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M Johnson

Publications and source records attributed to M Johnson.

At least 541 records · Page 30Linked to original sources
PubMed1991

A graph-theoretic approach to modeling metabolic pathways.

The metabolic pathways of medazepam, oxazepam, and diazepam were modeled using graph-theoretic transforms which are incorporable into computer-assisted metabolic analysis programs. The information, represented in the form of a graph-theoretic transform kit, which was obtained from these pathways was then used to predict the metabolites of other benzodiazepine compounds. The transform kits gave statistically significant predictions with respect to a statistical method for evaluating the performance of the transform kits.

Anti-Anxiety Agents↗
PubMed1991

In utero and milk-mediated effect of aldose reductase inhibitor on galactose cataracts.

Our previously reported investigations showed that cataracts could be induced in fetal lenses through the maternal feeding of galactose during pregnancy. We also reported that the lens opacity present at birth reverses completely by 30 days of age if there is no further post-natal exposure to galactose. This investigation was designed to investigate if an aldose reductase inhibitor (ARI) has any cross-placental effect in preventing galactose-induced cataracts in fetuses. We have also evaluated if there are any milk-mediated effects of galactose on cataract induction and of galactose and ARI on the maintenance or reversal of opacities induced in utero. Pregnant Sprague-Dawley rats were fed either 50% galactose or rat chow with or without the ARI, (2R,4S)-6-fluoro-2-methyl spirochroman-4,4'-imidazolidine-2',5'-dione (Eisai compound E-0722). Following parturition, pups of mothers from the different dietary groups were either fed by their own mothers or foster fed by lactating females fed either rat chow or 50% galactose with or without the ARI. Lenses of the pups were examined at desired intervals with light and scanning electron microscopes. We observed that: (a) both galactose and the ARI had a cross-placental effect on the fetal lenses in the development and inhibition of cataracts, respectively; (b) galactose had very little, if any, milk-mediated effect on either the induction of cataracts in newborn pups that were born with transparent lenses or the maintenance of cataracts induced in utero; (c) the ARI appeared to have a milk-mediated effect, which accelerates the reversal of cataract associated alterations in lenses of pups with cataracts induced in utero, leading to further reinstatement of lens transparency; and (d) the presence of ARI in the diet of rats during pregnancy and/or post-parturition provided continued protection to the lenses of pups that were exposed to a galactose diet following birth.

Aldehyde Reductase↗
PubMed1991

Norepinephrine does not contribute to methamphetamine-induced changes in hippocampal serotonergic system.

The purpose of this study was to determine whether norepinephrine (NE) mediated the reduction in the activity of tryptophan hydroxylase (TPH) in the hippocampus and other serotonergic changes, induced by a single or multiple administrations of methamphetamine. The NE in the hippocampus was depleted by injecting rats with DSP4 intraperitoneally, 10 days prior to administration of methamphetamine. A single administration of methamphetamine (15 mg/kg) reduced the activity of TPH to 40% of control after 3 hr. A 90 to 98% reduction in the concentration of NE in the hippocampus, failed to alter this methamphetamine-induced response. The reduction in serotonin (5-HT) in the hippocampus induced by methamphetamine, was not altered by the treatment with DSP4. These observations were confirmed by a lack of effect on methamphetamine-induced changes in 5-HT and TPH after inhibition of the synthesis of NE with U-14,624. The pretreatment with DSP4 also failed to block the decline in activity of TPH in the hippocampus or concentrations of 5-HT measured 18 hr after the last of 4 doses of methamphetamine (15 mg/kg, s.c.). The results presented in this study indicate that NE is not involved in the response of the serotonergic system to methamphetamine.

Animals↗
PubMed1991

The effects of soman poisoning in combination with hypovolemic shock.

Hemorrhage is a cause of death in both combat and civilian injuries. The specific objectives of this research were: (1) to determine the pathophysiologic effects of combined injuries from sublethal amounts of an organophosphate (soman) along with hypovolemic shock, and (2) to determine the efficacy of atropine sulfate and pralidoxime (2-PAM) therapy for organophosphate poisoning when combined injuries occur. Four groups of six beagle dogs/group were used: Group V/H, vehicle administration followed by hemorrhage; Group S/H, soman administration followed by hemorrhage; Group S/A/H, soman followed by antidote (atropine and 2-PAM) and then hemorrhage; and Group S, soman only. Acetylcholinesterase (AChE) activity, hemodynamic parameters, regional blood flow, plasma enzyme, and hematological changes were monitored. Soman rapidly decreased AChE activity in RBCs, plasma, and brain tissue. Treatment with atropine and 2-PAM resulted in only slight reactivation of AChE; they helped maintain blood gases, cortisol, plasma enzymes, inspiratory volume, and blood pressure nearer baseline values. The effects of combined injuries appear to be greater than those of either injury alone. This was indicated by increased plasma lactate, plasma enzymes indicative of tissue damage (aspartate amine transferase and creatine kinase), and increased lethality in dogs subjected to both soman and hemorrhage (5/12 died). All dogs subjected to only one insult survived the 6-hr experiment.

Acetylcholinesterase↗
PubMed1991

Assessing the reliability of methods for predicting drug metabolites.

An ability to predict the metabolic fate of a drug is important to drug design. Programs for predicting drug metabolites are becoming available, as are databases that will facilitate the development of such programs. Objective analysis of the performance of these programs will require statistical methods. The development of appropriate statistical methods must address a fundamental data representation problem that arises from the fact that the basic metabolic information uses chemical graph representations rather than the usual vector representations that typify statistical methodology. This study addresses the representation problem by using concepts arising from molecular similarity analysis. The statistical methods that are developed are illustrated by evaluating the performance of MetabolExpert in predicting the metabolic fate of benzodiazepines.

Biotransformation↗
PubMed1991

Nail is produced by the normal nail bed: a controversy resolved.

Nail thickness and mass (dry weight/unit surface area) of 21 toenails, removed from 19 patients after accidental injury, were measured over the mid point of the lunula, at the nail plate immediately distal to the lunula and at the distal end of the nail bed. Nail thickness increased from 43% of the final thickness over the mid-point of the lunula to 81% at its distal margin, the remaining increase in thickness being formed by the nail bed. The changes in nail mass were comparable. We conclude that ventral nail produced by the nail bed comprises about one-fifth of the terminal nail thickness and mass.

Adolescent↗
PubMed1991

An ERP-based, control-question lie detector analog: algorithms for discriminating effects within individuals' average waveforms.

Two experimental, P3-based analog control question tests were run. In both, guilty subjects were presented with a set of seven phrases describing antisocial acts of which they were innocent, plus one phrase describing a guilty act (the analog relevant question), and one act to which a "yes" response (yes-target stimulus) was required to assure attention. Innocent subjects (run only in Experiment 1) saw all innocent acts plus the yes-target act. Thus nine acts were seen by guilty and innocent subjects. In both experiments, all subjects had to selectively review their guilty acts privately. Also in both experiments, all subjects were especially questioned about four acts of which guilty subjects were known to be innocent of all but one, and of which innocent subjects were known to be innocent of all. (These falsely accused acts were regarded as control question analogs.) In Experiment 1, the private review and rehearsal took place on the same day as the main test. In Experiment 2, one subgroup (delay-only) of guilty subjects was run as in Experiment 1, except that the private review-rehearsal was separated from the main run by 7-14 days. Another subgroup (delay-rehearsal) of guilty subjects was run just as was the subgroup delay-only, except that the delay-rehearsal subgroup additionally received a non-selective additional interrogation/rehearsal on the delayed main run day. Parietally maximal P3 responses were obtained to yes-target items in all groups. In Experiment 1, only in the guilty group was the relevant-minus-control P3 amplitude difference significant. In Experiment 2, the difference was significant only in the delay-rehearsal subgroup. A four-step algorithm (involving relevant-control amplitude differences and relevant target vs. control-target cross-correlations) was used to assess effects within individuals. In Experiment 1, 12 of 13 guilty subjects and 13 of 15 innocent subjects were correctly diagnosed. In Experiment 2, 3 of 8 delay-only subjects and 7 of 8 delay-rehearsal subjects were correctly diagnosed. In Experiment 2, the relevant-minus-control group P3 amplitude difference was significant in the delay-rehearsal but not in the delay-only subgroup. The results suggest that temporally proximal, non-selective rehearsal procedures are sufficient to activate personal knowledge of a salient (oddball), P3-generating stimulus phrase, and that even selective rehearsal of guilty acts is not sufficient without temporal proximity.

Adolescent↗
PubMed1991

Salmeterol, a novel, long-acting beta 2-adrenoceptor agonist: characterization of pharmacological activity in vitro and in vivo.

1. Salmeterol, a novel, long-acting beta-adrenoceptor agonist, has been compared with isoprenaline and salbutamol for activity in vitro on a range of beta-adrenoceptor containing preparations from laboratory animals and man, and in vivo for bronchodilator activity in the conscious guinea-pig. 2. Salmeterol, like isoprenaline and salbutamol, relaxed preparations of both guinea-pig trachea (contracted by prostaglandin (PG)F2alpha or electrical stimulation) and human bronchus (contracted by PGF 2 alpha) in a concentration-related fashion. Salmeterol was of similar potency to isoprenaline and more potent than salbutamol on both airway preparations. 3. Relaxant responses of superfused guinea-pig trachea and human bronchus to isoprenaline and salbutamol declined rapidly when the agonists were washed from the tissues, with complete recovery within 10 min, whereas responses to salmeterol were more persistent. In electrically-stimulated guinea-pig trachea preparations, inhibition by salmeterol persisted for periods of up to 12h, despite continuous superfusion with agonist-free medium. However, these persistent responses were rapidly and fully reversed by the beta-adrenoceptor blocking drug, propranolol (0.1 microM). In further studies on guinea-pig trachea, propranolol caused concentration-related parallel, rightward shifts of salmeterol concentration-effect curves, yielding a pA2 of 9.0. The slope of the Schild plot was 1.02. 4. Another beta-adrenoceptor blocking drug, sotalol (10 microM), also fully and rapidly reversed established submaximal responses to salmeterol in superfused guinea-pig trachea. However, after administration of sotalol was stopped, the antagonism waned, and salmeterol responses were reasserted without the addition of further agonist. 5. In the beta 1-adrenoceptor containing preparation, rat left atria, isoprenaline exhibited potent, concentration-related, positive inotropic activity, whereas salbutamol and salmeterol were at least 2000-5000 fold less potent, and appeared to be partial agonists. At a concentration of 72 microM, salmeterol exhibited weak antagonism of isoprenaline-induced increases in atrial force of contraction. This antagonism was less marked than that caused by salbutamol (42 microM).6. On the guinea-pig isolated gastric fundus strip, a putative beta3-adrenoceptor containing preparation, salbutamol and salmeterol had only modest agonist activity, being 20-30 fold less potent than isoprenaline and the selective ,beta3-adrenoceptor agonist, BRL 35135.7. In conscious guinea-pigs, inhaled salmeterol and salbutamol were approximately equipotent in causing dose-related bronchodilatation. Whereas the duration of action of salbutamol at its threshold-effective dose was less than 90min, the responses to a similarly effective dose of salmeterol were well-maintained for at least 6 h.8. Salmeterol is therefore a potent and selective beta2-adrenoceptor agonist with a remarkably long duration of action in isolated superfused airways smooth muscle. It also causes persistent bronchodilatation in vivo, in the guinea-pig, when administered by the inhaled route.

Adrenergic beta-Agonists↗
PubMed1991

Salmeterol: a potent and long-acting inhibitor of inflammatory mediator release from human lung.

1. The effects of salmeterol, a novel long-acting beta 2-adrenoceptor agonist, have been investigated on antigen-induced mediator release from passively sensitized fragments of human lung in vitro. 2. Salmeterol was a potent inhibitor of the release of histamine (-log IC50 = 8.54), leukotriene C4 (LTC4)/LTD4 (-log IC50 = 9.07) and prostaglandin D2 (-log IC50 = 8.81). It was slightly less potent (1-3 fold) than isoprenaline, but significantly more potent (10-35 fold) than salbutamol. 3. Propranolol competitively antagonized the inhibitory effects of salmeterol on histamine release (pA2 = 8.41) and LTC4/LTD4 release, (pA2 = 8.40) indicating an action via beta-adrenoceptors. 4. The inhibitory effects of isoprenaline (20 nM) and salbutamol (200 nM) were removed after washing the lung tissue for 2 h and 4 h respectively. In contrast, the inhibitory effects of salmeterol (40 nM) were much longer-lasting, and were still evident after 20 h. 5. Salmeterol therefore exhibits potent and persistent inhibition of anaphylactic mediator release from human lung. This anti-inflammatory effect may be important for the therapeutic potential of salmeterol in the treatment of bronchial asthma.

Adrenergic beta-Agonists↗
PubMed1991

The mechanism of LTE4-induced histamine hyperresponsiveness in guinea-pig tracheal and human bronchial smooth muscle, in vitro.

1. Preincubation of guinea-pig tracheal smooth muscle with leukotriene E4 (LTE4) in vitro increased its subsequent responsiveness to histamine. 2. LTE4 pretreatment of guinea-pig tracheal strips did not affect the subsequent responsiveness to either the contractile agents, carbachol and KCl, or to the relaxant beta-adrenoceptor agonist, isoprenaline. 3. LTE4-induced airway histamine hyperresponsiveness was blocked by indomethacin (5 microM), GR32191 (3 microM), atropine (1 microM) and tetrodotoxin (1 microM). 4. U46619, a stable thromboxane A2-analogue, at a non-contractile concentration of 4 nM, increased tracheal smooth muscle sensitivity to histamine. 5. Both LTE4 and U46619 pretreatment increased the contractile response of tracheal smooth muscle to electrical field stimulation. 6. Preincubation of human bronchial spirals with LTE4 in vitro increased its subsequent responsiveness to histamine. 7. LTE4-induced histamine hyperresponsiveness of human bronchus was inhibited by GR32191 (3 microM) and atropine (1 microM). 8. It is proposed that LTE4 induces guinea-pig airway smooth muscle hyperresponsiveness to histamine via a facilitation of cholinergic neurotransmission, which is dependent upon the secondary generation of prostanoid mediator(s) acting on TP-receptors situated on cholinergic nerve terminals. In addition, it is suggested that LTE4 may induce histamine hyperresponsiveness of human bronchus in vitro by a similar mechanism as to that seen in guinea-pig central airway smooth muscle.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Changing patterns in the workload of a district HIV/AIDS counselling unit 1987-90.

OBJECTIVES: To describe the changing workload of an HIV/AIDS counselling unit between 1987 and 1990. DESIGN: Retrospective examination of data collected by the HIV/AIDS counselling unit between 1987-90 on the number of counselling sessions with patients, family members and staff. SETTING: An HIV/AIDS counselling unit established in 1987 in a London teaching hospital. MAIN OUTCOME MEASURES: Number of new referrals to the HIV/AIDS counselling unit and the number of follow-up sessions. Number of counselling sessions with family members, hospital staff and people making telephone contact with the unit. RESULTS: New referrals to the HIV/AIDS counselling unit increased from 117 (1987-88) to 926 (1989-90). Follow-up appointments increased from 403 to 2016 in the same period. Telephone counselling sessions increased five-fold, and counselling sessions with family members nearly ten-fold over the three year period. Staff consultations doubled. CONCLUSION: The increase in the HIV/AIDS counselling unit's workload may be partly attributable to the rising incidence of AIDS in the community, reflecting earlier patterns of HIV infection. In addition, new HIV/AIDS services were developed in the hospital between 1987 and 1990. These included the establishment of a same-day HIV test and result clinic; integrated management of patients with HIV/AIDS, with an emphasis on early intervention in HIV infection; specialist services for families, antenatal clinic attenders and others affected by HIV; and the appointment of a designated HIV/AIDS consultant. New approaches to counselling and training health care providers in counselling skills will assume increasing importance in meeting future demand for HIV/AIDS counselling.

AIDS Serodiagnosis↗
PubMed1991

The pressure and volume dependence of the rate of wash-out in the bovine eye.

The rate of increase of outflow facility (the wash-out rate) was measured in bovine eyes at 6 and 15 mm Hg. The time-rate-of-change of facility was less at 6 mm Hg (0.20: delta facility/hour) than at 15 mm Hg (0.44). However, when the data was analyzed as a function of volume passing through the outflow system, the volume-rate-of-change of facility was the same at 6 (0.35: delta facility/ml) and 15 mm Hg (0.34). This was consistent with the hypothesis of macromolecules "washing-out" of the aqueous outflow system, if these macromolecules were saturable in the perfusate.

Animals↗
PubMed1991

The specific hydraulic conductivity of bovine serum albumin.

Previous studies of extracellular matrix hydraulic conductivity have characterized the flow resistance of glycosaminoglycans, proteoglycans and collagen. This work focuses on serum albumin, present in significant quantities in many connective tissues, but not previously considered for its role in determining connective tissue flow resistance. The specific hydraulic conductivity of bovine serum albumin solutions, as a function of concentration, was calculated from sedimentation and ultrafiltration data available in the literature. A rigid particle hydrodynamic model compared favorably with these results. Experimental measurements on an albumin ultrafiltration cell were in agreement with this model (within experimental error); furthermore, the experimental data confirmed the theoretical prediction that there is no (or negligible) pressure drop through the concentration polarization layer. Use of the hydrodynamic model for albumin specific hydraulic conductivity with literature values for the hindrance of albumin when passing through a glycosaminoglycan (GAG) matrix allows an estimate of the relative importance of the albumin on tissue hydraulic conductivity: in non-cartilaginous tissues with moderate GAG concentrations, tissue levels of albumin can generate flow resistance effects comparable to those of the GAGs, although well less than the flow resistance of these tissues.

Animals↗