Biomedical subjects
Publications and source records attributed to E Wells.
New HindIII, RsaI and TaqI restriction fragment length polymorphisms (RFLPs) within the haemopoietic cell kinase gene in chromosome band 20q11.2 are described. These RFLPs provide a useful marker for linkage analysis in proximal 20q.
Men from a clinical treatment setting suffering from alcohol dependence, and randomly selected men from the community diagnosed as having alcohol abuse and/or dependence, completed the Parental Bonding Instrument. The men from the alcohol treatment setting perceived both parents as having been uncaring and overprotective. In the general population sample, an uncaring and overprotective parental style was strongly associated with childhood conduct disorder, but not with alcohol disorder symptoms. This discrepancy in perceived parenting highlights the difficulties in extrapolating findings about aetiological factors for alcohol disorders from clinical samples. It also suggests that childhood conduct disorder and adult antisocial behaviour could influence which men with alcohol disorders receive inpatient treatment.
Sputum samples submitted to the microbiology laboratory from general medical and respiratory wards were monitored for Moraxella catarrhalis on a prospective basis. All isolates were typed by restriction endonuclease typing. Nosocomial spread was found both by the clustering of cases and typing of isolates. Sampling of the environment of some cases was performed. Seven out of 37 samples revealed environmental contamination. Sampling for persistence of the organism in the environment was positive on one occasion out of 13. Evaluation of acquisition of M. catarrhalis in relation to length of stay showed that the average length of stay of a case with M. catarrhalis was considerably longer than average patient stay without M. catarrhalis. Four patients had two isolates available for typing. The type of M. catarrhalis was different on the second occasion to that on the first. Nosocomial spread of M. catarrhalis in the setting of general medical and respiratory wards was found to occur in the winter months.
Several ways in which research can be an important tool in creating culturally appropriate prevention programs are suggested. To illustrate cultural variability, we present data from a study of 5th-grade African-American and European-American students. These data describe rates of early initiation, levels of exposure to identified risk factors, and degree to which identified risk factors predict substances initiated. Results indicate that European-American Ss have higher rates of tobacco and alcohol initiation, that the same risk factors predict the variety of substances initiated for African-American and European-American Ss, and that several differences exist in the level of exposure to risk factors between the 2 groups. Implications of the findings for developing culturally appropriate drug abuse prevention are discussed.
Explore the source record for details and available documents.
1. FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotension converting enzyme (ACE) in vitro (IC50 0.51 nM). 2. In conscious normotensive dogs, FPL 63547 (10-300 micrograms kg-1 i.v.) produced prolonged, dose-related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. 3. In anaesthetized dogs, FPL 63547 diacid (3-300 micrograms kg-1 i.v. cumulatively) produced dose-related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. 4. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 X 10(-7)-10(-5) mol kg-1 p.o. (congruent to 0.13-4.5 mg kg-1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10(-6), 10(-6) and 3 X 10(-5) mol kg-1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. 5. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg-1 day-1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre- and post-dose, i.e. effective 24 h control had been achieved. 6. The profile of FPL 63547 is consistent with it being a potent, selective and long-acting ACE inhibitor. As an antihypertensive agent in SHR it compared favourably with other members of this class with respect to potency and duration of action.
1. The route of elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme (ACE), has been investigated in the anaesthetized rat. Comparisons have been made with other ACE inhibitors. 2. Bile and urine samples were collected over a 5 hour period following a single i.v. dose of ACE inhibitor (2 mumol kg-1). Samples were bioassayed for ACE inhibitory activity using affinity-purified rabbit lung ACE and the amounts of the active form of inhibitor present in each sample were calculated by comparison with a standard curve. 3. FPL 63547 was rapidly and extensively excreted as the diacid in the bile but appeared in the urine in negligible amounts. The bile:urine ratio was 21.4:1 indicating a marked preference for the biliary route. A similar elimination profile was observed when the compound was dosed in its active form (FPL 63547 diacid), 87.9% of which was found in the bile over the 5 h collection period, with a bile: urine ratio of 14.6:1. 4. The marked preference of FPL 63547 for biliary elimination was not shared by the other ACE inhibitors tested in this study. Lisinopril demonstrated the opposite pattern, being excreted almost exclusively by the kidney (bile:urine ratio 0.06:1). Enalapril was eliminated in approximately equal amounts in bile and urine (ratio 0.7:1) while spirapril diacid showed a slight preference for the bile (ratio 2.6:1). 5. The physical chemical properties of FPL 63547 diacid may be responsible for its unusual preference for biliary elimination. In particular, the amphipathic character and strong acid functionality of the compound are thought to favour transport into the bile. 6. Elimination by the biliary route will be preferred in patients whose renal function is impaired as a result of disease or age. In such patients the elimination of renally-excreted ACE inhibitors is known to be compromised, resulting in compound accumulation and the need for closer monitoring. Therefore, the elimination profile of FPL 63547, if confirmed in man, may prove to be clinically advantageous.
1. Cells were obtained from the lungs of Macaque monkeys by bronchoalveolar lavage in order to study the role of cellular interactions in the release of leukotriene C4 (LTC4). 2. In normal monkeys, macrophages were the most abundant cell type recovered, whereas in monkeys sensitized with Ascaris suum there was an increase in the numbers of eosinophils and mast cells recovered. 3. Challenge of cells from both groups of animals with an optimal concentration of opsonized zymosan (OPZ) resulted in the time-dependent release of LTC4 from macrophages. However, release was significantly greater in cells obtained from sensitized donors compared to normal donors. 4. Density-gradient centrifugation of cells lavaged from sensitized donors was used to prepare fractions containing both eosinophils and mast cells. Addition of these cells to macrophage populations obtained from non-sensitized donors caused a significant enhancement of OPZ-induced LTC4 release. In the absence of macrophages no significant release of LTC4 was detected from eosinophil/mast cell-containing fractions stimulated with OPZ, despite the fact that the zymosan had been phagocytosed by the eosinophils. 5. There was a significant correlation between the percentage enhancement of LTC4 release and the number of eosinophils added. However, there was not a significant correlation with the number of mast cells added. 6. These results suggest that a cellular interaction between macrophages and eosinophils may be important in the regulation of mediator synthesis and release. The precise mechanism of this effect remains to be elucidated.
A new primate model has been developed for the evaluation of antiallergic agents. Compounds are tested for their ability to inhibit anti-IgE induced histamine release from the bronchoalveolar mast cells lavaged from the lungs of Macaca arctoides infected with the parasite Ascaris suum. A number of 6-substituted pyranoquinoline derivatives have been evaluated and the activities were subjected to Hansch analysis. A highly significant correlation with lipophilicity (pi) and Hammett sigma p values was obtained. The relationship was used to predict further compounds for synthesis giving rise to new, potent analogues. Some apparently anomalous results could be explained by differences in the ionization of, or tautomerism in, the quinoline ring.
Explore the source record for details and available documents.
One hundred and one patients with osteoarthritis were randomly allocated to undergo total hip arthroplasty under either spinal (subarachnoid) or general anaesthesia. Venous blood was sampled before, during and after surgery and on the 5th day after operation to study the haemostatic mechanism. There were no preoperative differences between the two anaesthetic groups. Although there was pronounced individual variability, similar patterns of change in coagulation, platelets and fibrinolysis were seen in both groups. However, there were significant differences between the two groups in platelet count, thrombin production, and Factor VIIIRAg in the intra- and immediate postoperative periods. Also, compared with general anaesthesia, there was less intraoperative activation of fibrinolysis, as measured by the euglobulin clot lysis time, with spinal anaesthesia. These differences suggest slight modification of the haemostatic response to surgery with spinal anaesthesia, which could be consistent with a neuroendocrine mechanism. By the 5th day both groups exhibited a very similar "hypercoagulable" postoperative state.
1 Dopexamine hydrochloride, a compound under evaluation for the acute treatment of heart failure, was examined in vitro for its ability to prevent neuronal uptake of noradrenaline. 2 Despite possessing only weak beta 1-adrenoceptor agonist activity in paced guinea-pig left atria, dopexamine hydrochloride was only 23 times less potent than isoprenaline in augmenting responses of field-stimulated atrial preparations. 3 This potent effect was not observed in field-stimulated atria depleted of noradrenaline by reserpine and in the presence of cocaine was greatly reduced (1 microM) or abolished (50 microM). 4 Dopexamine hydrochloride (3 microM) potentiated the inotropic effect of exogenous noradrenaline in paced atria, thereby resembling cocaine (10 microM) and dopamine (30 microM), both of which are known inhibitors of Uptake. 5 The sodium-dependent uptake of [3H]-noradrenaline into rabbit brain synaptosomes was prevented by dopexamine hydrochloride (IC50 26 nM) and cocaine (IC50 108 nM), as well as by two other catecholamines used in the treatment of heart failure, dopamine (IC50 270 nM) and dobutamine (IC50 380 nM). 6 The cardiac stimulant effect of dopexamine hydrochloride reported in dogs and in patients with heart failure, may therefore be due in part to potentiation of endogenous catecholamines.
Large numbers of functional mast cells were obtained by bronchoalveolar lavage (BAL) of Macaca arctoides monkeys that had been infected with the nematode Ascaris suum. These lavage cells, of which 21% were mast cells, released histamine, LTC4, and PGD2 in a concentration-dependent fashion when challenged with ascaris antigen or antibody to human IgE. However, there was no release of histamine when these cells were challenged with compound 48/80. The amount of mediator released was highly dependent on the sensitivity of the cells to immunologic challenge, but was generally in the range of 2 to 5 micrograms histamine (30 to 70% of total), 20 to 80 ng LTC4, and 100 to 300 ng PGD2 per 10(6) mast cells when maximally challenged. Other eicosanoids measured were released only in much smaller quantities. Maximal values were 4 ng LTB4, 2 ng PGE2, and approximately 10 to 20 ng PGF2 alpha per 10(6) mast cells. The amount of LTC4 and PGD2 released correlated with the release of histamine, the calculated regression line indicating that 18 ng LTC4 and 50 ng PGD2 were released per microgram of histamine released. This correlation suggests that the majority of the LTC4 and PGD2 released was probably mast cell-derived. Further support for this conclusion was given by the observation that when lavage cells were fractioned on continuous Percoll gradients, the ability to release LTC4 and PGD2 on immunologic challenge coincided with the peak of mast cells.
As described in the preceding companion paper, bronchoalveolar lavage (BAL) of the primate Macaca arctoides infected with the nematode Ascaris suum yields a population of cells containing a high proportion of mast cells (21%). Nedocromil sodium, a new drug undergoing clinical evaluation for the treatment of reversible obstructive airways disease, inhibited the release of histamine, LTC4, and PGD2 from these cells challenged with antigen (with IC30 values of 2.1 X 10(-6) M, 2.3 X 10(-6) M, and 1.9 X 10(-6) M, respectively) and with anti-human IgE (IC30 values of 4.7 X 10(-6) M, 1.3 X 10(-6) M, and 1.3 X 10(-6) M, respectively). Cromolyn sodium was essentially inactive. Histamine release from rat peritoneal mast cells induced by anti-rat IgE was, however, inhibited by both nedocromil sodium and cromolyn sodium with IC30 values of 1.1 X 10(-6) M and 5.5 X 10(-7) M, respectively. Both compounds induce phosphorylation of a 78,000 m.w. protein in the rat peritoneal mast cell in the absence of any stimulus at the same concentrations as those required to inhibit histamine release stimulated by anti-IgE. This event may be part of a feedback mechanism to limit degranulation. Nedocromil sodium and cromolyn sodium were equipotent in their ability to inhibit anti-IgE-induced histamine release from rat peritoneal mast cells, but differed markedly in their ability to inhibit histamine release from macaque BAL cells.
Nedocromil sodium inhibited the bronchoconstriction caused by antigen challenge in Ascaris-sensitive monkeys and in addition it prevented the release of histamine from mast cells lavaged from sensitive monkeys. Sodium cromoglycate was relatively inactive in both these systems. It is suggested that nedocromil sodium can stabilize both mucosal and connective tissue mast cells and may represent a new type of drug.
The substituted chromone carboxylic acid FPL 52694 inhibited models of IgE-mediated immediate hypersensitivity reactions in the rat by a mechanism similar to that of sodium cromoglycate. The compound was more potent than sodium cromoglycate but unlike cromoglycate was active following oral administration.
Challenge of rat peritoneal mast cells with anti-rat IgE induces a similar pattern of protein phosphorylation to that already reported for compound 48/80. Rapid phosphorylation of a mast cell protein, mol. wt 78,000, is induced by sodium cromoglycate and several chemically related anti-allergic agents in the absence of any challenge. Phosphorylation of this protein reflects their potency in inhibiting anti-IgE-induced histamine release. Compounds which inhibit histamine release by elevating intracellular cAMP levels do not induce phosphorylation. However, dibutyryl-cGMP induces phosphorylation of the 78,000 mol. wt protein in the absence of any challenge, at concns which inhibit IgE-dependent histamine release. Sodium cromoglycate appears to activate an endogenous control mechanism for switching off mediator release using a mechanism mediated by cGMP.