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Biomedical subjects

A R McLellan

Publications and source records attributed to A R McLellan.

At least 19 recordsLinked to original sources
PubMed1999

Bone density and antiepileptic drugs: a case-controlled study.

This case-controlled study explored the relationship between bone mineral density (BMD) and long-term treatment with antiepileptic drugs (AEDs) in older adults with epilepsy. Seventy-eight patients (47 post-menopausal females, 31 males, aged 47-76 years) with epilepsy participated in the study. Each had only ever received treatment with either enzyme-inducing (n = 52) or non-inducing (n = 26) AEDs. Individuals were matched for age, sex, height and weight with a drug-naive control. All patients underwent bone densitometry at the lumbar spine and femoral neck and had blood sampling and urine collected for a range of bone markers. Male patients had lower BMD than controls at the lumbar spine (P < 0.01) and neck of the femur (P < 0.005). Female patients had significantly reduced bone density at the femoral neck (P < 0.05) only. AED usage was independently associated with an overall reduction in bone density at femoral sites and contributed to just over 5% of the variance at the femoral neck. Duration of treatment and type of AED were not independent factors for reduction in BMD. This case-controlled study supports the hypothesis that long-term AED therapy is an independent risk factor for reduced BMD in epileptic patients. Adults receiving treatment for epilepsy are at higher risk of osteoporosis and should be offered bone densitometry.

Adult↗
PubMed1993

G-proteins in experimental hypertension: a study of spontaneously hypertensive rat myocardial and renal cortical plasma membranes.

OBJECTIVE: Spontaneously hypertensive rat (SHR) myocardium is known to exhibit reduced beta-adrenergic agonist-stimulated adenylyl cyclase activity. As G-proteins play a pivotal role in transducing information from the receptor to adenylyl cyclase, a study was undertaken to assess whether changes in G-protein expression and functioning could explain this. DESIGN: Studies were performed in plasma membrane homogenates from vascular tissue (myocardium) from 11-week-old SHR (weighing 255 g) and control rats from both Wistar-Kyoto (WKY) and Wistar strains. Similar studies were performed in non-vascular tissue (renal cortical plasma membranes) to assess whether any observed changes are part of a more widely distributed membrane defect. METHODS: G-protein function was inferred from studies of adenylyl cyclase activity and levels of G-protein subunits (Gs alpha, Gi alpha 1, Gi alpha 2, Gi alpha 3, Go alpha and beta) were assessed by immunoblotting. RESULTS: Differences in adenylyl cyclase activity were seen in SHR compared with WKY rat myocardium: in WKY rats adenylyl cyclase activity was greater than in SHR under forskolin-stimulated conditions and in the presence of fluoride and several ligands which couple to the catalytic unit of adenylyl cyclase via Gs, including the receptor-linked species prostaglandin E1, glucagon and isoproterenol. However, with the exception of forskolin-stimulated activity, which in SHR was greater than in Wistar rats, SHR myocardial adenylyl cyclase activities were similar to those in Wistar rat membranes. Immunoblotting studies showed similar levels of G-protein subunits in all three strains. Studies of renal cortical plasma membranes failed to identify any differences in adenylyl cyclase activity or in G-protein subunit levels. CONCLUSIONS: SHR, WKY rats and Wistar rats exhibit differences in myocardial adenylyl cyclase activity which are not seen in renal cortical plasma membranes. These are not related to hypertension or to differences in G-protein levels, and probably reflect strain differences in Gs function.

Adenylyl Cyclases↗
PubMed1993

G-proteins in essential hypertension: a study of human platelet plasma membranes.

AIM OF STUDY: Guanine nucleotide regulatory (G) proteins act as key signal transducers for many hormones, growth factors and neurotransmitters, and have been shown to have an important influence on platelet function. As abnormal G-protein levels and activity have been reported in platelets from human non-insulin-dependent diabetics (NIDDM) we studied G-protein function in essential hypertension, a condition which is also associated with insulin resistance and in which abnormal platelet function has been reported. METHODS: G-protein function was deduced from studies of adenylyl cyclase activity in platelet membrane preparations from 14 untreated essential hypertensives and 14 controls matched as far as possible for age and sex. Levels of G-protein subunits (Gs alpha, Gi alpha 2 and beta-subunits) were assessed by immunoblotting, using platelets from 15 subjects with untreated essential hypertension and 15 controls. RESULTS: No changes in levels of G-proteins (Gs alpha, Gi alpha 2 and beta-subunits) were seen. However, in contrast to the observations in NIDDM, the studies of adenylyl cyclase function identified greater prostaglandin E1-stimulated activity in hypertensive platelet membranes than in controls (88.8 verus 72% stimulation, P = 0.018). This may have a physiological basis in protecting cells against a Ca2+ overload. CONCLUSION: These data are in opposition to the theory that a common defect in G-proteins can explain the association between hypertension and NIDDM.

Adenylyl Cyclases↗
PubMed1993

Guanine nucleotide regulatory proteins in the spontaneously hypertensive rat.

We compared guanine nucleotide regulatory protein (G protein) levels and function in plasma membranes from resistance vessels (mesenteric arteries) isolated from spontaneously hypertensive (SHR) and normotensive Wistar rats. G protein function was deduced from studies of adenylate cyclase activity. Although the basal level of adenylate cyclase activity (+/- Mn2+ ions) was significantly greater in SHR membranes, addition of agents that function via the stimulatory G protein--i.e., NaF (10(-2) M), (-)-isoproterenol (10(-4) M), and prostaglandin E1 (10(-5) M)--resulted in a significantly lower stimulatory response in SHR membranes. Ligands that function via the inhibitory G protein--i.e., adrenaline (10(-5) M)/propranolol (10(-5) M) (this combination being equivalent to an alpha 2-receptor agonist), carbachol (10(-3) M), and serotonin (10(-5) M)--were responsible for only slight inhibitory responses in both SHR and Wistar rat membranes, which were not significantly different. Western blotting identified the presence of Gs, Gi2, and Gi3 alpha-subunits in rat vascular smooth muscle, but there were no differences in the levels of these G protein alpha-subunits found in SHR and Wistar rat plasma membranes. The levels of the beta-subunit in the two sets of membranes were also similar. In conclusion, there is a reduced response in adenylate cyclase activity to agents that function via the stimulatory G protein in SHR membranes. However, this is not a consequence of altered levels of the different G protein subunits.

Adenylyl Cyclases↗
PubMed1992

Guanine nucleotide regulatory protein levels and function in spontaneously hypertensive rat vascular smooth-muscle cells.

We compared G-protein levels and function in membranes from vascular smooth-muscle cells (VSMC) derived from mesenteric arteries from SHR, WKY and Wistar rats. Basal adenylyl cyclase activity was significantly reduced in SHR membranes compared with Wistar, but was similar to WKY. Isoproterenol stimulation (10(-4) M) was significantly lower in SHR membranes compared to WKY, but was similar to that in Wistar, which was also significantly lower than WKY. Forskolin (10(-4) M) and NaF (10(-2) M), resulted in a higher stimulatory response in SHR membranes. Biphasic effects of GTP on isoproterenol-stimulated membranes demonstrated unaltered Gi function in SHR membranes. No significant differences were seen in the levels of Gs alpha (44- and 42-kDa forms), Gi2 alpha and the beta-subunit in immunoblotting studies of the membranes. Amounts of Gq alpha/G11 alpha and Gi3 alpha were also unchanged. In conclusion, there are differences in adenylyl cyclase responses in SHR VSMC membranes which are not a consequence of altered levels of G-proteins, but may reflect genetic differences rather than effects of hypertension.

Adenylyl Cyclases↗
PubMed1992

Effects of dexamethasone on G protein levels and adenylyl cyclase activity in rat vascular smooth muscle cells.

Dexamethasone administration in vitro has been shown to increase adenylyl cyclase activity in vascular smooth muscle cells (VSMC) from renal arteries and in non-vascular cell lines. To investigate whether G proteins are involved in this response, cultured VSMC from mesenteric arteries of Sprague-Dawley rats were incubated in the presence and absence of 10 nM dexamethasone for 24 and 48 h. Basal and stimulated adenylyl cyclase activities were increased by approximately 50% after treatment with dexamethasone. The changes were neither specifically associated with ligands which stimulate adenylyl cyclase catalytic unit via Gs (isoproterenol and prostaglandin E1) nor with guanylylimidodiphosphate (0.1 nM), which inhibits the catalytic unit via Gi. This suggests that dexamethasone enhances adenylyl cyclase activity through changes at the level of the catalytic unit, rather than through the G proteins which modulate its activity. No differences were seen in immunoblotting studies of the levels of Gi alpha 2, Gs alpha, Gi alpha 3 and beta subunits. Similarly, dexamethasone had no effect on the expression of mRNA for Gi alpha 2 and Gs alpha. The results indicate that glucocorticoid-induced increases of adenylyl cyclase activity are due to changes at the level of the adenylyl cyclase catalytic unit rather than alteration of the levels or turnover of Gs alpha, Gi alpha 2, Gi alpha 3 and beta subunits in the membranes of VSMC.

Adenylyl Cyclases↗
PubMed1991

Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects.

Adenylate cyclase activity and levels of guanine nucleotide regulatory proteins (G-proteins) were compared in platelets from normal and non-insulin-dependent diabetic (NIDDM) male subjects. Whilst no differences were noted in basal and NaF-stimulated adenylate cyclase activities the degree of stimulation achieved by both forskolin and prostaglandin, E1 was lower by some 34 and 52% respectively, in platelet membranes from diabetic subjects compared with those from normal control subjects. Altered alpha 1-adrenoceptor-mediated inhibition of prostaglandin E1-stimulated adenylate cyclase activity was evident; it being some 34% lower in platelet membranes from diabetic subjects compared to controls. Analysis of G-protein alpha-subunits, using specific anti-peptide antisera, showed that platelets from all subjects exhibited the Gi-2 and Gi-3, but not the Gi-1 forms of the inhibitory G-protein 'Gi' and all expressed the 42 kDa species of alpha-subunit of the stimulatory G-protein Gs. Whilst platelets of diabetic subjects had levels of Gs which were comparable to those found in control subjects their levels of Gi-2 and Gi-3 were some 49 and 75%, respectively, of those found in platelets from control subjects. It is suggested that changes in adenylate cyclase functioning and G-protein expression may contribute to altered platelet functioning in non-insulin-dependent diabetic subjects.

Adenylyl Cyclases↗
PubMed1991

Elderly patients with suppressed serum TSH but normal free thyroid hormone levels usually have mild thyroid overactivity and are at increased risk of developing overt hyperthyroidism.

The clinical and biochemical characteristics of 15 elderly patients with low levels of thyrotrophin (TSH) (< 0.1 mU/L) but normal free tri-iodothyronine (T3) and free thyroxine (T4) (group S) were compared with 10 euthyroid subjects (group E) and 10 hyperthyroid patients (group T). Free T3 and free T4 were significantly higher (p < 0.05) in group S (6.3 +/- 0.5 and 18.6 +/- 1.0 pmol/l, respectively) than in group E (4.6 +/- 0.3, 12.6 +/- 0.6). In common with elderly hyperthyroid patients (group T), patients in group S had few signs or symptoms of thyrotoxicosis, but the Wayne score (clinical index of hyperthyroidism) was higher in group S than in euthyroid subjects (p < 0.05). Thyroid microsomal, thyroglobulin or thyrotrophin receptor antibodies were common in group T (n = 9) but not in groups S (n = 2) or E (n = 1). This suggests a low prevalence of Graves' disease in group S compared to group T. Combined thyrotrophin releasing hormone (TRH; 200 micrograms i.v.) and gonadotrophin releasing hormone (GnRH; 100 micrograms i.v.) tests were performed; no cases of low TSH due to hypopituitarism were identified in group S. During a mean of 7.9 (4-12) months of observation TSH reverted to the normal range (> 0.2 mU/L) in 7 of 15 patients in group S; thyroid hormone concentrations rose above the normal range in four, however, only two patients required treatment for hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Hypertension, insulin, and atherogenesis.

Essential hypertension and non-insulin-dependent diabetes mellitus are both associated with hyperinsulinemia and it has been proposed that this might contribute to increased atherogenesis in these conditions. In hypertension, hyperinsulinemia probably reflects reduced insulin-stimulated glucose uptake, but the reason for this, and the contribution of hyperinsulinemia (or of resistance to insulin) to the development of hypertension and atheroma, remains unclear. As well as glucose uptake, insulin has important effects on other aspects of cell function; for example, the hormone is an important regulator of the expression and function of the major inhibitory guanine nucleotide binding protein Gi. In insulin deficiency, Gi levels and function are greatly reduced and are restored by insulin treatment. We have examined whether in human hypertension or in animal models of hypertension there is evidence of abnormal regulation of this protein. Platelet membranes from humans and rat membranes from a range of tissues, including myocardium and vasculature, were studied. No alteration in Gi levels or function was found in these studies, and there is no evidence that this aspect of insulin action on cell function is abnormal. Insulin is also involved in the regulation of cell growth, and in vascular smooth muscle cells there is evidence that this effect involves action of other growth factors, such as PDGF. If the growth regulatory actions of insulin are also unimpaired despite limitation of insulin-stimulated glucose uptake, chronic hyperinsulinemia could lead to increased vascular smooth muscle cell growth and contribute to development of atheroma.

Animals↗
PubMed1990

Hilus cell pathology and hirsutism.

Hilus cell abnormalities are uncommon causes of hirsutism with virilization. Although hilus cell tumours have been well described, hilus cell hyperplasia is rare and is poorly defined clinically. We describe three cases of hilus cell hyperplasia and compare them with a case of hilus cell tumour. Both pathologies were associated with increased testosterone and oestradiol secretion. Suppression of testosterone to the 'normal range' in response to exogenous oestrogen was seen only in the cases with hyperplasia; only partial responsiveness was seen in the case with hilus cell tumour. Bilateral oophorectomy offers the potential for cure for both hilus cell hyperplasia and tumour.

Aged↗
PubMed1990

A comparison of calcium pentagastrin and TRH tests in screening for medullary carcinoma of the thyroid in MEN IIA.

Intravenous injections of calcium gluconate and pentagastrin (CPG) or TRH were compared as secretagogues for calcitonin (CT) in screening for medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type IIA (MEN IIA). Administration of CPG resulted in a prompt increase in plasma CT in all five patients with MTC studied, one of whom had a normal baseline value (peak 412-371,000 ng/l, 636-4847% above basal). TRH produced a rise in plasma CT levels only in MTC patients with elevated basal values; the magnitude of increase was less than that observed with CPG (peak 168-17,200 ng/l, 113-180% above basal). CT levels did not rise above 300 ng/l with either test in four unaffected first-degree relatives of MEN IIA patients, three subjects with sporadic unilateral phaeochromocytomas and five controls with essential hypertension. CPG remains the CT secretagogue of choice in screening for MTC in MEN II A.

Adult↗
PubMed1989

Lack of effect of spironolactone on hair shaft diameter in hirsute females.

Because of its anti-androgenic activity spironolactone 50-200 mg daily is advocated widely for the management of female hirsutism but this practice lacks adequately controlled experimental support. In a double-blind placebo controlled study of the efficacy of spironolactone 100 mg daily in idiopathic hirsutism we were unable to demonstrate objective benefit from spironolactone treatment. The mean effect of spironolactone given over a 9 month period was to increase hair shaft diameter by +15% with 95% CI (-0.4% to +29%). In addition there were no changes in circulating serum androgen concentrations.

Androgens↗
PubMed1989

Effect of hyperthyroidism on bronchial reactivity in non-asthmatic patients.

Thyrotoxicosis may be associated with deterioration in asthma. To determine whether bronchial reactivity to histamine is increased in hyperthyroidism 10 thyrotoxic non-asthmatic patients were assessed before and after treatment of their thyrotoxicosis. No significant change in bronchial reactivity was found after treatment.

Adult↗
PubMed1988

Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design. 2 VPA alone had no effect on antipyrine clearance, urinary 6 beta-hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady-state concentration (90 +/- 6 mg 1(-1)) well within the target range (50-100 mg 1(-1)) for the drug. 3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P less than 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P less than 0.02) and half-life of unbound CBZ 16% longer (P less than 0.02) during VPA treatment. CBZ-10,11 epoxide (CBZ-E) levels (52%) and CBZ-E/CBZ ratios (45%) were both elevated by concurrent VPA (P less than 0.05) and free CBZ fraction was increased by 7% (P less than 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P less than 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P less than 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Clinical response of thyrotropin-secreting macroadenoma to bromocriptine and radiotherapy.

A patient presenting with hyperthyroidism was treated initially with antithyroid drugs and subsequently radioiodine. Thereafter he was noted to have inappropriately elevated thyrotropin. A bitemporal visual field defect was noted and CT scan confirmed the presence of a pituitary tumour. TSH was elevated and unresponsive to TRH stimulation. alpha subunit was not elevated. Long-term bromocriptine therapy (doses up to 50 mg/day) resulted in partial, but incomplete suppression of thyrotropin secretion. Following radiotherapy there was resolution of the visual field defect; the TSH, however, remains elevated at greater than 20 mU/l. Radiotherapy and bromocriptine may provide a clinically useful alternative to pituitary surgery in patients with TSH-secreting macroadenoma with suprasellar extension.

Adenoma↗