Biomedical subjects
R Sheaves
Publications and source records attributed to R Sheaves.
An Asian multicenter clinical trial to assess the efficacy and tolerability of acarbose compared with placebo in type 2 diabetic patients previously treated with diet. Asian Acarbose Study Group.
OBJECTIVE: To assess the efficacy, safety, and tolerability of acarbose versus placebo during a 24-week treatment period in Asian type 2 diabetic patients with dietary failure. RESEARCH DESIGN AND METHODS: After a 6-week screening period, 126 multiethnic Asian type 2 diabetic patients (64 men, 62 women; mean age +/- SD, 53.4 +/- 10 years) were randomized to receive acarbose (n = 63) or placebo (n = 63). The dosage was increased from 50 mg t.i.d. at week 0 to 100 mg t.i.d. at week 4. Patients were then followed up at weeks 10, 16, and 24. At each visit, body weight, blood pressure, and metabolic indexes were measured. At weeks 0 and 24, fasting plasma glucose and insulin were measured before and 1 h after the administration of an individually tailored breakfast. RESULTS: Using the intention-to-treat analysis, there were greater reductions in (mean [95% CI]) HbA1c (-0.70 [-1.00 to -0.39] vs. -0.27% [-0.54 to 0]; P = 0.04), fasting plasma glucose (-0.37 [-0.75 to 0.02] vs. 0.41 mmol/l [-0.08 to 0.90]; P = 0.017) and 1-h plasma glucose (-0.77 [-1.44 to -0.10] vs. 0.65 mmol/l [-0.07 to 1.36]; P = 0.05) in the acarbose group compared with the placebo group. With acarbose treatment, 78% of patients achieved an HbAlc < 8% compared with 56% in the placebo group (P = 0.003). There was a greater reduction in body weight (-1.31 [-2.46 to -0.15] vs. 0.16 kg [-3.36 to 0.10]; P = 0.02) and higher incidence of flatulence (56 vs. 37%; P = 0.032) in the acarbose than in the placebo group. Using baseline HbA1c and race as covariates, there were no significant interethnic differences in treatment responses (P = 0.232 for treatment-race interaction; P < 0.001 for treatment effect). The dropout rates were similar between the two groups (acarbose, 11 of 63; placebo, 6 of 63). There were no significant laboratory adverse events in either group. CONCLUSIONS: In this multicenter study involving six ethnic groups, acarbose 100 mg t.i.d. was an effective, safe, and generally well-tolerated therapy in Asian type 2 diabetic patients with dietary failure. In some patients with troublesome gastrointestinal symptoms, a lower dosage may be necessary.
Outcome of transsphenoidal surgery for acromegaly using strict criteria for surgical cure.
OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.
Relative value of computed tomography scanning and venous sampling in establishing the cause of primary hyperaldosteronism.
The purpose of this study was to evaluate the relative merits of the postural stimulation test, adrenal computed tomography (CT) and venous sampling in the differential diagnosis of patients presenting with primary hyperaldosteronism. The records of 20 patients presenting with primary hyperaldosteronism were reviewed retrospectively. There were 15 patients with a unilateral aldosterone-producing adenoma (APA), four patients with idiopathic hyperaldosteronism (IHA) and one patient with primary adrenal hyperplasia (PAH). The postural stimulation test was based on measurements of plasma aldosterone and renin activity at 08.00 h and at noon after 4 h of ambulation. The CT scans of the adrenals were reviewed by a single radiologist. Bilateral venous sampling of adrenal veins was attempted in all patients and blood collected for aldosterone and cortisol assay. Plasma aldosterone concentration increased after 4 h of standing in all cases of hyperplasia but was also demonstrated in 10/15 patients with a surgically-proven APA. If one defines a significant postural rise as being greater than 30%, then 8/15 patients with APA can be considered as being posturally responsive. Computed tomography scanning correctly identified all 15 cases of APA and also classified correctly the remaining five cases of hyperplasia (four cases of IHA and one case of PAH). Venous sampling failed technically in 4/15 cases of APA and in one case of IHA: a total of 5/20 (25%,). A correct diagnosis of APA or IHA was established in all the remaining cases. However, the one case of PAH was treated successfully by adrenalectomy following venous sampling, which suggested a unilateral adrenal lesion: this one result was the only instance where venous sampling altered clinical decision-making. Computed tomography scanning may be used alone to confirm the cause of hyperaldosteronism where postural studies suggest an adrenal adenoma, and such patients may be considered for early surgery. Venous catheterization studies are not necessary routinely. but may still be useful in selected patients, particularly when CT scanning shows no clear lesion.
The dangers of unopposed beta-adrenergic blockade in phaeochromocytoma.
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Gene deletion causing adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.
We report a patient with X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism in whom there were no clinical or biochemical features of either glycerol kinase deficiency or Duchenne muscular dystrophy. (The adrenal hypoplasia congenita and glycerol kinase loci map in Xp21 distal to Duchenne muscular dystrophy, and proximal to DXS727). DNA isolated from our patient was analysed by PCR amplification with primers for appropriate loci in the Xp21 region. This analysis revealed the absence of DXS319, which lies near the adrenal hypoplasia congenita deletion critical region, and the presence of DXS727, which is distal to the gene. The absence of glycerol kinase deficiency biochemically and clinically was consistent with the presence of one glycerol kinase exon product from PCR primers P17/P18 which lies within the glycerol kinase gene. The hypogonadotrophic hypogonadism is universally found in X-linked adrenal hypoplasia congenita and is thought to be pituitary in origin. These findings suggest that a gene locus resulting in hypogonadotrophic hypogonadism is present in the Xp21 region and is an integral part of the adrenal hypoplasia congenita gene or in close relationship to it.
Bilateral phaeochromocytomas in von Hippel-Lindau disease: diagnosis by adrenal vein sampling and catecholamine assay.
Three unrelated patients with von Hippel-Lindau disease had phaeochromocytomas diagnosed as a result of screening in their third decade. All had raised 24-h urinary noradrenaline levels and obvious unilateral adrenal tumours on ultrasound scanning and computed tomography. The contralateral adrenal appeared either normal or equivocally abnormal using the same imaging techniques. Radiolabelled meta-iodo-benzylguanidine uptake and enhanced T2-weighted magnetic resonance signals confirmed the ipsilateral lesion, but showed no abnormality in the contralateral adrenal. Nevertheless, venous sampling demonstrated abnormally elevated noradrenaline:adrenaline ratios (normal < 1) in blood draining both adrenals in all three patients. All underwent bilateral adrenalectomy: histological examination confirmed bilateral phaeochromocytomas in all three patients, with the smaller adrenal showing tumours between 3 and 11 mm in diameter. A fourth patient with von Hippel-Lindau disease was also evaluated because of a left 'suprarenal' mass discovered by ultrasound scanning. Urinary and plasma catecholamines were normal. Computed tomography showed a normal right adrenal, with a left para-aortic mass lying superior to the left adrenal. Magnetic resonance scanning showed an enhanced T2 signal from the mass, which also showed positive uptake with radiolabelled mIBG. At operation, a non-secretory left para-aortic paraganglioma was found. Venous sampling suggested that the left adrenal was normal, and this was confirmed on histology. Venous sampling for catecholamine assays is effective in locating small bilateral phaeochromocytomas and defining a normal adrenal gland, and can be useful in preventing unnecessary or repeat operations in patients with non Hippel-Lindau disease.
Handwashing and cohorting in prevention of hospital acquired infections with respiratory syncytial virus.
Hospital acquired infections with respiratory syncytial virus are a major problem. The virus is spread predominantly by infected nasal secretions and we investigated whether we could reduce its incidence by cohorting babies on each ward into designated areas and encouraging staff and parents to wash their hands. We examined the incidence of hospital acquired infection due to respiratory syncytial virus in all children less than 2 years old and in those with congenital heart disease. In 1986-7, before any intervention, 18 (4.2%) of 425 hospitalised children less than 2 years old developed hospital acquired infection due to respiratory syncytial virus. In 1987-8, after intervention, five (0.6%) of 840 children developed hospital acquired infection but there were fewer ward admissions with community acquired infections due to the virus. In 1988-9, when there were more community acquired infections than 1986-7, six (1.1%) of 552 children developed hospital acquired infection. In 1986-7, eight (34.8%) of 23 children less than 2 years old with congenital heart disease developed hospital acquired infection due to respiratory syncytial virus; all eight were among 11 children with congenital heart disease hospitalised for more than 14 days. In 1987-8, one (3.3%) of 30 children with congenital heart disease developed hospital acquired infection due to respiratory syncytial virus and in 1988-9 there was one (2.1%) case out of 47 children with congenital heart disease. Handwashing and cohorting significantly reduce the incidence of nosocomial respiratory syncytial virus infection.
Central adrenergic activity in the mediobasal hypothalamus is temporally related to surge outputs of gonadotrophins in oestrogen-stimulated infant female rats.
In the mediobasal hypothalamus (MBH) of pro-oestrous rats or acutely ovariectomized oestrogen-treated adults a marked but short-lived increase in adrenergic activity occurs at 16.00 h, 2 h before the oestrogen-dependent surge of gonadotrophins at 18.00 h. In this study oestrogen-stimulated (noon on day 1) 22-day-old female rats were used which are known to produce surge levels of prolactin at 18.00 h on day 2 and surges of both prolactin and LH at 18.00 h on day 3; although similar treatment of 18-day-old animals or oil-treated 22-day-old rats failed to produce these effects. Radioenzymatic assays of adrenaline concentrations and of the activity of its synthesizing enzyme (phenylethanolamine-N-methyl transferase; PNMT, EC 2.1.1.28) in the MBH of oestrogen-treated 22-day-old rats showed significant (P less than 0.05-0.01) increases in both parameters at 16.00 h (i.e. 2 h before surge levels of gonadotrophins) on days 2 and 3 when compared with other times of day. Such effects were not seen in oil-treated 22-day-old animals or in oestrogen-treated 16-day-old rats. Noradrenaline and dopamine concentrations in the MBH of oestrogen-treated 22-day-old rats remained at baseline levels on days 2 and 3 with the exception of noradrenaline at 17.00 h on day 3 when levels appeared higher (P less than 0.05) than at either 15.00 or 16.00 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Reduction of central epinephrine concentrations is consistent with the continued occurrence of ovulation in rats treated with an inhibitor (LY 134046) of phenylethanolamine N-methyltransferase.
Groups of 4-day cyclic rats were injected (i.p.) with LY 134046 (50 mg/kg), a central inhibitor of phenylethanolamine N-methyltransferase, or saline at 09.00, 13.00 and 19.00 h on the day of proestrus. The incidence of ovulation was examined the following estrous morning. There was no difference in the number of ova in drug-treated animals compared to saline-treated controls. In other groups of 4-day cyclic rats, LY 134046 or saline was injected daily at 10.00 h for 5 consecutive days from proestrus to proestrus inclusive. The animals were decapitated the following day and ova were counted. Epinephrine concentrations were determined by radioenzymatic assay in the mediobasal hypothalamus (MBH) and the medial preoptic area (MPOA). All saline-treated controls and 10/14 of the drug-treated animals had ovulated, while epinephrine concentrations in the MBH and MPOA had been reduced by 95.8 and 94.7%, respectively, compared to saline-treated controls. These experiments suggest that a significant surge of luteinizing hormone occurs to initiate ovulation even after a severe reduction in central epinephrine concentration has taken place.
Evidence that central epinephrine neurons participate in the control and regulation of neuroendocrine events during the estrous cycle.
Although evidence has shown that central epinephrine (E) neurons play an essential role in the control of preovulatory gonadotropoin surge in rats, their function and site(s) of action are unknown. These experiments were performed in an attempt to identify any changes in E concentration or activity that might take place in areas of the brain known to receive adrenergic axon terminals and to be associated with increased output of gonadotropins (LH, FSH, and PRL) during the estrous cycle. E concentrations were measured by radioenzymatic assay, and E activity was assessed by the linear rate of decline of E (RDE) which occurs 2 h after administration of the centrally active E synthesis inhibitor, SKF 64139. During the proestrous critical period (1500-1700 h), significant increases in both concentration and RDE occurred in the medial preoptic area (mPOA) accompanied by a smaller but significant increase in the RDE in the mediobasal hypothalamus (MBH); 4 h later (2100-2300 h), significant increases in both concentration and RDE were seen in the MBH. At estrus, although E concentrations were generally higher in both the mPOA and MBH than on other days of the cycle, the concentration and RDE in the MBH increased significantly between 1500-1700 h, while RDE in the mPOA increased again between 1700-1900 h. There were no significant changes in either E concentration or RDE in the mPOA or MBH at metestrus or diestrus or in the perifornical area at any of the times studied. Thus, these findings may be associated with the output of gonadotropins over the periovulatory period.
Changes in concentrations and rate of decline of adrenaline in the medial preoptic area and mediobasal hypothalamus of acutely ovariectomized steroid-treated rats.
The presence of adrenaline within the central nervous system appears to be essential for the occurrence of an oestrogen-stimulated surge of LH in both pro-oestrous and ovariectomized rats. Previous measurements of adrenergic activity based on the rate of decline of adrenaline (RDA) 2 h after injection of a synthesis inhibitor (SKF 64139) suggested that adrenergic activity increases in both the medial preoptic area (MPOA) and the mediobasal hypothalamus (MBH) at the start of the LH surge (15.00-17.00 h). The purpose of the present studies was to see whether oestrogen and progesterone affected this increase in adrenergic activity at the sites of the cell bodies (MPOA) and axon terminals (MBH) of the gonadotrophin-releasing hormone-synthesizing neurone. Rats ovariectomized at dioestrus showed a reduction in both plasma LH concentrations and RDA (P less than 0.01) in the MBH between 15.00 and 17.00 h on the day of expected pro-oestrus. Oestrogen replacement at operation restored LH levels and the RDA to values found in intact rats. Injection of an antioestrogen (Cl-628), with or without oestrogen, also reduced plasma LH levels and the RDA (P less than 0.01) in the MBH. Removal or replacement of oestrogen apparently had little effect on the RDA in the MPOA. In ovariectomized oestrogen-primed rats an injection of progesterone on the morning of expected pro-oestrus advanced and enhanced not only the LH surge but also the RDA in the MBH (P less than 0.001). Moreover, concentrations of adrenaline in the MBH (but not the MPOA) decreased (P less than 0.001) consistently over a 2-h period following injection of progesterone.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenaline concentration and turnover in the arcuate nucleus and median eminence during the critical period in the rat.
Previous work has shown a relatively high turnover of adrenaline in the mediobasal hypothalamus during the critical period (15.00-17.00 h) of the proestrous rat. We now report that this high level of adrenergic activity can be detected in the median eminence (turnover rate 1.62 +/- 0.36 pg/micrograms protein/h) rather than the arcuate nucleus (turnover rate 0.18 +/- 0.32 pg/micrograms protein/h). In addition the median eminence was isolated as medial and lateral components and determination of catecholamine concentrations revealed a greater proportion of adrenaline (A) (59%) in the lateral median eminence whereas a larger proportion of dopamine (60%) was found in medial median eminence.
Hypothalamic adrenergic activity precedes the preovulatory luteinizing hormone surge in the rat.
A preovulatory surge of luteinizing hormone (LH) is stimulated by an increase in plasma oestrogen (E2) and a proestrous neural signal which occurs during the 'critical period' (CP). Adrenergic activity during the CP in brain areas concerned with LH release and receiving adrenergic nerve terminals, increased in the arcuate nucleus-median eminence area (AN-ME) during the CP (14.30-16.30 h), but not in the adjacent perifornical area. Pentobarbital injected prior to the CP inhibited the effect as did ovariectomy, while E2 replacement restored it. Thus increased adrenergic activity in the AN-ME may represent the neural signal that triggers the preovulatory LH surge [5].
Adrenal profiles.
Tests for adrenal hormone abnormalities are important in the investigation of endocrine hypertension and adrenal insufficiency. This article assesses the suitability of the available tests. Particular attention is paid to the specificity and sensitivity of tests to exclude phaeochromocytoma and Cushing's syndrome.