Biomedical subjects
Publications and source records attributed to J A Davies.
We have isolated and sequenced a cDNA from the shaking-B locus of Drosophila melanogaster. The cDNA contains an open reading frame with extensive homology to another D. melanogaster gene, l(1)ogre. This suggests the existence of a new family of proteins required for the development and maintenance of the D. melanogaster nervous system.
The effects of calcium channel blockers and tetrodotoxin on the potassium-stimulated release of endogenous glutamate from rat cerebellar slices was assessed. Verapamil (10 microM), omega-conotoxin (1 and 10 microM) and cobalt (2 mM) all significantly decreased release. Amiloride (100 microM) and tetrodotoxin (0.5 and 1 microM) had no effect. The results suggest a role for N-type voltage-operated calcium channels in the potassium-stimulated release of glutamate.
The relationship between blood pressure and platelet basal cytoplasmic calcium concentration ([Ca2+]i) and platelet sensitivity to aggregating agents in hypertension has been investigated in hypertensive patients and normotensive subjects. Ten severely hypertensive patients whose blood pressures were poorly controlled with metoprolol, were given calcium antagonist (either nifedipine or felodipine) as a second line agent. Venous blood samples were collected at each treatment phase for measurement, in whole blood, of platelet aggregation in response to ADP and collagen, and of basal [Ca2+]i using fura-2. Control of blood pressure by the combination of metroprolol and a calcium antagonist induced a significant decrease in median [Ca2+]i from 116 (76-181) to 73 (60-83) nM, which was similar to the median value of 70 (61-80) nM obtained in 14 normotensive subjects. Overall [Ca2+]i correlated with mean blood pressure (r = 0.51). Treatment of hypertension with calcium antagonist did not change the response of platelets to collagen or ADP. The results confirm that effective treatment of hypertension significantly reduced basal [Ca2+]i in platelets but raise doubts whether elevated basal [Ca2+]i is necessarily the sole mechanism by which the sensitivity of platelets to aggregatory agents is increased in hypertension.
We have done a randomised controlled trial to assess the effect on primary management and outcome of routine doppler ultrasound examinations of the umbilical and uterine arteries during pregnancy. Over 9 months, 2600 women with singleton pregnancies were recruited from a general obstetric population. Of 2475 women who delivered in hospital after 20 weeks' gestation, 1246 had been allocated at random to receive standard antenatal care with routine doppler examinations. The first doppler ultrasound was done at 19-22 weeks' gestation, and thereafter examinations were monthly if the pregnancy was considered high risk (192) or once at 32 weeks if considered low risk (1054). The control group of 1229 women received standard, antenatal care without doppler ultrasonography. The study groups did not differ in number of antenatal admissions or cardiotocographs, gestational age at delivery, method of delivery, frequency of deliveries with fetal distress, or need for resuscitation or admission to the neonatal intensive care unit. More perinatal deaths occurred in the doppler group (17 vs 7, relative risk 2.4, 95% Cl 1.00-5.76), but only 1 of 11 normally formed stillbirths and none of the 4 normally formed neonatal deaths after 24 weeks' gestation had an abnormal umbilical-artery doppler examination. We did not demonstrate any improvement in neonatal outcome by routine doppler ultrasound screening of a general obstetric population.
The aim of this study was to determine the effects of the surgical treatment of morbid obesity on some aspects of haemostatic and fibrinolytic function. Measurement of haemostatic and fibrinolytic factors was performed before and again 6 and 12 months after operation in 19 patients suffering from morbid obesity. Surgical treatment resulted in a mean decrease in body weight of 50 kg at 6 months and 64 kg at 12 months. Weight loss was accompanied at 12 months by significant reductions in median (interquartile range) concentrations of serum cholesterol from 5.3 (4.5-6.2) mmol/l to 3.6 (2.9-4.6) mmol/l; factor VII from 113 (92-145)% of normal to 99 (85-107)%; of fibrinogen from 3.5 (3-9.3) g/l to 2.8 (2.4-3.8) g/l; and of plasminogen activator inhibitor-1 (PAI-1) activity from 21 (11-30) IU/ml to 6.3 (5-10) IU/ml. The decrease in PAI-1 activity probably accounted for a significant reduction in euglobulin clot lysis time. Tissue plasminogen activator activity was undetectable in most patients pre-operatively but increased slightly after 1 year to 110 (100-204) mIU/ml. There were no significant changes in plasma levels of KCCT, factor VIII, von Willebrand factor antigen, alpha-2-antiplasmin, antithrombin III, protein C antigen, beta thromboglobulin, platelet factor 4, fibrinopeptide A or platelet count. These findings provide support for the hypothesis that the surgical treatment of morbid obesity may have a long-term beneficial effect on mortality from cardiovascular and thromboembolic disease.
There is some doubt as to the mechanism of action of the widely-used anticonvulsant drug, carbamazepine. In cortical wedges prepared from genetically epilepsy-prone DBA/2 mice, carbamazepine at therapeutic concentrations (1-10 microM) markedly reduced the depolarization produced by N-methyl-D-aspartate (NMDA). The NMDA sub-type of glutamate receptor has been implicated in the pathogenesis of epilepsy and the inhibitory action of carbamazepine on this response suggests that the anticonvulsant action of the drug may be due to its blockade of NMDA receptor-mediated events.
OBJECTIVE: To define the relation between mood and autoimmune thyroid dysfunction during the eight months after delivery. DESIGN: Double blind comparison of the psychiatric status of women positive and negative for thyroid antibodies. Clinical examination and blood sampling for free triiodothyronine and thyroxine, thyroid stimulating hormone, and thyroid antibody concentrations at four weekly intervals. Psychiatric assessment at six, eight, 12, 20, and 28 weeks post partum. SETTING: Outpatient department of district hospital. PATIENTS: 145 antibody positive women and 229 antibody negative women delivering between August 1987 and December 1989. MAIN OUTCOME MEASURES: Thyroid status. Number of cases of mental ill health by the general health questionnaire, research diagnostic criteria, Hamilton 17 item depression scale, hospital anxiety and depression scale, and Edinburgh postnatal depression scale. RESULTS: Six weeks after delivery the general health questionnaire showed 62 (43%) antibody positive women and 65 (28%) antibody negative women had mental ill health (chi 2 = 8.18, p less than 0.005). Follow up of 110 antibody positive and 132 antibody negative women showed significantly greater depression by research diagnostic criteria in antibody positive women (47%) than antibody negative women (32%) regardless of thyroid dysfunction. Antibody positive women showed higher mean scores for depression on the Hamilton (6.01 v 3.89, p = 0.0002), Edinburgh (7.45 v 5.92, p = 0.031), and hospital depression scales (4.95 v 3.79, p = 0.003). CONCLUSION: Depressive symptoms are associated with positive thyroid antibody status in the postpartum period.
To investigate the effect of increasing FVIII:C in-vivo on coagulation ex-vivo, DDAVP was infused over 15 min in 10 volunteers and in-vitro thrombin generation measured. FVIII:C rose from 0.42 and 0.43 IU/ml before DDAVP to 1.38, 1.73 and 1.78 IU/ml at 15, 30 and 60 min respectively (p less than 0.001). A computer-assisted thrombin generation test was performed in defibrinated plasma using chromogenic substrate, S2238. Time to reach 50% maximal thrombin activity (T50/s) and lag phase of thrombin generation (lag/s) were measured. Lag shortened from 75 and 60 s before to 45 s during and after infusion (p less than 0.001). T50 shortened from 78.5 and 76.0 to 62.5, 60.0 and 58.5 s at times 15 (p less than 0.01), 30 (p less than 0.001) and 60 (p less than 0.001) min. FVIII:C correlated inversely with lag and T50 (r = -0.847, p less than 0.001, r = -0.826, p less than 0.001, n = 10) respectively. These findings show that acute elevations of FVIII:C in-vivo accelerate in-vitro thrombin production. This work suggests that elevated FVIII:C levels in-vivo may be important in thrombo-occlusive disease.
The Scottish Health Boards' Dental Epidemiological Programme, a joint venture between the Scottish Chief Administrative Dental Officers and the Dental Health Services Research Unit at the University of Dundee, was instigated in 1987 in response to the Chief Dental Officer's concern at the lack of any coordinated dental health information about children residing in the 15 Scottish Health Board areas. Each year a standardised dental survey of a random sample of children is now undertaken across Scotland. This paper reports, principally, the caries results of the first three surveys of 5, 12 and 5-year-olds undertaken at the end of 1987, 1988 and 1989, respectively. Marked variations in caries prevalence were found in different parts of Scotland, higher levels being recorded in the urbanised central belt and in the West. While there have been overall improvements since 1983, caries prevalence in Scotland remains substantially higher than in many other parts of the UK (mean DMFT for 12-year-olds in 1988 = 2.23, mean dmft for 5-year-olds in 1989 = 2.82), with 67.8% of 12-year-olds and 59.2% of 5-year-olds (in 1988 and 1989, respectively) still suffering from dentinal caries or past caries experience (DMFT/dmft greater than 0) when assessed by clinical examination alone. No continued improvement in caries prevalence was seen in the 1989 survey of 5-year-olds compared to the 1987 examination. Continued monitoring of this situation is indicated.
Parental permission was sought to monitor longitudinally the dental care of a sample of 5, 8, 12 and 15-year-olds in Scotland who took part in the 1983 national survey of children's dental health. The dental treatment records of those who volunteered were released by the Scottish Dental Practice Board and the Information and Statistics Division of the Common Services Agency to the Dental Health Services Research Unit at Dundee University. The baseline epidemiological survey data was passed on by the Office of Population Censuses and Surveys. During the period 1983 to 1988, less than half of the children in the sample attended for dental care at least once a year on average (ie at least five times in five years) and most also let a lapse of more than 2 years occur between dental visits at some time within the 5-year study period. Around 20% of the three youngest age groups changed dentist three or more times. These results indicate that steps need to be taken to improve the dental attendance of children in Scotland if the principle of continuing care underlying the new General Dental Service contract is to be achieved.
We report that stimulation of neonatal rat cerebellar slices with N-methyl-D-aspartate (NMDA) release nitric oxide (NO) and also increased the release of aspartate. Inhibition of NMDA receptors with the specific antagonist, 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) prevented the NMDA-induced release of both NO and aspartate. Similar results were obtained with the inhibitor of NO synthase, NG-nitroargine (NG-ARG). The NO scavenger, haemoglobin prevented the release of aspartate. Under calcium-free conditions NMDA-induced aspartate release was abolished and NO release significantly reduced. These results indicate that NO has a physiological role in the release of aspartate.
Thrombotic diseases increase in incidence with advancing years and this might be partly due to an increased propensity for fibrin formation in older individuals. Accordingly we decided to investigate whether the time taken to generate 50% thrombin activity in vitro varied with the age of the plasma donor. Coagulation was initiated in defibrinated, diluted plasma by contact activation and thrombin activity measured using the chromogenic substrate, S2238. The rate of thrombin generation was assessed by measuring the time taken to reach 50% maximal activity (T50/s). There was a highly significant negative correlation between T50 and age, T50 declining from 93 s at 19 years to 71 s at 65 years (r = -0.637, p less than 0.0001). A strong negative correlation was demonstrated between T50 and FVII level (r = -0.415, p = 0.0007) and FVIII:C level (r = -0.465, p = 0.0001). Although FVII concentration correlated with age (r = 0.307, p = 0.014) no relationship was seen between age and FVIII:C. These data suggest that coagulation rates in plasma accelerate with age.
A possible association between plasma coagulant activity and the presence of vascular complications in patients with diabetes mellitus was studied by measuring the generation of thrombin in plasma of 20 control subjects and 50 diabetic patients classified according to the presence or absence of microvascular complications. Thrombin production was determined in defibrinated plasma using a semi-automated technique with measurement of thrombin activity using chromogenic peptide S2238. Values determined were the lag time to appearance of thrombin activity and time taken to generate 50% maximal thrombin activity. Thrombin activity was related to concentrations of coagulant factor VIII activity and fibrinopeptide A and these were correlated with HbA1C levels. The median time to generate 50% maximal thrombin activity was not significantly reduced in diabetic patients compared with control subjects (53 vs 54 s, p = 0.076) and there were no significant differences between patients with and without microvascular complications. There were no differences in median fibrinopeptide A concentrations between the diabetic and control subjects (1.5 vs 2.2 nmol/l, p = 0.169). Time to 50% maximal thrombin activity correlated inversely with factor VIII:C concentrations in diabetic patients (r = -0.344, p = 0.015, n = 50) and both this and lag time correlated with factor VIII:C in diabetic patients and control subjects combined (r = -0.395, p less than 0.01; r = -0.327, p = 0.006, n = 70). Factor VIII:C concentrations increased with age of the subject and with HbA1C concentrations. The results failed to show enhancement of coagulation in contact-activated diabetic plasma compared with control plasma and suggest that a relationship between high levels of factor VIII:C in diabetes and the development of mcirovascular complications is unlikely to be mediated through procoagulant activity in plasma.
We compared the urinary excretion of albumin, transferrin, N-acetyl-beta-D-glucosaminidase and alpha-1-microglobulin in 78 Type 1 (insulin-dependent) diabetic patients: 39 with retinopathy and 39 without. The two groups were matched for age, sex and duration of diabetes. The patients with retinopathy had increased excretion (median and range) of albumin [1.7(0.3-399.1) versus 1.0(0.3-116.6) mg/mmol creatinine, P less than 0.05], transferrin [114.2 (4.1-37126.2) versus 33.4 (1.0-4176.7) micrograms/mmol creatinine, P less than 0.01] and N-acetyl-beta-D-glucosaminidase [23.8 (1.1-119.1) versus 15.0 (0.1-65.1) mumol/h/mmol creatinine, P less than 0.05] but not alpha-1-microglobulin. Transferrin excretion correlated with albumin excretion. The prevalence of increased transferrin excretion (transferrinuria) was greater than that of microalbuminuria in patients both with and without retinopathy (P less than 0.01 in both cases). Urinary transferrin seems likely to be predominantly of glomerular origin and merits prospective longitudinal evaluation as a potential index of the microangiopathic process.
A phase I, double-blind, single-dose, randomized, two-period crossover study was conducted to investigate the effects of pimobendan on renal function to assess whether renal events were a contra-indication to its administration. Results in eight healthy volunteers indicated no significant adverse events on renal plasma flow, glomerular filtration rate, or laboratory safety screens; side-effects were also found to be minimal. Further studies are indicated to assess whether, in the proposed treatment group, i.e. patients with heart failure (in whom compromised renal function is common), pimobendan similarly elicits no serious adverse renal effects.
There already exists a body of literature on the conduct of classical epidemiological studies. However, guidelines tend towards detailing how such studies should be conducted and may not prepare the reader for the less-than-perfect scenarios that will inevitably be encountered. The Dental Health Services Research Unit in Dundee has been involved in longitudinal studies of dental treatment and dental health since its inception in 1979. The problems encountered in this research are considered under the headings of mounting the studies, samples, data collection, external changes, internal changes, dissemination and curtailment. It is hoped that a description of the often unpredictable problems associated with a particular set of studies will provide an insight which may assist others embarking on analogous projects in health services research.
The non-opioid antitussive drugs, dextromethorphan, caramiphen and carbetapentane, are also anticonvulsant. The effects of these antitussives on potassium-stimulated release of endogenous amino acids from rabbit hippocampal slices was tested. All 3 drugs significantly reduced the release of glutamate, with carbetapentane being the most potent (IC50 approximately 40 microM). We suggest that the anticonvulsant action may be due to their ability to decrease glutamate release.
The dental attendance of a sample of dentate adults (n = 702) within the National Health Service in Scotland was monitored longitudinally between 1978 and 1988. The attendance pattern of the sample appeared to be no different between 1983-88 than in the preceding 5 years, which suggests that the attendance behaviour of the sample has not changed significantly. National figures, available for the same period, show an increase in the number of courses of dental treatment provided. These figures were examined in detail, and the analysis suggested that only 40% of the increase in number of courses provided in 1988 compared with 1978 could be accounted for by an improvement in attendance patterns among Scottish adults as a whole. The remaining 60% could be attributed to a greater requirement for dental care to cater for the increased proportion of the Scottish population who retained their own teeth in 1988. Only 16% of the sample consistently attended for dental care within 2 years of a previous dental course (which is the criterion for remaining under continuing care in the new General Dental Service contract).