University of Bristol School of Veterinary Science.
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England↗
Biomedical subjects
J Webster
Publications and source records attributed to J Webster.
Intronic sequences modulate the sensitivity of beta-lactoglobulin transgenes to position effects.
We have analysed the expression of beta-lactoglobulin (BLG) gene constructs with combinations of introns deleted to further define the role of intronic regions in directing position-independent mammary expression of BLG transgenes. Intron removal had no obvious effect on hormonal induction of BLG expression in vitro but dramatically reduced expression in vivo, in that removal of intron pairs always resulted in a proportion of the transgenic lines generated failing to express the transgene in the mammary gland. Position-dependent expression was seen for all intron-deleted transgenes regardless of which introns were removed and the ability of the intron-deleted transgenes to be expressed bore no relationship to transgene copy number. Thus, intron removal per se increases the sensitivity of BLG transgenes to position effects.
Animals↗
Effect of enalapril and quinapril on forearm vascular ACE in man.
OBJECTIVE: Different ACE inhibitors can be distinguished in vitro by their affinity for converting enzyme in vascular and other tissues. Quinapril appears to be amongst the more effective inhibitors of vascular tissue ACE in vitro. This study assesses the in vivo effect of single oral doses of quinapril and enalapril, in attenuating the vasoconstrictive action of angiotensin I (AI) (which we have previously shown depends on its conversion to angiotensin II (AII) by vascular ACE) in the forearm resistance vessels of man. METHODS: The design was of randomized, open, placebo controlled, two way crossover type, Forearm blood flow (FABF) was measured simultaneously in both forearms by mercury in silastic strain gauge plethysmography. AI infusion were via a fine bore cannula in the left brachial artery with the right arm serving as a control. RESULTS: Mean plasma ACE on placebo was 34.3 U.l-1. Both quinapril and enalapril produced a similar degree of plasma ACE inhibition reducing concentrations to 2.8 U.l-1 and 2.6 U.l-1 respectively. Quinapril caused a significantly greater inhibition of AI induced vasoconstriction with a 30.0% reduction compared with 67.0% and 85.0% for enalapril and placebo respectively. Enalapril attenuated AI induced vasoconstriction to a greater degree than placebo but the difference was not significantly different. CONCLUSION: These results indicate that when quinapril and enalapril are administered as single 20 mg doses, each of which produces the same degree of plasma ACE inhibition and blood pressure reduction- quinapril inhibits vascular ACE to a greater degree than both enalapril and placebo.
Adult↗
Calcium channel blockers and cardiac mortality in the treatment of hypertension: a report from the Department of Health Hypertension Care Computing Project (DHCCP).
OBJECTIVE: A case control study has reported a 60% higher risk of myocardial infarction in hypertensives treated with a calcium channel blocker (CCB). We examined the Department of Health Hypertension Care Computing Project (DHCCP) data to see if we could confirm or refute this suggestion. DESIGN: Two case control studies, matched and unmatched, plus two longitudinal studies from 1 year of presentation, one for all subjects given a CCB for more than 1 year compared with those not given this drug, and the second comparing survival on the different drugs initially given between 3 and 12 months of follow-up. SUBJECTS: A total of 9328 subjects were included in the analyses and 2154 died. Of these, 6406 received one or more of the following index drugs: 26% a calcium channel blocker (CCB); 84% a diuretic; 29% alpha methyldopa; 12% a beta-blocker (BB); and 11% an angiotensin-converting enzyme (ACE) inhibitor. The CCBs were nifedipine, diltiazem or verapamil. RESULTS: In the case control studies a group given diuretics +/- other treatments (but not including one of the index drugs) provided a reference group with a relative risk (RR) of 1.0. In the matched case control study the adjusted RR for a CCB without a diuretic was 1.32 (95% CI 0.64-2.70) for IHD mortality and 1.05 (95% CI 0.60-1.84) for cardiovascular mortality. Similar results were observed for methyldopa, BBs and ACE inhibitors. The results in the unmatched case control analysis were also similar. The longitudinal study comparing all those treated for over 1 year with a CCB with all other treatments showed a RR for total mortality of 1.03 (95% CI 0.85-1.25). The longitudinal study of total mortality according to treatment initiated at 3-12 months found results of a similar magnitude for CCBs, methyldopa and BBs. CONCLUSIONS: The reference diuretic group had less severe cardiovascular disease than other groups. Treatment with a CCB, BB or methyldopa was associated with an excess mortality in comparison with this reference group. The excess was similar in the different drug groups.
Adolescent↗
Do trandolapril and indomethacin influence renal function and renal functional reserve in hypertensive patients?
AIMS: To assess the effect of trandolapril (2 mg once daily) and indomethacin (25 mg three times daily), alone and in combination, on renal function and renal functional reserve in hypertensive patients (DBP 95-115 mmHg) requiring regular non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: Randomized, double-blind, placebo-controlled, four way crossover design. After 3 weeks treatment renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured using the p-aminohippurate (PAH) and inulin methods. Renal functional reserve was estimated by measuring RPF and GFR at the end of an intravenous infusion of dopamine 2 microg kg(-1) and 10% amino acid solution. RESULTS: There was no significant difference in RPF between treatments: -22.79 ml min(-1) (95% CI -54.82, 9.24) for placebo and trandolapril, -10.37 ml min(-1) (95% CI -30.7, 9.96) for placebo and indomethacin, -14.78 ml min(-1) (95% CI -50.33, 20.77) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve RPF between treatments: -34.96 ml min(-1) (95% CI -119.8, 49.88) for placebo and trandolapril, 29.78 ml min(-1), -15.18, 74.74) for placebo and indomethacin, and -25.84 ml min(-1) (95% CI -87.62, 35.94) for placebo and trandolapril with indomethacin. There was no significant difference in GFR between treatments: -1.01 ml min(-1) (95% CI -7.45, 5.42) for placebo and trandolapril, -7.88 ml min(-1) (95% CI -15.08, -0.68) for placebo and indomethacin, and -0.36 ml min(-1) (95% CI -7.58, 6.86) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve GFR between treatments: 5.13 ml min(-1) (95% CI -4.97, 15.23) for placebo and trandolapril, 6.31 ml min(-1) (95% CI -1.88, 14.5) for placebo and indomethacin, 7.21 ml min(-1) (95% CI 1.26, 13.16) for placebo and trandolapril with indomethacin. CONCLUSION: In hypertensives chronic treatment with NSAIDs or ACEI alone or in combination did not change RPF or GFR and did not change renal functional reserve capacity of RPF or GFR.
Adult↗
The Edmans ADL index: validity and reliability.
The Edmans ADL index was developed to assess functional abilities in stroke patients, including the activities necessary to enable a person to live independently at home, and graded to enable staff to monitor patient's progress over time. Content validity was established by comparing the Edmans ADL index with other published ADL assessments. Construct validity was established by comparing the Edmans and Barthel ADL indices, for 60 patients admitted consecutively to the Nottingham stroke unit. This showed a strong association between assessments. Inter-rater reliability was assessed by two occupational therapists, who independently and simultaneously assessed 20 patients individually on the stroke unit. This showed 96% excellent/good agreement between observers. Test-retest reliability was established by assessing 20 patients, 1 year post-stroke, on two separate occasions, 1 month apart. Results showed 85% excellent/good agreement over time. We conclude that the Edmans ADL index has content and construct validity, is sensitive to change over time, and has inter-rater and test-retest reliability.
Activities of Daily Living↗
Effect of the non peptide angiotensin II antagonist, GR117289C on the vasoconstrictor actions of angiotensin II in the human forearm.
AIMS: GR117289C is a non peptide, selective angiotensin (AT1) receptor antagonist. The purpose of this study was to determine whether this agent, given orally, could attenuate the vasoconstrictor effects of angiotensin II(AII) infused locally into the forearm circulation in man. METHODS: Eight healthy male subjects were studied on four occasions in a randomized, double-blind, placebo controlled, crossover study. Five hours (approximate time of peak dynamic effect) following dosing with GR117289C (300 mg, 100 mg, 10 mg or placebo), A II was infused in incremental doses (0, 0.1, 0.4, 1.6, 6.2, 25 and 100 pmol min-1) into the left brachial artery, each for 10 min. Forearm blood flow was measured using venous occlusion plethysmography. RESULTS: GR117289C inhibits the vasoconstrictor effects of A II in a dose dependent manner. The active treatment: placebo ratios of forearm blood flow in the infused arm during the highest dose of AII (100 pmol min-1) were: GR117289C 10 mg, 1.12 (95% C.I. 0.81-1.55; P = 0.478), 100 mg, 1.43 (95% C.I. 1.01-2.01; P = 0.042) and 300 mg, 1.62 (95% C.I. 1.17-2.24; P = 0.006). There was no significant difference in blood pressure between each of the treatment groups and placebo. CONCLUSIONS: GR117289C is a pharmacologically active, oral A II antagonist in healthy men.
Administration, Oral↗
The impact of screening for risk factors associated with postnatal depression at the first prenatal visit.
Although 10-15% of Australian women suffer from postnatal depression (PND), few efforts have been made, prenatally, to predict which women may develop the condition. The objective of this study was to evaluate the impact on patients, staff and services of an intervention designed to identify women at risk for PND. Women were screened at their first prenatal visit for factors associated with PND, and were asked to complete a questionnaire at their next clinic visit to assess the impact of the screening questions and the usefulness of a PND information kit. To assess the impact of the intervention on the prenatal clinic routine, all staff associated with the intervention were interviewed individually and their responses were tape recorded and analysed for themes. Patients reported a high level of satisfaction with the intervention. Staff responded well to the new procedure and offered constructive comments to improve the process.
Attitude of Health Personnel↗
Determination of choline in pharmaceutical formulations by reversed-phase high-performance liquid chromatography and postcolumn suppression conductivity detection.
Choline is a primary degradation product of succinylcholine chloride. Determination of low concentration choline in succinylcholine chloride bulk drug and formulation is a challenge, due to the lack of sensitive detection methods. A reversed-phase separation method with postcolumn suppression conductivity detection is described for the determination of choline. Hexanesulfonic acid is employed as an ion-pair reagent in the mobile phase, which allows the accomplishment of both reversed-phase separation and a sensitive conductivity detection. Detection sensitivity is significantly enhanced by passing the mobile phase through a postcolumn cation suppressor, where hexanesulfonic acid is removed and the background conductance is reduced. This method is simple and sensitive. No sample derivatization procedure is required. The detection limit for choline is about 10 pmol.
Choline↗
Pregnancy outcomes and health care use: effects of abuse.
OBJECTIVE: Our purpose was to determine whether pregnancy and neonatal outcomes differed between abused and nonabused women. STUDY DESIGN: Women (N=1014) who completed an abuse questionnaire during pregnancy were followed up after delivery. The 242 women reporting past abuse and the 59 women reporting abuse in pregnancy were grouped in terms of recency and severity of domestic abuse, and their pregnancy and birth outcomes were compared with those of nonabused women with the chi-square test, analysis of variance, and multivariate logistic regression techniques. RESULTS: Abused women smoked more cigarettes (p<0.0001) and took more prescription drugs (p<0.03) and antidepressants (p>0.05) than nonabused women; they were more likely to have epilepsy (p=0.0002) and asthma (p=0.0018), and also they used social work services more often (p>0.0001). Obstetric histories revealed a higher incidence of miscarriage (p=0.0014), two or more pregnancy terminations (p>0.0001), and neonatal death (p=0.0503) among the abused group. Although abused women delivered infants whose mean birth weight was 132 gm lower than that of nonabused women, the difference was not significant after adjustments were made. Mildly and moderately abused women were admitted to the hospital more frequently during pregnancy (p=0.0067). CONCLUSION: Domestic abuse adds significantly to the cost of health care during pregnancy and is associated with poor maternal and fetal outcomes.
Abortion, Induced↗
Disinhibition, apathy, indifference, fatigability, complaining, and negativism.
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Aged↗
Laparoscopic trans-peritoneal adrenalectomy: a preliminary report of 14 adrenalectomies.
OBJECTIVES: Laparoscopic adrenalectomy offers the potential benefits of a smaller operation with more rapid hospital discharge, compared to open surgery. Only a few small series have been reported so far. We describe our preliminary experience of 14 adrenalectomies using this new technique. DESIGN: Review of all adrenalectomies (with the preoperative intention of laparoscopic removal) performed in an endocrine unit whose surgeon already had abdominal laparoscopic experience, particularly with cholecystectomy. PATIENTS AND MEASUREMENTS: Twelve patients (3 with Conn's syndrome, 3 Cushing's syndrome, 1 Cushing's disease, 2 phaeochromocytomas and 3 adrenal incidentalomas) were operated between September 1993 and February 1996. Operating times, operative technique, time from surgery to discharge, outcome and all complications were recorded prospectively. Comparative data were obtained from 14 consecutive open adrenalectomies performed by the same surgeon between February 1989 and February 1995. RESULTS: Fourteen glands were removed, two with a cholecystectomy, in 12 operations. Operating time (mean (range) 120 (60-225) min) was reduced with experience. Positioning the patient in the right lateral position facilitated left adrenalectomy. Time to discharge (mean (range)) was 5.3 (1-12) days. There were relatively minor complications in three patients, including two with Cushing's syndrome: a hernia at a port site, intra-peritoneal/wound haemorrhage and a pressure sore. Time to discharge for open adrenalectomy (mean (range)) was 6.5 (2-11) days and one case was complicated by wound infection. CONCLUSIONS: Laparoscopic adrenalectomy is a practical technique for appropriately trained surgeons who regularly undertake adrenalectomy. The smaller incisions offer potential advantages, particularly for patients with poor tissue quality due to Cushing's syndrome, but tissue haemorrhage may still be a problem in these patients. Time to hospital discharge was similar to that for open surgery.
Adenoma↗
Sevoflurane degradation to compound A in anaesthesia breathing systems.
Determination of an effective rate constant and activation energy allowed the application of steady-state theory to predict concentrations of compound A from sevoflurane concentrations, fresh gas flow rate, absorbent temperature and amount of absorbent. Studies by eight research groups were compared. Lower concentrations of compound A than predicted were observed at low flow rates, suggesting that its degradation by the absorbent is important in limiting the maximum observed concentrations in closed and low-flow breathing systems. Trial-to-trial and batch-to-batch variations in compound A concentrations were observed in model system tests of commercial and pilot-plant absorbents. Chemical modification of the absorbent with glycerol lowered concentrations of compound A, possibly by formation of a nucleophilic addition product. An ideal chemical scavenger would remain stable and non-volatile in the absorbent before irreversibly reacting with compound A to form a stable non-volatile product.
Absorption↗
Aspects of tolerability of centrally acting antihypertensive drugs.
Traditional centrally acting antihypertensives have been associated with a high incidence of adverse effects and are no longer recommended as first-line therapy. The newer imidazoline receptor agonists must overcome this reputation if they are to gain recognition as potential first-line agents for hypertension. Methyldopa, a centrally acting alpha(2)-agonist, is characterized by a number of serious adverse reactions that limit its use. Although unpredictable idiosyncratic or hypersensitivity reactions are uncommon, these include hepatitis, myocarditis, and hemolytic anaemia. Less serious problems such as abnormal liver function tests, positive Coombs test, drug-induced fever, and pancreatitis also occur. Central side effects include drowsiness, fatigue, lethargy, sedation, depression, psychotic reactions, nasal stuffiness, impotence, and exacerbation of Parkinsonism. In hypertensive men, methyldopa is less well tolerated than either captopril or propranolol, and up to 20% of patients discontinue therapy because of adverse effects. Clonidine acts primarily as an alpha(2)-agonist but also acts as an agonist at imidazoline receptors in the rostroventrolateral medulla. It is equipotent to most other antihypertensives but is considerably less well-tolerated in comparative trials. The principal adverse effects of clonidine are drowsiness, sedation, lethargy and dry mouth. Reserpine acts primarily by depleting central catecholamine neurotransmitter stores. It was very extensively used in early hypertension trials, but its central side effects of sedation, nasal stuffiness, and severe depression are now considered so undesirable that the drug is seldom prescribed. The imidazoline (I1) agonists moxonidine and rilmenidine act selectively and have very little central alpha(2)-agonist activity. In comparative studies against placebo and other reference antihypertensives, the only adverse effect consistently associated with these drugs was dry mouth (approximate placebo-corrected incidence 10%). Sedation was not pronounced. Withdrawal syndromes are complex pathophysiologic processes and occur with a variety of antihypertensive drugs. Cessation of therapy with clonidine and, to a lesser extent, methyldopa may result in a severe withdrawal syndrome characterized by restlessness, sweating, anxiety, tremor, palpitations, and headache. There may be a rapid rise in blood pressure, often with a true "rebound" to higher than pretreatment levels. Plasma and urinary catecholamine levels are increased, and fatalities have been reported. It is important to stress that such a syndrome has not been recorded, in animal or human studies, with either moxonidine or rilmenidine.
Antihypertensive Agents↗
Sharing antenatal care: client satisfaction and use of the 'patient-held record'.
Two hundred women (148 shared care patients and 52 clinic patients) completed a questionnaire about care received during pregnancy and the use of a patient-held record. Women receiving shared care reported higher levels of satisfaction with their care than clinic patients (p < 0.0001). Thirty-six percent of the women in shared care forgot to take their record to an appointment on at least 1 occasion. During the pregnancy, over half of the respondents in both groups made contact with the hospital for reasons other than for their regular visit. For both groups, convenience was the most frequently reported reason for choosing their model of care. Other important issues for shared care patients were that the service was more personal and more information was provided. Among clinic patients, safety and quality of care were identified as important. Problems involved with the patient holding the only complete pregnancy record are discussed.
Family Practice↗
Ambulatory monitoring uncorrected for placebo overestimates long-term antihypertensive action. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators.
This study compares blood pressure (BP) changes during active antihypertensive treatment and placebo as assessed by conventional and ambulatory BP measurement. Older patients (> or = 60 years, n=337) with isolated systolic hypertension by conventional sphygmomanometry at the clinic were randomized to placebo or active treatment consisting of nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d). At baseline, clinic systolic/diastolic BP averaged 175/86 mm Hg and 24-hour and daytime ambulatory BPs averaged 148/80 and 154/85 mm Hg, respectively. After 13 months (median) of active treatment, clinic BP had dropped by 22.7/7.0 mm Hg and 24-hour and daytime BPs by 10.5/4.5 and 9.7/4.3 mm Hg, respectively (P<.001 for all). However, clinic (9.8/1.6 mm Hg), 24-hour (2.1/1.1 mm Hg), and daytime (2.9/1.0 mm Hg) BPs decreased also during placebo (P<.05, except for daytime diastolic BP); these decreases represented 43%/23%, 20%/24%, and 30%/23% of the corresponding BP fall during active treatment. After subtraction of placebo effects, the net BP reductions during active treatment averaged only 12.9/5.4, 8.3/3.4, and 6.8/3.2 mm Hg for clinic, 24-hour, and daytime BPs, respectively. The effect of active treatment was also subject to diurnal variation (P<.05). Changes during placebo in hourly systolic and diastolic BP means amounted to (median) 21% (range, -1% to 42%) and 25% (-3% to 72%), respectively, of the corresponding changes during active treatment. In conclusion, expressed in millimeters of mercury, the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement. Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring, a substantial proportion of the long-term BP changes observed during active treatment may be attributed to placebo effects. Thus, ambulatory monitoring uncorrected for placebo or control observations, like conventional sphygmomanometry, overestimates BP responses in clinical trials of long duration.
Aged↗
AMP is a component of the low molecular weight mitogenic activity present in human pituitary tumours.
The mitogenic activity of extracts of human non-functional pituitary tumours has been studied. Previously we have reported that the tumour extracts could be resolved into both high (> 13,000) and low (< 3,000) molecular weight fractions using Sephadex G-50 chromatography. Mitogenic activity was assayed by looking at trichloroacetic acid precipitable 3H-thymidine incorporation into GH3 cells. We have now purified the major component of the low molecular weight mitogenic fraction using reversed phase HPLC: the material was identified and found to be 5'-adenosine monophosphate (5'-AMP) using electron spray mass spectrometry. The mitogenic activity of 5'-AMP and the purified tumour extract was confirmed as both produced an increase in GH3 cell number after 4 days of treatment. In conclusion our results show that the major component of the low molecular weight mitogenic activity in human non-functional pituitary tumour extracts is 5'-AMP.
Adenosine Monophosphate↗
A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation.
Dopamine agonists are the treatment of choice for the majority of patients with hyperprolactinaemic disorders. Although characterised by a relatively high incidence of adverse effects, most commonly gastrointestinal, cardiovascular and neurological, these are usually mild and transient, and can be minimised by starting with a low dose and gradually increasing it, or taking the drug with food or while recumbent. Bromocriptine, introduced in 1971, is the reference preparation against which newer dopamine agonists are compared. It is effective in suppressing prolactin secretion, reducing prolactinoma size and restoring gonadal function. However, up to 12% of patients cannot tolerate the drug at therapeutic dosages. Cabergoline, a long-acting dopamine agonist administered once or twice weekly, has been shown to be significantly more effective than bromocriptine in suppressing prolactin secretion in hyperprolactinaemic patients, and is better tolerated, particularly in terms of nausea and vomiting. In suppressing physiological lactation, cabergoline is at least as effective as bromocriptine, and is associated with significantly fewer rebound symptoms and adverse effects. Quinagolide is a non-ergot dopamine agonist that is administered once daily. It has similar efficacy to bromocriptine, but is probably less effective than cabergoline in hyperprolactinaemic patients; it is not licensed for suppression of lactation. It is better tolerated than twice-daily bromocriptine, but is probably inferior to cabergoline in this regard. Neither bromocriptine, cabergoline nor quinagolide has been associated with any detrimental effect on pregnancy or fetal development. However, experience with bromocriptine is far more extensive; thus, for women requiring treatment for subfertility, this drug remains the treatment of choice in most centres, with cabergoline and quinagolide as acceptable second-line drugs in bromocriptine-intolerant patients. In hyperprolactinaemic men, hyperprolactinaemic women not wishing to become pregnant, and for suppression of physiological lactation, cabergoline is recommended as first-line treatment.
Aminoquinolines↗