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Biomedical subjects

J R Mitchell

Publications and source records attributed to J R Mitchell.

At least 73 records · Page 4Linked to original sources
PubMed1989

Glutathione disulfide formation and lipid peroxidation during cardiac ischemia and reflow in the dog in vivo.

The content of glutathione disulfide (GSSG) in tissue, coronary sinus blood plasma, and in cardiac lymph was measured in a well-characterized model of regional cardiac ischemia and reflow in dogs in vivo in order to assess the magnitude of the oxidant stress produced. No increase in GSSG content was observed during 60 min of occlusion of the circumflex or left anterior descending arteries, or during up to 70 min of reflow. The contents of 11-, 12-, and 15-hydroxyeicosatetraenoates (HETEs) in total lipids also were not increased following 60 min of regional ischemia and up to 60 min of reflow. In addition, global ischemia produced by aortic crossclamping and cardiopulmonary bypass did not increase HETE content. In contrast, infusion of tertiary butyl hydroperoxide (tBHP) into the left atrium produced readily measurable increases in GSSG content with or without prior induction of myocardial ischemia. Infusion of tBHP also increased tissue contents of the HETEs. These findings indicate that the canine myocardium subjected to ischemia-reflow conditions does not generate large amounts of reactive oxygen and does not form significant amounts lipid peroxidation products.

Animals↗
PubMed1989

Mitochondria and xanthine oxidase both generate reactive oxygen species in isolated perfused rat liver after hypoxic injury.

Hypoxia caused severe damage in isolated perfused livers from fasted male Fischer rats without evidence of the formation of reactive oxygen species during hypoxia. Reoxygenation caused a significant increase in intracellular oxygen species in the injured liver, as indicated by increases in sinusoidal GSSG efflux and tissue GSSG levels. Both parameters were elevated further by addition of KCN (100 microM) or antimycin A (8 microM). Sinusoidal GSSG efflux was suppressed in part by addition of allopurinol (500 microM) and enhanced by hypoxanthine (250 microM). Xanthine oxidase appears to be a partial source, and damaged mitochondria a continuous and quantitatively greater source, of reactive oxygen as a result of liver injury following hypoxia.

Adenosine Triphosphate↗
PubMed1989

Is an information booklet for patients leaving hospital helpful and useful?

OBJECTIVE: To determine whether a booklet given to patients being discharged from hospital giving details of their admission and treatment increased their knowledge and recall when reviewed in outpatient clinics. DESIGN: Patients alternately allocated to receive a booklet or to serve as controls. Assessment by a questionnaire at first attendance at outpatient clinic after discharge. Data were collected over nine months. SETTING: One general medical and cardiological ward in a large teaching hospital and associated outpatient clinics. PATIENTS: One hundred and thirty one patients discharged taking at least one drug and scheduled to return to clinic within 12 weeks. Patients stratified by age and by the number of weeks between discharge and outpatient appointment. INTERVENTION: A booklet was given to 65 patients at discharge from the ward; 66 patients served as controls. MAIN RESULTS: Of the patients who received the booklet, 56 (86%) knew the names of their drugs, 62 (95%) the frequency of the dose, and 55 (85%) the reasons for taking each drug. The numbers in the control group were 31 (47%), 38 (58%), and 28 (42%) respectively. These differences were highly significant (p less than 0.001). Twenty six (40%) who received the booklet brought all their drugs to clinic compared with 12 (18%) control patients. Appreciably more of the first group of patients than control patients knew the reason they had been in hospital, and more of the first group indicated that they would take the correct action when their prescribed drugs ran out. Most general practitioners thought that the booklet was a good idea, that it was helpful, and that it was better than the existing interim discharge letter. CONCLUSIONS: Giving patients an information booklet at discharge from hospital appreciably increased the accuracy and thoroughness of their recall of important medical details concerning their illness and its treatment. The booklet was shown to be feasible, helpful in the outpatient clinic, and preferred by most general practitioners.

Adult↗
PubMed1989

Spectrum of dysautonomia in mitral valvular prolapse.

PURPOSE: Symptoms suggesting altered autonomic regulation of cardiovascular function have been noted in some patients with mitral valvular prolapse (MVP) but may also occur in patients with other disorders. We evaluated cardiovascular responses to autonomic stimuli in 118 patients with symptoms of dysautonomia, 78 of whom had MVP, and 40 of whom did not, to determine if unique patterns of these responses distinguished patients in one symptomatic subgroup from another. SUBJECTS AND METHODS: The responses of patients to standing, quantitated Valsalva maneuver, facial immersion in ice water, and administration of isoproterenol, phenylephrine, and tyramine were compared with those in 12 asymptomatic patients with MVP and 23 normal volunteers. RESULTS: Constitutional, cardiovascular, and neuropsychiatric symptoms occurred with similar frequency in the two symptomatic patient groups. The most common pattern of abnormal responses in symptomatic patients with or without MVP was (1) an increased heart rate and elevated plasma norepinephrine levels while supine and then while standing quietly for five minutes, (2) an exaggerated increase in heart rate during phase II of Valsalva, (3) a diminished bradycardic response during phase IV of Valsalva, and (4) an exaggerated heart rate response to administration of isoproterenol. The increased heart rate during Valsalva, but not the exaggerated sensitivity to isoproterenol, was correlated with the magnitude of the chronotropic response to standing only in symptomatic patients with MVP. Exaggerated hypertensive overshoot during phase IV of Valsalva was observed in only a few symptomatic patients. No consistent pattern of these abnormalities, however, was noted in any of the patient subgroups. Hemodynamic responses to autonomic stimuli in asymptomatic MVP patients were generally indistinguishable from those observed in normal subjects. CONCLUSION: These findings suggest that abnormal cardiovascular responses to autonomic stimuli may occur in any patient with symptoms of dysautonomia regardless of the presence or absence of MVP and that the pattern of these abnormal responses may be diverse. It is therefore important to characterize the pattern of altered autonomic regulation of cardiovascular function in each patient when considering mechanistic implications or making therapeutic decisions about these patients.

Adolescent↗
PubMed1989

Quantitation of leukotriene B4 in human serum by negative ion gas chromatography-mass spectrometry.

Leukotriene B4 (LTB4) is a potent chemotactic agent formed via the 5-lipoxygenase pathway from arachidonic acid. To understand the role LTB4 plays in several pathological processes it is essential that endogenous concentrations of LTB4 be accurately quantitated. We have developed a method based on electron capture negative ion mass spectrometry for the analysis of LTB4 in serum at low picogram per milliliter concentrations. Blood is collected into the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) to suppress ex vivo formation. Serum is isolated, equilibrated with the internal standard [2H4]LTB4, and extracted using octadecyl-silica (C-18) cartridges. After conversion of the carboxylic acids to their pentafluorobenzyl esters the extract is purified by straight-phase HPLC. Gas chromatographic-mass spectrometric analysis is accomplished on the tert-butyldimethylsilyl ether derivatives using dual-selected ion monitoring of m/z 431 and 435. These ions correspond to loss of tert-butyldimethylsilanol from the (M-PFB)- ion of endogenous and [2H4]LTB4, respectively. The concentration of LTB4 in human serum samples was 10.0 +/- 4.0 pg/ml (n = 5). The assay exhibited satisfactory precision, with an intraassay coefficient of variation of 17% and a high degree of accuracy. The concentration of LTB4 in serum collected with (NDGA) was less than 10% of that observed in blood collected without the lipoxygenase inhibitor. Ex vivo formation can therefore be a major obstacle in assessing circulating levels of LTB4.

Chromatography, High Pressure Liquid↗
PubMed1989

Diquat hepatotoxicity in the Fischer-344 rat: the role of covalent binding to tissue proteins and lipids.

Diquat produces hepatic necrosis in the Fischer-344 rat, and although reactive oxygen species generated by redox cycling are thought to mediate the damage, the possibility that covalent binding of diquat or diquat metabolites to tissue macromolecules contributes to the observed hepatotoxicity of diquat needed to be examined experimentally. Intraperitoneal administration of [ethylene-14C]diquat (0.1 mmol/kg) results in distribution of radioactivity to all organs examined. Measurable radioactivity remains associated with hepatic and renal protein even after extensive solvent extraction, but the amount (12-16 pmol/mg protein) is 100-fold less than the extent of covalent binding observed with comparably hepatotoxic doses of other hepatotoxins such as acetaminophen and bromobenzene. Similarly, although small amounts of radioactivity remain in Folch lipid extracts of liver and kidney (56-179 pmol/mg lipid), this is virtually completely removed by transesterification of the lipid (less than 5 pmol/mg lipid), indicating that the radioactivity does not represent an alkylation of electroneutral alkyl residues of the lipid. The diquat-induced increase in biliary excretion of glutathione disulfide temporally parallels the biliary excretion of radioactivity. Although the present results do not prove the absence of a contribution by alkylation mechanisms to diquat hepatotoxicity, the extremely low upper limits placed on possible covalent interactions reinforce the confidence with which the diquat-treated Fischer-344 rat can be employed as an animal model for mechanisms of cell death mediated by reactive oxygen species.

Animals↗
PubMed1989

How do we know who has had deep vein thrombosis?

An attempt was made to identify all patients diagnosed as having deep vein thrombosis (DVT) in a large teaching hospital during one year. A review of the radiology records showed that 124 (81%) of the 154 venograms performed were for suspected DVT, and that the diagnosis was confirmed in 57 (46%). During the same period, the Hospital Activity Analysis (HAA) records revealed 174 episodes classified as 'phlebitis or thrombophlebitis' in 162 patients. Only 37 of these episodes (21%) had been confirmed by X-ray venography and at least 29 patients were incorrectly classified by HAA. 'Medical' patients accounted for 54% of the episodes of DVT, yet in only 25% of these was the diagnosis confirmed by venography, while 'surgical' DVTs were less frequent but were more often confirmed by venography.

England↗
PubMed1989

Predicting the outcome of acute stroke: do multivariate models help?

Data collected by a single observer on 362 patients taking part in an acute intervention trial were used to derive simple methods of predicting outcome in conscious stroke victims. The effectiveness of these univariate methods was then compared with that of multivariate models based on discriminant function analysis. The multivariate models were somewhat better at predicting death within the first month in newly-admitted patients, and in predicting lack of functional improvement between one and six months in those still in hospital at one month. Even so, these predictions could not be made with certainty and the improvements in probability offered by multivariate over univariate analysis are unlikely to be of practical benefit to the clinician. Single variables such as power in the affected arm and continence were as good as the discriminant functions at predicting discharge within the first month and first six months, respectively. The predictive power of these single simple clinical variables was validated in a separate group of 277 stroke patients. The various proposed methods of prognostication in stroke need to be compared in prospective studies, but until this is done, we recommend a simple approach using the best available clinical information.

Activities of Daily Living↗
PubMed1988

Randomised double-blind placebo-controlled trial of feverfew in migraine prevention.

The use of feverfew (Tanacetum parthenium) for migraine prophylaxis was assessed in a randomised, double-blind, placebo-controlled crossover study. After a one-month single-blind placebo run-in, 72 volunteers were randomly allocated to receive either one capsule of dried feverfew leaves a day or matching placebo for four months and then transferred to the other treatment limb for a further four months. Frequency and severity of attacks were determined from diary cards which were issued every two months; efficacy of each treatment was also assessed by visual analogue scores. 60 patients completed the study and full information was available in 59. Treatment with feverfew was associated with a reduction in the mean number and severity of attacks in each two-month period, and in the degree of vomiting; duration of individual attacks was unaltered. Visual analogue scores also indicated a significant improvement with feverfew. There were no serious side-effects.

Adult↗
PubMed1988

Alkylation of the liver plasma membrane and inhibition of the Ca2+ ATPase by acetaminophen.

Acetaminophen is activated metabolically to yield reactive species that bind covalently to liver cell macromolecules. The extent of covalent binding correlates with the occurrence and severity of hepatic necrosis. We reported previously [J. O. Tsokos-Kuhn, E. L. Todd, J. B. McMillin-Wood and J. R. Mitchell, Molec. Pharmac. 28, 56 (1985)] that active Ca2+ accumulation of isolated liver plasma membranes is decreased 60-75% after a hepatotoxic dose of acetaminophen in vivo. We now report that the protein of isolated liver plasma membranes was substantially labeled with drug metabolites after administration of [3H]acetaminophen. There was no increase in passive membrane permeability that might cause diminished Ca2+ accumulation. Intravesicular volume and relative purity of the vesicle preparations after acetaminophen were not different from controls. However, (Ca2+,Mg2+)-ATPase, a possible biochemical expression of the Ca2+ pump, was decreased 31% (P less than 0.025) after acetaminophen treatment. ATPase activity in both control and treated groups was enhanced by isolating membranes in the presence of 5 mM reduced glutathione (GSH), but the effects of drug treatment were not reversed. A similar effect of GSH on Ca2+ accumulation was observed previously [J. O. Tsokos-Kuhn, E. L. Todd, J. B. McMillin-Wood and J. R. Mitchell, Molec. Pharmac. 28, 56 (1985)]. These data are consistent with a hypothesis wherein alkylation of membrane proteins by reactive acetaminophen metabolites is a factor in the onset of hepatic necrosis after acetaminophen. They are not consistent with an oxidative stress hypothesis where thiol S-thiolation of membrane components is postulated to produce altered membrane permeability or thiol-reversible alterations in membrane protein structure and enzymatic function.

Acetaminophen↗
PubMed1988

Low dose beta blockade in acute stroke ("BEST" trial): an evaluation.

The beta blocker stroke ("BEST") trial was designed to see if the apparent protective effect of propranolol on cerebral function in patients with subarachnoid haemorrhage applied also to patients suffering from acute stroke. Three hundred and two conscious patients with clinically diagnosed hemispheric strokes sustained within the past 48 hours were randomly assigned to receive atenolol, propranolol, or matching placebo capsules for three weeks. More early deaths occurred among the patients allocated to receive beta blockers, but this was largely explained by differences in the initial characteristics of the patients among the different treatment groups. By contrast, the outcome in a further 60 patients, who had been taking beta blockers at the time of their stroke but were otherwise similar to the patients in the trial, was considerably better, suggesting that prior treatment with beta blockers might be protective. The search for an effective medical treatment for acute stroke must continue. The approach used here, in which neurological outcome was assessed in a modest number of patients with a view to proceeding subsequently to a full scale trial of functional outcome, allows practical benefits of a treatment to be evaluated under realistic conditions and an ineffective treatment to be eliminated without undue cost.

Activities of Daily Living↗
PubMed1988

Hypoxic damage generates reactive oxygen species in isolated perfused rat liver.

The aim of the present study was to investigate the possible role of reactive oxygen species in the pathogenesis of hypoxic damage in isolated perfused rat liver. One hour of hypoxia caused severe cell damage (lactate dehydrogenase release of greater than 12,000 mU/min/g liver wt) and total irreversible cholestasis which was accompanied by a loss of cellular ATP and a marked decrease in lactate efflux. Tissue glutathione disulfide (GSSG) content and GSSG efflux as a measure of hepatic reactive oxygen formation was less than 1% of total glutathione before and during hypoxia. Upon reoxygenation, however, hepatic GSSG content increased sharply to about twice the control values and GSSG efflux increased several-fold to around 3-4 nmol GSH-equivalents/min/g. The release of lactate dehydrogenase decreased upon reoxygenation and tissue ATP content recovered partially. When livers were reoxygenated at an earlier time interval than 1 hr of hypoxia, i.e., before the onset of damage, no enhanced GSSG formation was observed. The results demonstrate that hypoxic damage is a prerequisite to reactive oxygen formation during the subsequent reoxygenation period. Thus, reactive oxygen species appear unlikely to play a crucial role in the pathogenesis of hypoxic liver damage in the hemoglobin-free, isolated perfused liver model.

Adenosine Triphosphate↗
PubMed1988

Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design. 2 VPA alone had no effect on antipyrine clearance, urinary 6 beta-hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady-state concentration (90 +/- 6 mg 1(-1)) well within the target range (50-100 mg 1(-1)) for the drug. 3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P less than 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P less than 0.02) and half-life of unbound CBZ 16% longer (P less than 0.02) during VPA treatment. CBZ-10,11 epoxide (CBZ-E) levels (52%) and CBZ-E/CBZ ratios (45%) were both elevated by concurrent VPA (P less than 0.05) and free CBZ fraction was increased by 7% (P less than 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P less than 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P less than 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

The pragmatic approach to stroke trial design: stroke register, pilot trial, assessment of neurological then functional outcome.

Assessment of the results of medical intervention in acute stroke presents particular difficulties. Firstly the condition is extremely variable both in its clinical presentation and in its underlying pathology. Secondly, extreme care must be taken over the methods used to assess outcome. A reduction in mortality is no indication of success if there is a consequent increase in the number of survivors with extreme disability. Nor is it valid to compare functional or neurological outcome in survivors, since differences in mortality between treatment groups may upset the balancing effect of initial randomisation. Furthermore, overall 'neurological scores' are of dubious validity when the progress of patients with different patterns of disability has to be compared. Despite these difficulties a pragmatic approach can be used in which the design and conduct of a stroke trial closely resemble the normal clinical situation. This requires a knowledge of the range and natural history of stroke cases seen, best obtained from a stroke register. A pilot trial is then needed to assess the extent of variation in outcome and thus to estimate the numbers needed for the main study. The latter should then be conducted in two stages. Initially 'neurological benefit' should be assessed by counting the number of individual neurological signs which show improvement or deterioration in patients in each treatment group. Finally, a simple functional end-point should be compared in large numbers of patients with death being treated as equivalent to the worst possible non-fatal outcome. These principles are now being applied in a large, double-blind, placebo-controlled trial of low-dose beta-blockers in conscious stroke victims.

Aged↗