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Biomedical subjects

J R Mitchell

Publications and source records attributed to J R Mitchell.

At least 127 records · Page 7Linked to original sources
PubMed1984

Age-related changes in the abdominal aorta shown by computed tomography.

A study of the computed tomographic appearances of the abdominal aorta in 257 patients confirms previous observations on the progressive increase in aortic diameter which occurs with advancing years. This progressive dilatation is more marked in males. No statistically significant difference was found in the age of onset of mural calcification between the sexes, although calcification was seen in more males than females aged 30-60 years. In the seventh and eighth decades annular calcification was seen more frequently in females. The normal values provided may be of help in the assessment of the diseased aorta.

Adolescent↗
PubMed1984

Verapamil and norverapamil determination in human plasma by gas-liquid chromatography using nitrogen-phosphorus detection: application to single-dose pharmacokinetic studies.

A sensitive (to 0.5 ng/ml) and specific method for the determination of verapamil and norverapamil which utilizes gas-liquid chromatography with nitrogen-phosphorus detection is described. A basic extraction with acid back-wash and final basic reextraction is used for the preparation of plasma samples. Standard curves using alpha-isopropyl-alpha-[(N-methyl-N-homoveratryl)-beta-aminoethyl]- 3,4- dimethoxyphenylacetonitrile hydrochloride (D-517) are linear for concentrations from 0.5 to 200 ng/ml for both verapamil and norverapamil. Within-day and between-day reproducibility is good with a coefficient of variation less than 10% for all concentrations. Recovery is complete for both verapamil and norverapamil. Application of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 10 mg verapamil hydrochloride by intravenous infusion.

Adult↗
PubMed1984

Biliary excretion of glutathione and glutathione disulfide in the rat. Regulation and response to oxidative stress.

Regulation of the biliary excretion of reduced glutathione (GSH) and glutathione disulfide (GSSG) and responses to selected model toxins were examined in male Sprague-Dawley rats. In control and phenobarbital-pretreated rats in which the intrahepatic concentration of GSH was modulated by the administration of diethyl maleate or acetaminophen, the biliary concentration of GSH was consistently lower than, but directly proportional to, the intrahepatic concentration of GSH. Furthermore, increments in bile flow produced by the infusion of sulfobromophthalein (BSP)-glutathione were associated with proportional increases in the biliary excretion of GSH, suggesting that GSH passes into bile passively along a concentration gradient. In contrast, GSSG appears to be secreted into bile against a steep concentration gradient. An increased hepatic production and biliary excretion of GSSG resulted from the administration of t-butyl hydroperoxide. Measurement of biliary GSSG and BSP during a constant infusion of the GSH adduct of BSP indicated that GSSG shares a common excretory mechanism with GSH adducts. Diquat, nitrofurantoin, and paraquat also markedly stimulated the biliary excretion of GSSG. On a molar basis, these compounds generated much more GSSG than a direct substrate for glutathione peroxidase such as t-butyl hydroperoxide, indicating that the compounds undergo redox-cycling with concomitant production of hydrogen peroxide. Aminopyrine (0.8 mmol/kg) also significantly increased biliary GSSG. This increase, however, was associated with a proportional increase in bile flow and in the biliary excretion of GSH such that the GSSG/GSH ratio in bile did not change. Acetaminophen and chloroform, two compounds generating electrophilic metabolites that deplete intrahepatic GSH, led to a progressive decrease in the biliary excretion of GSH and GSSG. Furosemide and dimethylnitrosamine, the electrophilic metabolites of which do not deplete hepatic GSH, minimally altered biliary GSH and GSSG. Similarly, carbon tetrachloride and iproniazid, which yield organic radical metabolites that can peroxidize membrane lipids, did not increase the biliary excretion of GSSG. This finding indicates that membrane-bound lipid hydroperoxides may not be good substrates for glutathione peroxidases. The measurement of the biliary excretion of GSSG and of the GSSG/GSH ratio in bile is a sensitive index of oxidative stress in vivo and thus complements other in vivo parameters for the study of reactive intermediates of xenobiotics such as the determination of covalent binding, the formation of lipid hydroxy acids, and the depletion of intracellular GSH.

Acetaminophen↗
PubMed1984

Effects of serum treated semen, bulls, and herdsmen-inseminators on conception to first service in large commercial dairy herds.

Semen from each of 10 Holstein bulls was extended to 15 X 10(6) total spermatozoa per dose in egg yolk-Tris and in egg yolk-Tris containing 20% (vol/vol) heat-treated heifer serum. Semen was used during 12 mo by 11 herdsmen-inseminators in four commercial dairy herds to inseminate 2820 Holstein cows on the first postpartum service. Percentage conception of cows free of clinical disorders at breeding was determined by rectal palpation at 30 to 60 days after insemination. Addition of serum to the extender did not influence percentage conception. A significant interaction of bull x seminal treatment was found. Least squares means of percentage conception to first service ranged from 45.3 to 59.9% among the 10 bulls. When bulls were classified as either high (greater than 55%), average (50 to 55%), or low conception (less than 50%), approximately 200 first services were required to classify correctly 80 to 90% of the bulls. Least squares means of conception rates ranged from 40.1 to 62.7% among the 11 herdsmen-inseminators. 1) Addition of heat-treated homologous heifer serum to the extender does not influence conception in a predictable fashion; 2) fertility inherent to the bull significantly influences conception; and 3) inseminator skill affects conception greatly.

Animals↗
PubMed1984

Proliferation and differentiation of human myeloid leukemic cells in immunodeficient mice: electron microscopy and cytochemistry.

To study the influence of a biologic environment on cultured human leukemia cells, KG-1, KG-1a, and HL-60 cells were inoculated subcutaneously into newborn nude mice. The cells developed myelosarcomas at the site of inoculation and in lungs and kidneys. KG-1 and HL-60 myelosarcomas were successfully passaged through adult nude mice, whereas KG-1a tumors proliferated only after transplantation into newborn hosts. The human nature of the cells forming myelosarcomas in mice was assessed by chromosomal analyses and detection of cross-reactivity with an antibody to the human leukemia cell line K562. We undertook electron microscopic and cytochemical examinations of the cells proliferating in vitro and in the mice. The granules of KG-1 cells in vivo did not react for acid phosphatase, as observed in vitro, and the HL-60 cells proliferating in mice lost the perinuclear myeloperoxidase (MPO) demonstrated in cultured cells. Although the influence of an in vivo selection of cell subpopulations cannot be ruled out, the enzymatic changes are compatible with induced cell differentiation. Conclusive evidence of differentiation in vivo was observed in the KG-1a cell subline. The undifferentiated KG-1a blasts developed cytoplasmic granules and synthesized MPO during proliferation in vivo. These observations indicate that human leukemia cells from established cell lines proliferate in nude mice and may acquire new differentiated properties in response to the in vivo environment.

Animals↗
PubMed1984

Homocystinuria presenting as multiple arterial occlusions.

We describe a patient with pyridoxine-responsive homocystinuria who presented with multiple arterial occlusions after pregnancy but who showed no other stigmata of the disease and we suggest that in patients with unusual vascular lesions, screening for homocystinuria should be carried out even in the absence of the other manifestations of the condition. Family screening showed that her brother was also affected but that their children were not, confirming the autosomal recessive model of inheritance. We found the index case to have normal platelet behaviour; both she and her brother had normal veins and arteries on biopsy, so the mechanisms underlying the thrombotic complications remain uncertain. It seems likely that pregnancy contributed to the time of onset of the thrombotic complications in the index case, because of the foetal demands for pyridoxine or folate during gestation.

Adult↗
PubMed1984

Plasma glutathione disulfide as an index of oxidant stress in vivo: effects of carbon tetrachloride, dimethylnitrosamine, nitrofurantoin, metronidazole, doxorubicin and diquat.

The plasma concentrations of glutathione and glutathione disulfide were measured in rats following the administration of diquat, metronidazole, nitrofurantoin, doxorubicin, dimethylnitrosamine or carbon tetrachloride. None of these agents significantly influenced the plasma concentrations of glutathione. Diquat, metronidazole and nitrofurantoin acutely increased plasma glutathione disulfide by 4 to 13 fold from 0.3 +/- 0.1 microM to 3.8 +/- 1.1 microM, 2.0 +/- 0.5 microM and 1.2 +/- 0.3 microM, respectively. Carbon tetrachloride, doxorubicin and dimethylnitrosamine did not affect plasma glutathione disulfide. The determination of plasma glutathione disulfide identifies compounds that generate potentially toxic amounts of reactive oxygen species during their metabolism and helps to distinguish these compounds from xenobiotics which generate organic free radicals and electrophilic metabolites under toxicologically relevant conditions.

Animals↗
PubMed1984

Ethanol suppresses hepatic glutathione synthesis in rats in vivo.

Ethanol-induced depletion of hepatic glutathione has been construed as evidence supporting the hypothesis that reactive oxygen intermediates generated during the metabolism of ethanol lead to glutathione oxidation and lipid peroxidation and are responsible for the toxic effects of ethanol. However, the evidence for a pathogenetic role of lipid peroxidation in ethanol-induced liver injury is indirect and a decreased synthesis might well account for the glutathione depletion produced by large doses of ethanol. In order to determine whether a decreased synthesis or an increased consumption of glutathione is responsible for the ethanol-induced glutathione depletion, hepatic glutathione turnover, plasma glutathione and the biliary excretion of glutathione and its disulfide were measured in rats. The administration of 5 g/kg of ethanol p.o. resulted in a decreased incorporation of labeled cysteine and labeled methionine into the hepatic glutathione pool and decreased the hepatic concentration of glutathione from 3.7 +/- 0.1 to 2.7 +/- 0.2 mumol/g. Kinetic analysis of the specific activity-time curves revealed that ethanol decreased significantly the rate of influx of cysteine into the glutathione pool but did not stimulate the rate of consumption of glutathione. Moreover, the plasma concentration of glutathione and the biliary excretion of glutathione disulfide and reduced glutathione decreased after the administration of ethanol, indicating that ethanol does not increase the efflux of glutathione from the liver. Our data demonstrate that a large dose of ethanol does not produce an oxidative stress, which would increase glutathione consumption, but rather impairs glutathione synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Free radicals in vivo. Covalent binding to lipids.

As one means of determining the extent to which free radical metabolites are involved in the interaction of hepatotoxic drugs with target tissues, we have measured the covalent binding to hepatic lipids of carbon tetrachloride, acetaminophen, 2-furamide, furosemide, dimethylnitrosamine, and bromobenzene. Transesterification of the Folch lipid fraction was required to distinguish radioactive label present but not covalently bound to alkyl residues through radical addition or combination reactions. Although all hepatotoxins were covalently bound to hepatic protein in the range of 1-2 nmoles/mg, thereby confirming tissue alkylation by reactive metabolites under the present experimental conditions, only carbon tetrachloride gave significant covalent binding to the alkyl residues of hepatic lipids (4.34 nmoles/mg). Thus, although these data further support the already well-documented role of a free radical in the reaction of carbon tetrachloride with target tissue molecules, none of the other hepatotoxins gave similar indications. Dimethylnitrosamine did give significant covalent binding to lipids, but the removal of the binding by transesterification indicates that the binding apparently resulted from electrophilic attack on nucleophilic centers present in phospholipids rather than from radical attack on electroneutral alkyl residues of the lipids.

Acetaminophen↗
PubMed1983

ADP-induced platelet release reaction in acute stroke.

The extent of the ADP-induced platelet release reaction has been determined in 107 patients admitted to hospital with acute stroke. In 43 of the patients a precise diagnosis was obtained and in those with proven thromboembolic stroke the mean extent of the release reaction was significantly higher than for those with either primary haemorrhagic stroke or those with subarachnoid haemorrhage. Enhanced platelet reactivity was also found in the patients in whom a precise diagnosis could not be obtained, most of whom probably had cerebral infarction. Comparison of the results obtained for patients with stroke with those obtained for individuals who had not experienced a stroke showed that thromboembolic stroke is associated with platelet hyperactivity while haemorrhagic stroke is associated with platelet hypoactivity. The part that abnormalities of platelet behaviour, whether causal or consequential, might play in occlusive stroke and intra-cranial haemorrhage is discussed and the need for large scale prospective studies is emphasised.

Acute Disease↗
PubMed1983

Rhesus diploid rabies vaccine (adsorbed), a new rabies vaccine. II. Results of clinical studies simulating prophylactic therapy for rabies exposure.

Rhesus diploid-cell-strain rabies vaccine (RDRV) (adsorbed) is a new rabies vaccine intended for use in man. Sixty volunteers were given five doses of RDRV at 0, 3, 7, 14, and 28 days to simulate prophylactic treatment of persons exposed to a rabid animal. Thirty-five volunteers were given commercial high-titer rabies immune globulin, 20 IU/kg, before the first dose of RDRV, and 25 were given RDRV without prior rabies immune globulin. Antibody responses at 14, 28, and 42 days were comparable with those reported with human diploid rabies vaccine. Simulated postexposure prophylactic treatment with RDRV was associated with acceptable levels of local and constitutional symptoms.

Adsorption↗
PubMed1983

High-performance liquid chromatography and gas chromatography-mass spectrometry determination of specific lipid peroxidation products in vivo.

Peroxidation of membrane lipids has been implicated in the toxicity of reactive oxygen intermediates and of several hepatotoxins, but the specific products of this peroxidation in vivo have not been chemically identified. A method for the isolation, identification, and quantitation of specific lipid hydroperoxy and hydroxy acids formed in vivo has been developed. Hydroxylated derivatives of linoleic, arachidonic, and docosahexaenoic acids formed in mouse liver phosphatidylcholines following carbon tetrachloride administration were isolated by high-pressure liquid chromatography and identified as the trimethylsilyl ether methyl ester derivatives by gas chromatography-mass spectrometry. This methodology should be important for the investigation of the role of lipid peroxidation in a variety of normal physiologic and pathologic processes.

Animals↗