amount of tetramer formed during reassociation was calculated from the light-scattering data. Evidence for the accumulation of catalytically active intermediates was obtained by comparing the rate of association of monomers (detected by light scattering) to the rate of return of enzymic activity. The accumulation of intermediates was most strikingly seen at low monovalent cation concentration at low ionic strength. Evidence is also presented that sedimentation favors reassociation of the enzyme. The reassociation data were fit to a second-order reversible rate equation. Interestingly, although the data were derived from the same experiments, the kinetic plot based on light-scattering measurements yielded a straight line function with an abrupt change in slope about 10 min after initiation of reassociation, while plots based on enzymic activity measurements gave a single slope.
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A patient with a rupture of the ascending aorta after a non-penetrating chest trauma is presented. The aortic tear, angiographically demonstrated, was situated just above the left coronary ostium. Only three examples of angiographically established cases of rupture of the ascending aorta were found in the literature. The point that the distal tip of the catheter should be placed proximally in the ascending aorta, is emphasized After operation the patient went well.
Clostridium cylindrosporum formyltetrahydrofolate synthetase tetramers cross-linked with dimethyl suberimidate remained active in the absence of the monovalent cations normally required for enzymic activity and the tetrameric conformation. The modified enzyme was analyzed by sodium dodecyl sulfate electrophoresis, sedimentation velocity, and gel permeation chromatography. Under the experimental conditions used, the enzyme was only partially cross-linked; 74% of the enzyme was cross-linked dimer or monomer. Nonetheless, the modified enzyme is able to retain enzymic activity and the tetrameric structure under conditions where native enzyme would be completely dissociated and inactivated. The result suggests that cross-linked dimers strongly associate with each other and with monomers. Flame emission spectroscopy indicates that cross-linked enzyme contains two monovalent cations per tetramer.
Lithium chloride administered to rats in drinking water for 30 days caused an increase of whole brain monoamine oxidase specific activity to approximately 140% of control. Carboxylesterase and formyltetrahydrofolate synthetase activities were not affected by Li+ either in vivo or in vitro.
A rabbit antiserum to first-trimester human fetal tissue had greater reactivity in complement fixation and saturation binding assays with fetal tissues than with both a pool of normal adult lung, liver, and kidney and pools of the individual organs. This anti-fetal membrane reactivity was only partially inhibited by carcinoembryonic antigen. The serum still reacted strongly with human fetal and tumor cells after rendering it specific for plasma membrane components by adsorption to and elution from intact human fetal tissue culture cells. This plasma membrane-specific serum was then used to monitor the purification of the fetal membrane-associated antigens. The fetal antigens copurified with the putative plasma membrane enzymatic markers 5'-nucleotidase and Mg2+-adenosinetriphosphatase through differential and density gradient centrifugation. Insulin-binding activity only partially copurified with the antigenic activity. Little antigenic activity was found in nuclear and mitochondrial fractions. The isolation protocol gives fetal plasma membrane-associated antigens in approximately 50% yield with moderate purification. The sera and isolation procedures described should have general utility for the detection of human oncofetal antigens.
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