Biomedical subjects
Publications and source records attributed to G D Clarke.
A pulse sequence which produces the inversion of magnetization at a selected chemical shift for in vivo surface coil spectroscopy is proposed. The sequence uses a shaped, complex sech inversion pulse and "depth pulse" phase alternation. The sequence can be used for both in vivo inversion transfer and inversion recovery experiments.
Explore the source record for details and available documents.
A number of 2-benzylaminophenols, prepared from the corresponding 2-aminophenols by reductive alkylation, have been identified as highly potent inhibitors of 5-lipoxygenase with IC50 values in the nanomolar range. Most compounds were also shown to inhibit the release of the peptidoleukotrienes when administered intraperitoneally in a rat model of peritoneal anaphylaxis. Two compounds evaluated for their effects on anaphylactic contractions in isolated human lung were shown to attenuate the leukotriene-induced component of the response.
1. The potential of the potassium channel activator, cromakalim (BRL 34915), as a bronchodilator has been evaluated in guinea-pig models in comparison with nifedipine. Some effects of the compounds on guinea-pig tracheal spirals have been studied in an attempt to elucidate their different efficacies in vivo. 2. When given by the intraduodenal route to anaesthetized guinea-pigs, cromakalim (3 and 10 mg kg-1) inhibited 5-hydroxytryptamine (5-HT)-induced bronchospasm for at least 60 min. When given by the i.v. route, the dose of cromakalim producing 50% inhibition of the 5-HT response was 84 micrograms kg-1. Nifedipine failed to show any protective effect up to 100 micrograms kg-1, i.v. and was lethal at higher dose levels. 3. Cromakalim protected conscious guinea-pigs from asphyxic collapse in response to histamine aerosol. The maximal effect occurred 60 min following oral dosing, with 2.5 mg kg-1 providing complete protection for almost half of the animals. Nifedipine had only a weak protective effect even at a high dose level of 50 mg kg-1, p.o. 4. Cromakalim prolonged the time before convulsive cough in response to an antigen challenge in actively sensitized guinea-pigs. Its minimum protective dose was 1 mg kg-1, p.o. Nifedipine (50 mg kg-1, p.o.) was ineffective. 5. Cromakalim inhibited both spontaneous and prostaglandin E2-induced tone in guinea-pig isolated tracheal spirals with IC50 values, relative to the maximum inhibition achieved by isoprenaline (10(-3)M), of 1.1 x 10(-6)M and 8.9 x 10(-7)M, respectively. Its maximal effect was 89% of that produced by isoprenaline. Removal of the epithelium did not influence its activity. Studies using the two enantiomers showed that the activity of cromakalim resided almost entirely in the (-)-enantiomer. 6. Nifedipine (2 x 10-SM) achieved only 49% of the relaxant effect of 10 -3M isoprenaline in isolated tracheal spirals. Addition of cromakalim (10- 5 M) at the end of the nifedipine concentrationresponse experiment caused further relaxation to 94% of the effect of isoprenaline. 7. It is concluded that cromakalim has greater potential than nifedipine as a bronchodilator. It appears that opening of potassium channels, with consequent hyperpolarization and stabilization of the membrane potential, prevents calcium entering the cytosol through routes that are unaffected by calcium entry blockers.
Sixty single afferent fibers with endings in the stomach wall were isolated from the cervical vagus of urethan-anesthetized Sprague-Dawley rats. All the fibers, most of which were spontaneously active, increased their discharge after gastric distension or during spontaneous contractions of the stomach. Because of this and the characteristic dynamic and static features of their response to inflation and deflation, they were identified as in-series tension receptors. Certain features of their responses, previously suspected from studies on reflex modulation of vagal efferent fibers or brain stem neurons, were directly confirmed. These included a broad range of mechanical thresholds and spontaneous firing frequencies that were correlated and a sensitivity only to dynamic stretch and active contraction in the highest threshold endings. The tension receptors could also be activated by circulating cholecystokinin, an effect unrelated to changes in intraluminal pressure and hence gastric wall tension, suggesting that there may be humoral modulation of visceral sensory signals that might be relevant to several behavioral situations, such as food intake regulation.
Clinical and experimental evidence suggests that head injury can cause alterations of cerebral energy metabolism. However, the etiology of this metabolic perturbation is not known. The objective of this study was to determine the effect of fluid-percussion trauma on cerebral energy metabolism. Seven ventilated, chloralose-anesthetized cats were subjected to a 3.2-atm fluid-percussion brain injury. Before and for 8 hours after trauma, continuous phosphorus-3 1 magnetic resonance spectrography was obtained to noninvasively monitor tissue pH, phosphocreatine (PCr), and inorganic phosphate (Pi) levels. Measurement of cerebral blood flow (CBF) by the radioactive microsphere technique and calculation of oxygen and glucose consumption (CMRO2 and CMRG1) were also performed before trauma as well as 30 minutes and 1, 2, 4, and 8 hours after trauma. The data showed a moderate decrease in tissue pH from 7.04 to 6.89 at 30 minutes following trauma with return to control levels by 3 hours posttrauma. During the 8-hour observation period, CBF, CMRO2, and CMRG1 remained at control levels. Tissue PCr and Pi levels were also unchanged. Fluid-percussion trauma at the 3.2-atm level in ventilated cats causes a moderate and transient decrease in tissue pH that returns to control levels after trauma. No other metabolic changes are seen later than 30 minutes posttrauma. This indicates that a mild metabolic disturbance occurs after trauma in the ventilated animal and quickly returns to normal.
Cerebral energy metabolism was studied in cats subjected to fluid-percussion brain trauma followed immediately by 30 minutes of controlled hypoventilation for the purpose of simulating a more realistic model of human head injury. The cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRGl) were measured, with simultaneous phosphorus-31 magnetic resonance spectroscopy quantifications of cerebral tissue pH, phosphocreatine (PCr), and inorganic phosphate (Pi). Hypoventilation alone did not produce marked changes in CMRGl, tissue pH, or PCr:Pi ratios. When hypoventilation was combined with trauma, marked alterations in CBF, CMRGl, PCr:Pi ratio, and tissue pH were seen, indicating relative ischemia. The alterations of cerebral energy metabolism produced by combining trauma and hypoventilation are more severe than those caused by fluid-percussion trauma alone, and may provide a more realistic model of human head injury.
Lactate dynamics in the brain, cerebrospinal fluid (CSF), and serum were studied in 20 chloralose-anesthetized cats following fluid-percussion trauma. Brain lactate and brain tissue pH were measured by hydrogen-1 and phophorus-31 magnetic resonance spectroscopy. The CSF, arterial, and cerebrovenous serum lactate levels as well as serum glucose concentration were quantified. In the six sham-operated control animals, brain, CSF, cerebrovenous, and arterial lactate levels as well as brain pH remained at normal values. In the five animals in the mild-trauma group (1.6 atm), brain and CSF lactate levels were moderately elevated, although the brain pH and serum lactate content remained at control values. Severe trauma (3.1 atm) in nine cats produced an 82% increase in the brain lactate index and a reduction in brain tissue pH (7.02 +/- 0.02 to 6.95 +/- 0.02; mean +/- standard error of the mean), indicating brain tissue acidosis caused by excessive lactate accumulation. Brain lactate levels reached a peak 1 1/2 hours after severe trauma, then steadily decreased to normal levels by 8 hours posttrauma. Maximum increases of CSF and arterial lactate levels (from 1.4 +/- 0.2 to 4.1 +/- 0.4 and from 1.6 +/- 0.2 to 4.1 to 0.6 mmol/liter, respectively) were observed 15 minutes after trauma, and the values decreased during the next 2 hours. The response was biphasic, with a secondary rise observed in both CSF and serum lactate levels during the remaining 4 hours of the experiment. The difference between the arterial and venous lactate levels (A-Vlact) gradually increased and reached a peak 2 hours postinjury (from -0.05 +/- 0.10 to -0.41 +/- 0.09 mmol/liter). The results of this study show that the production of lactate in brain tissue, CSF, and blood increased in proportion to the severity of the injury. The observation that lactate levels in blood and CSF are maximum immediately following impact while brain lactate and A-Vlact are gradually increasing suggests that the brain-tissue production of lactate fails to account for the rapid appearance of lactate in CSF and blood. It is speculated that the initial elevation of CSF lactate values reflects the systemic response of trauma, and the secondary rise of CSF lactate levels following severe trauma is due to slow seepage of lactate produced by brain tissue into the CSF space. These studies are the first to describe the temporal profile of brain lactate production and eventual clearance by CSF and blood in fluid-percussion injury.(ABSTRACT TRUNCATED AT 400 WORDS)
Most phantom media in current use exhibit T1 relaxation times that are significantly dependent on both temperature and operating frequency. This can introduce undesirable variability into relaxation measurements due to temperature fluctuations, and complicates direct comparison of imagers operating at different magnetic field strengths. Our investigations of a nickel-doped agarose gel system have demonstrated near independence of the proton relaxation rates to a wide range of temperatures and frequencies. We therefore propose the adoption of Ni2+ as a relaxation modifier for phantom materials used as relaxometry standards.
The oxidation products of Oleum Terebinthinae "Landes" (Ozothin; in the following briefly called Ox. O. T. L.) have been described in many studies as being of benefit in the treatment of disturbed tracheobronchial function in obstructive airways diseases. Previous literature has dealt mainly with the influence of Ox. O. T. L. on the visco-elastic properties of mucus. However, the purpose of the present work was to study the bronchospasmolytic component. Using a standard methodology for the measurement of bronchospasmolytic effects, it could be demonstrated that Ox.O.T.L., given orally or as an aerosol, protected conscious guinea pigs against histamine-induced bronchoconstriction. The potency was lower than that of isoprenaline but was significant and reproducible. These results in vivo are paralleled by effects observed on guinea pig lung strips and tracheal spiral preparations. Ox.O.T.L. relaxed, in a dose-dependent fashion, guinea pig lung strip preparations contracted with histamine. Potency and efficacy was, however, less than that of isoprenaline. Similarly, in guinea pig tracheal spiral preparations, Ox.O.T.L. was less potent than isoprenaline in counteracting carbachol-elevated tone. However, efficacy equalled that of isoprenaline. Ox.O.T.L. was approximately 3 times more potent in the isolated tracheal spiral preparation than in lung strips. The activity of non-oxidised turpentine oil and terpin hydrate against histamine-induced bronchoconstriction in conscious animals and in the isolated organ preparations was substantially lower than that of the oxidation products of O.T.L.
The content and state of actin in baby hamster kidney (BHK) cells before and after transformation with polyoma virus were examined by deoxyribonuclease assay and gel electrophoresis followed by dye elution. The actin content of the transformed cells, relative to total cell protein, was lower than that of the normal cells by 30-50%. In both the normal and transformed cells the greater part of the total actin was found on lysis to be in the monomeric state. Cytoplasmic and membrane fractions of the two cell lines were, in qualitative terms, very similar in their protein compositions. The plasma membrane isolated from the transformed cells was richer in actin than that from the untransformed, and both membrane fractions contained proteins corresponding to myosin, filamin and alpha-actinin on SDS-polyacrylamide gels. The cell extract from both the normal and transformed lines formed an actin-based gel on incubation at 30 degrees C, although the amount of the cross-linked actin was much smaller in the latter. This was a consequence not only of the lower concentration of total actin in the cell, but also, presumably, of a gross relative deficiency in the concentration or activity of filament cross-linking protein(s) in the cytoplasm. Thus, small aliquots of cytoplasmic fractions from transformed cells, when added to an excess of exogenous F-actin, were able to cross-link the filaments to a much smaller extent than those from the normal cells. A similar range of proteins was found to be associated with the actin gels formed from both cell extracts. One conspicuous difference was that a species migrating in SDS-gel electrophoresis as a doublet with a subunit molecular weight of about 58,000, and tentatively identified as intermediate filament protein, was replaced in the transformed cells by a single band. Filament cross-linking activity of the cytoplasmic fractions was enhanced by addition of Triton extracts of crude membranes, although the latter were not capable of cross-linking exogenous F-actin on their own. The effect of Triton extracts was much greater in the case of membranes from the transformed cells. The cytoplasmic fractions of BHK cells contain capping protein(s) and/or complexes of such proteins with actin; these reveal themselves by the propensity of the extracts to nucleate polymerization of exogenous G-actin. This activity was more abundant in transformed cells, despite their lower actin content. Their membranes were also more effective in nucleating G-actin polymerization, indicating the presence of a greater number of filament ends.(ABSTRACT TRUNCATED AT 400 WORDS)
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Compounds of diverse structure induce murine Friend erythroleukaemia (MEL) cell differentiation. Seeking a common property, Bernstein reported that the relationship between activity and octanol/water partition coefficients for inducers resembled that reported for anaesthetics; moreover, anaesthetics inhibited induction. Since anaesthetics were known to increase membrane fluidity, they suggested that inducers might decrease it. Reporting evidence against unitary theories of anaesthesia, Richards et al. suggested that lipophilic drugs competed, according to their individual structure, with membrane lipids for hydrophobic regions on membrane proteins. The antagonism between pairs of anaesthetics, anaesthetics and inducers and pairs of inducers, might thus be explained economically by Richards' anaesthesia model, inducers and lipophilic drugs acting by similar rather than contrary mechanisms. Lipophilic drugs should, therefore, induce differentiation. We report here that some tranquillizers do so. As reported elsewhere for classical inducers, they also block non-differentiating 3T3 cells in pre-S. These findings may have application in cancer chemotherapy.
Explore the source record for details and available documents.
1. Electrical stimulation of the abdominal vagi revealed that abdominal vagal fibres are distributed throughout the cervical vagal trunk. Conduction velocities of the main group of abdominal fibres ranged from 0.4 to 1.5 m.sec-1. 2. Thirty-seven single afferent fibres, with endings in the gastric and intestinal mucosa, were isolated from the cervical vagus of adult rats. Conduction velocities of eighteen of these endings ranged from 0.5 to 2.5 m.sec-1. 3. Light mechanical stimulation, such as stroking the mucosa, evoked a rapidly adapting response from these endings. Sustained pressure or distension with fluid or air did not excite these endings although excessive stretching of the mucosa excited three units. Balloon distension usually evoked an 'on-off' response due to phasic stimulation of the mucosa by the balloon during inflation and deflation. 4. These same endings also functioned as non-specific, slowly adapting chemoreceptors responding to various organic and inorganic acids, tap water and distilled water, alcohol, hypertonic saline, NaOH, NH4Cl, CuSO4, casein hydrolysate, mustard powder and cayenne pepper. Hypertonic glucose and guinea-pig bile were ineffective as stimuli. 5. In the presence of an excess of chloride ions the effectiveness of acids in stimulating these endings was in part determined by the pK of the acid. However pH per se was not the basic determining factor but rather the molecular size of the acid.