Health care the tie that binds.
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Canada↗
Biomedical subjects
A D Brown
Publications and source records attributed to A D Brown.
A kinetic study of the hydrolysis of the N-tosylalanine ester of 3-hydroxy-5-phenylpyrrole and related compounds by human leukocyte elastase.
The tosylalanine ester of 3-hydroxy-5-phenylpyrrole (HOPPy) is localized on reagent strips (Ames LEUKOSTIX) and used diagnostically to test urine for the presence of human leukocyte elastase (HLE) as an indication of urinary tract infection. We have determined the kinetic constants for the HLE-catalyzed hydrolysis of this substrate and the related substrates Tos-Ala-ONp, Cbz-Ala-OPPy, and Cbz-Ala-ONp, in solution at three different pH values. In the reagent strip matrix, diazo coupling of 4-diazo-3-hydroxy-1-napthylsulfonate (HONapN+2) with the enzymatic hydrolysis product HOPPy generates a purple color. We have also studied the kinetics of the reaction of HOPPy with HONapN+2 and other related diazonium salts such as 4-diazo-3-hydroxy-7-nitro-1-napthylsulfonate, 4-diazo-3-hydroxy-1,7-napthyldisulfonate, and 2-methoxy-4-(N-morpholinyl)benzene diazonium chloride. Tos-Ala-OPPy is the most reactive substrate among the compounds examined and kinetic studies indicate that deacylation is rate-limiting for HLE hydrolysis. The presence of decanol accelerates the enzymatic hydrolysis of Tos-Ala-OPPy with a kcat/KM = 10(7) M-1 s-1, which is close to the diffusion-controlled limit. For the diazo coupling reaction, the rate is affected by the substituents on the naphthalene ring and by the buffer in which the reaction occurs. This research has elucidated some important mechanistic features for the reaction of these compounds and may lead to improved methods for the detection of leukocyte elastase.
Alanine↗
Promoters containing ATF-binding sites are de-regulated in cells that express the EWS/ATF1 oncogene.
Chromosomal translocations that fuse the N-terminal region of the Ewings sarcoma oncogene (EWS) to the C-terminal region (including the DNA-binding domain) of the cellular transcription factor ATF1 are associated with a tumour type termed malignant melanoma of soft parts (MMSP). It is envisioned that transformation by the EWS/ATF1 fusion protein results from aberrant transcriptional regulation of genes that are normally regulated by ATF1. To examine this hypothesis we have expressed exogenous EWS-ATF1 in JEG3 cells and tested its ability to activate several promoters that contain binding sites for ATF1. We show that EWS-ATF1 is a strong constitutive activator of some promoters tested but represses others. Significantly, the ability of particular promoters to be activated by EWS/ATF1 in JEG3 cells correlates with promoter activity in two MMSP-derived cell lines (SU-CCS-1 and DTC1). Our results therefore provide evidence that endogenous EWS/ATF1 can de-regulate transcription and that this capacity may contribute to transformation in MMSP.
Activating Transcription Factor 1↗
Management perspectives. Trouble recruiting nurses as head nurse of our medical center's newly opened subacute care units.
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Humans↗
Rates of thrombin acylation and deacylation upon reaction with low molecular weight acylating agents, carbamylating agents and carbonylating agents.
Acylated derivatives of thrombin have been made using low molecular weight acylating agents, carbamylating agents and carbonylating agents. The compounds used to acylate the active site serine include isatoic anhydrides, benzoxazinones, benzylisocyanate, N-(benzylcarbonyloxy)succinimide and p-(dimethylamino)benzoylimidazolide. The rates of acylation and deacylation were determined. The best overall inhibitors of thrombin are 2-ethoxy-4H-3,1-benzoxazin-4-one, isatoic anhydride and tert-butyl-2,4-dioxo-2H-3,1-benzoxazine-1(4H)-acetate, which have k2/Ki values of 52,700 M-1s-1, 48,900 M-1s-1 and 5400 M-1s-1, respectively. The carbamyl derivative of thrombin formed with benzylisocyanate had the slowest rate of deacylation (2.3 x 10(-7) s-1), while the ester derivative formed with 2-(N,N-dimethylamino)methylimino-4H-3,1-benzoxazin-4-one had the fastest rate of deacylation (1.9 x 10(-4) s-1).
Acylation↗
Acting in medical practice.
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Attitude of Health Personnel↗
alpha-Aminoalkylphosphonate di(chlorophenyl) esters as inhibitors of serine proteases.
alpha-Aminoalkylphosphonate di(chlorophenyl) esters and (alpha-aminoalkyl)phenylphosphinate phenylesters have been tested as irreversible inhibitors of human neutrophil elastase, porcine pancreatic elastase and chymotrypsin, serine proteases important in biochemical processes. Peptidyl derivatives of diphenyl (alpha-aminoalkyl) phosphonates have previously been shown to be potent and specific inhibitors of serine proteases at low concentrations. Addition of a halogen to the phenoxy group of the inhibitors should make the leaving group more electrophilic, and thus more reactive. Peptide phosphonate inhibitors with chlorine in the meta- or para-positions of the phenoxy ester moiety were synthesized and shown to be potent inhibitors of elastase. Tripeptide phosphonates are more potent inhibitors than dipeptide phosphonates, however, addition of the halogen did not increase the inhibitory potency of these phosphonates with elastase compared to the non-halogenated phosphonates. In the case of chymotrypsin, the halogenated phenoxy esters were more reactive, possibly due to an alternate binding mode. The novel (alpha-aminoalkyl)phenylphosphinate phenylesters were poor inhibitors of serine proteases.
Amino Acid Sequence↗
The professional perspective--why get involved?
Four myths threaten Canadian medical education and the health care system. These myths are: (1) that health care costs are out of control; (2) that physicians can stimulate demand for health services; (3) that health research is a nicety; and (4) that health is an externality to considerations of economic policy. These myths tend to focus current concerns on sustainability, rather than on the ideal of continuous improvement. Comparative examinations reveal that Canadian health care spending is not out of line with that in other developed countries and suggest relative efficiency in the Canadian health care system. A broad and introspective approach to medicine is required that can critically address diverse issues such as variance in clinical practice patterns and the impact of poverty and unemployment. If health care educators can enshrine this approach in medical schools, professional medicine will be able to respond to the changing needs of Canadian society.
Canada↗
A system for quantitative morphological measurement and electronic modelling of neurons: three-dimensional reconstruction.
A system for accurately reconstructing neurones from optical sections taken at high magnification is described. Cells are digitised on a 68000-based microcomputer to form a database consisting of a series of linked nodes each consisting of x, y, z coordinates and an estimate of dendritic diameter. This database is used to generate three-dimensional (3-D) displays of the neurone and allows quantitative analysis of the cell volume, surface area and dendritic length. Images of the cell can be manipulated locally or transferred to an IBM 3090 mainframe where a wireframe model can be displayed on an IBM 5080 graphics terminal and rotated interactively in real time, allowing visualisation of the cell from all angles. Space-filling models can also be produced. Reconstructions can also provide morphological data for passive electrical simulations of hippocampal pyramidal cells.
Animals↗
Dietary variability in Cebus apella in extreme habitats: evidence for adaptability.
The dietary composition of Cebus apella in two subtropical forest environments of Argentina reflects the seasonal availability of potential food resources. In the marginal areas of the geographical distribution of this species, different resources are used during periods of scarcity. A greater tendency to use leaves in the diet is observed in the northwest (El Rey National Park), where there is greater seasonal variation of fruit availability. In El Rey, where there are few potential resources, the diet is dominated by a few resources, notably bromeliads. Where the resources are more abundant and the availability is more constant throughout the years (Baritú and Iguazú National Parks), the monkeys exhibit a feeding behavior similar to that seen in tropical areas. This ability of the genus Cebus to exploit resources not accessible to other primate species is one of the reasons for its wide geographical distribution and its widespread existence in ecosystems marginally used by primates.
Adaptation, Biological↗
The Burch Colposuspension operation for stress urinary incontinence.
One hundred and thirteen patients with genuine stress incontinence were treated by a modified Burch Colposuspension after having failed an adequate trial with medical management. Three-quarters of patients were evaluated with pre-operative video-cystometry (video-C.M.G.) while a third underwent post-operative video-cystometry. Flow rates were generally lower after surgery with 3 of the 113 patients developing post-surgery bladder instability. Previous incontinence surgery and higher parity produced statistically a greater number of failures. The overall subjective success of the operation was 80% with another 12% improved at 2 years. A 5 year long-term questionnaire follow-up did not demonstrate marked changes in these figures. The operation itself carries a 16% incidence of significant early complications, while late complications totalled 23%, the latter being primarily minor conditions. Patients left hospital after an average of 10 days.
Adult↗
Regulation of adrenergic receptor number following chronic noradrenaline infusion in the rabbit.
In order to study noradrenaline-induced regulation of alpha- and beta-adrenoceptors, groups of male New Zealand White rabbits (n = 8) were treated with intravenous noradrenaline (0.09 mumol/kg x h) or ascorbate (0.1%) for 10 days via osmotic minipumps implanted in the femoral vein, and the number of cardiac, lung and lymphocyte beta-adrenoceptors as well as renal and platelet alpha 2-adrenoceptors were determined. 1. The mean arterial blood pressure, heart rate and catecholamine levels were measured before commencing, and after 24 h and 10 days infusion. Circulating noradrenaline concentrations were elevated approximately 6-fold at 24 h and were sustained at these levels after 10 days administration of noradrenaline. There were no significant alterations in the blood pressure while a significant decrease in the heart rate was observed at 24 h. 2. Alpha 2-adrenoceptor density was assessed using [3H]-yohimbine. A significant decrease in the number of alpha 2-adrenoceptors in the kidney was observed following the 10 days infusion with noradrenaline. This down-regulation was in marked contrast to the lack of alteration in platelet alpha 2-adrenoceptor number and the platelet alpha 2-adrenoceptor mediated aggregatory response. 3. The density of beta-adrenoceptors in lymphocytes, heart and lung were quantified using (-)[125I]iodocyanopindolol (ICYP). The noradrenaline infusions caused significant reductions in beta-adrenoceptor number in the heart and lung (containing predominantly beta 1-adrenoceptors) but not in lymphocytes (possessing mainly beta 2-adrenoceptors). The KD-values (pM) for ICYP binding to heart and lung were also significantly decreased in the present studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Synthesis and pharmacological activity of angiotensin converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines.
The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described. These compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE), and selected compounds were evaluated in vivo for ACE inhibition. The most potent compounds in vitro are 108, 109, 111, 114, and 116, having relative potencies of 1.0, 1.0, 1.3, 1.1, and 2.6 as compared to the potency of captopril. The most potent compounds in vivo intravenously are 108, 111, 114, 116, 117, and 97.
Angiotensin-Converting Enzyme Inhibitors↗
Water stress plating hypersensitivity of yeasts: protective role of trehalose in Saccharomyces cerevisiae.
Water stress plating hypersensitivity was studied in two strains of Saccharomyces cerevisiae, one of them being a mutant incapable of accumulating trehalose to significant levels. The wild-type strain was grown in a defined medium with glucose, maltose or ethanol as carbon/energy source. In each case plating hypersensitivity was demonstrated and resistance to the stress developed in the second half of the exponential growth phase. Development of resistance was accompanied by accumulation of trehalose and was apparently unrelated to glycerol content which, under these conditions, was always low. A qualitatively similar trend was observed in the mutant grown on glucose but trehalose levels remained low and recovery of stress resistance was only slight. Dinitrophenol induced trehalose breakdown in resting yeast and simultaneously induced the onset of plating hypersensitivity. A negative correlation was demonstrated between trehalose content and 'plating discrepancy' (log colony count on 'normal' agar-log colony count on stressing agar) for both strains under all experimental conditions. The correlation held for trehalose contents up to about 50 mg (g dry yeast)-1, above which the yeasts were apparently fully resistant. Trehalose was evidently a more effective compatible solute, per mole, than glycerol.
Colony Count, Microbial↗
The GP's role in the management of female urinary incontinence.
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Family Practice↗
Protective action of SCH 12223 against experimentally induced gastric and intestinal lesions.
The gastrointestinal protective action of SCH 12223 [3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one hydrate, sodium salt] against various noxious stimuli was characterized in rats. SCH 12223 inhibited the ethanol-induced gastric lesions when given p.o. (0.3-3 mg/kg) or i.v. (1 and 3 mg/kg). Indomethacin pretreatment (10 mg/kg p.o.) did not interfere with this effect. SCH 12223 was also active p.o. in five gastric erosion models: aspirin (1-10 mg/kg), aspirin + acid (1-30 mg/kg), indomethacin (1-10 mg/kg), stress (1 and 3 mg/kg) and reserpine (0.3-10 mg/kg)-induced erosions. The compound lacked antisecretory activity in the pylorus-ligated rats (10 mg/kg p.o.) but increased total gastric mucus (N-acetylneuraminic acid measurements) (1-10 mg/kg p.o.). SCH 12223 (10 and 30 mg/kg p.o.) attenuated intestinal lesions provoked by indomethacin (20 mg/kg p.o. or s.c.) and the protected animals showed better weight gain and food intake than controls. In a 38-day study, SCH 12223 also improved survival from indomethacin lethality (6 of 16 vs. 16 of 16 in the control, P less than .05). The protection cannot be attributed to changes in biliary excretion and plasma levels of indomethacin. We conclude that SCH 12223 is a unique agent which protects both gastric and intestinal epithelia from noxious stimuli, a feature shared by prostaglandins.
Administration, Oral↗
Treatment with oral piperazine oestrone sulphate for genuine stress incontinence in postmenopausal women.
The use of oestrogens in the treatment of genuine stress incontinence was assessed by a double-blind prospective trial in 36 postmenopausal women with genuine stress incontinence who received 3 months of cyclical treatment with either piperazine oestrone sulphate or a matching placebo. Patients were assessed subjectively and objectively before and after treatment by 7-day bladder charts, urethral pressure profiles (UPP), the Urilos nappy test, vaginal cytology and hormone assays (plasma oestrogens and gonadotrophins). There was no statistical difference in the subjective response to treatment between the two groups. After 6 weeks of treatment there was a greater reduction in the number of pad changes/24 h in the oestrogen-treated patients that approached statistical significance but, because of a marked response in the placebo group, this difference was not significant after 3 months of treatment. There were also no significant differences between the two groups with respect to the UPP or Urilos measurements but the vaginal cytology and hormone profiles were significantly affected by oestrogens. In view of the possible risks of oestrogen therapy its use in genuine stress incontinence is limited.
Aged↗
An objective assessment of physiotherapy for female genuine stress incontinence.
Sixty women with genuine stress incontinence were consecutively assigned to one of four physiotherapy groups who were treated for 6 weeks by either (1) pelvic floor exercises (PFE) in hospital; (2) PFE and faradism; (3) PFE and interferential therapy; (4) PFE at home. Assessment before and after treatment was by 7-day bladder charts, urethral pressure profiles and perineometry. Approximately two-thirds of the hospital-treated patients (groups 1, 2 and 3) experienced marked or moderate subjective improvement and at 6 months, 27% were dry or almost dry. There was little difference in outcome between groups 1, 2 and 3 but hospital-based therapy was more effective than home treatment. Statistical analyses showed that there were significant improvements in the objective indices measured in the 45 hospital-treated patients. Successful treatment was more likely in younger patients, in those with lesser degrees of genuine stress incontinence and those who had had no previous pelvic floor surgery.
Adult↗