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Biomedical subjects

A B Atkinson

Publications and source records attributed to A B Atkinson.

At least 37 records · Page 2Linked to original sources
PubMed2000

The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic-pituitary-adrenal axis following pituitary surgery.

OBJECTIVE: To compare the insulin hypoglycaemia test with the short overnight metyrapone test in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis posthypophysectomy. DESIGN: Prospective comparative study of the insulin hypoglycaemia test and the overnight metyrapone test in 32 patients 4-6 weeks after pituitary surgery. SUBJECTS: Thirty-two patients with known pituitary disease. None with present or previous Cushing's syndrome. OUTCOME MEASUREMENTS: Maximum serum cortisol achieved during insulin induced hypoglycaemia compared with 0900 hours serum 11-deoxycortisol level following a weight related oral dose of metyrapone at 0000 h. RESULTS: One of the 32 patients required further surgery and was studied twice after each operation. Thirty-three results are therefore compared. Twenty-six of these had a normal cortisol response of 550 nmol/l or above leading to the cessation of replacement hydrocortisone. Six of these 26 patients however, failed the metyrapone test (11-deoxycortisol level less than 200 nmol/l). After 3-40 months (median 20 months) of follow-up off steroid therapy, no patient to date has displayed any clinical evidence of steroid deficiency. Of the seven patients who failed the insulin hypoglycaemia test, six also failed the metyrapone test. CONCLUSIONS: The overnight metyrapone test identified more patients with possible ACTH deficiency than the insulin hypoglycaemia test. Further follow-up of these patients is required before a final judgement can be made as to whether more subtle but clinically relevant ACTH deficiency can be detected by the metyrapone test. Our clinical follow-up to date would not support this.

Adenoma↗
PubMed2000

Comparison of one week 0900 h serum cortisol, low and standard dose synacthen tests with a 4 to 6 week insulin hypoglycaemia test after pituitary surgery in assessing HPA axis.

OBJECTIVE: To compare the use of 0900 h serum cortisol and both low and standard dose Synacthen tests, one week after pituitary surgery with an insulin hypoglycaemia test performed 4-6 weeks after surgery in assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: 0900 h basal serum cortisol was measured on days 6 and 7 after pituitary surgery (24 h off replacement hydrocortisone) followed by a low dose Synacthen test (1 microg intravenously) on day 6 and a standard dose Synacthen test (250 microg intramuscularly) on day 7. Three to 5 weeks later an insulin hypoglycaemia test was performed on all patients. Both low and standard dose Synacthen tests were performed on control subjects using an identical protocol. SUBJECTS: Forty-two patients (21 male, 21 female), median age 49 years (range 23-73) who had pituitary surgery (Cushing's disease excluded). One patient had undergone repeat surgery for residual tumour and was studied following each operation. Sixteen healthy normal volunteers, median age 37 years (range 21-55). MEASUREMENTS: Serum cortisol measured by radioimmunoassay. RESULTS: Two standard deviations below the mean serum cortisol (logarithmic transformation) in the normal volunteers 30 minutes after low dose Synacthen (1 microg) was 496 nmol/l and after standard dose Synacthen (250 microg) was 504 nmol/l. A normal response was therefore taken as serum cortisol > 500 nmol/l at 30 minutes in both tests (using 496 and 504 nmol/l did not alter results). 0900 h serum cortisols 1 week after surgery were > 250 nmol/l in 31 patients and 29 of these had a normal response to hypoglycaemia (peak serum cortisol > 550 nmol/l). Of the remaining two patients, one had 0900 h serum cortisol on day 6 and 7 after surgery of 405 and 441 nmol/l with a peak serum cortisol response to hypoglycaemia of 451 nmol/l; the other patient had 0900 h serum cortisols of 416 and 251 nmol/l and a peak cortisol response to hypoglycaemia of 498 nmol/l. All eight patients who had a 0900 h serum cortisol < 100 nmol/l failed a subsequent insulin hypoglycaemia test. Seven discrepancies were noted between the low dose Synacthen test and the insulin hypoglycaemia test in the 41 patients who had both tests. In six of these, a subnormal response to low dose Synacthen was followed by a normal response to hypoglycaemia. Three discrepancies were noted between the standard dose Synacthen test and the insulin hypoglycaemia test in the 40 patients who had both tests. In all three cases a normal response to Synacthen was followed by a subnormal response to hypoglycaemia. CONCLUSIONS: A 0900 h serum cortisol < 100 nmol/l (24 h off replacement hydrocortisone) indicated ACTH deficiency and need for lifelong steroid replacement. A 0900 h serum cortisol > 450 nmol/l one week after pituitary surgery is highly suggestive of a normal cortisol response to hypoglycaemia. A 0900 h serum cortisol between 250 and 450 nmol/l one week after pituitary surgery permits safe withdrawal of steroid therapy pending an insulin hypoglycaemia test 1 month after surgery. Patients with 0900 h serum cortisol between 100 and 250 nmol/l should continue replacement steroids until definitive testing. Low dose and standard dose Synacthen tests 1 week after pituitary surgery are unreliable and should not be used.

Adenoma↗
PubMed2000

Insulin resistance and insulin pulsatility in essential hypertension.

OBJECTIVE: Studies in normal humans and in patients with type 2 diabetes mellitus have demonstrated a close inverse relationship between peripheral insulin sensitivity and the frequency of short-term insulin secretory pulses in the systemic circulation. Our objective was to study this relationship in essential hypertension. DESIGN: Study of insulin sensitivity and insulin pulse characteristics in hypertensive subjects and normotensive controls using well-established techniques. METHODS: Twelve subjects with essential hypertension and 12 age- and sex-matched normotensive controls were recruited. Insulin action was measured using the glucose clamp technique combined with isotope dilution methodology. Insulin pulsatility in the peripheral circulation was assessed by sampling every 2 min for 90 min after an overnight fast Pulses were identified using the computer program Pulsar. RESULTS: Insulin sensitivity index (glucose infusion rate/ serum insulin) was lower in the hypertensive patients (P= 0.01) and fasting insulin was increased (P= 0.008) compared to controls. The frequency and amplitude of insulin pulses were similar in the two groups. Insulin pulse frequency and insulin sensitivity were inversely related in the normotensive group (r= -0.68, P= 0.015), but not in the hypertensive group (r= -0.23, P= 0.48). Insulin clearance was reduced in the hypertensive group (P= 0.03), and was inversely related to insulin pulse frequency in the two groups combined (r = -0.51, P= 0.01). CONCLUSIONS: Insulin action was not related to insulin pulse frequency in essential hypertension, in contrast to the situation in normal man.

Adult↗
PubMed2000

Bilateral inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome: a comparison with other diagnostic tests.

To compare bilateral inferior petrosal sinus sampling (IPSS) with high dose dexamethasone (HDD) and CRH testing (using recently proposed stringent response criteria) in the differential diagnosis of ACTH-dependent Cushing's syndrome, we reviewed 53 consecutive cases. The main analysis was limited to 45 cases with confirmed diagnosis: 44 with pituitary dependency, proven by confirmatory histology and/or significant biochemical improvement after pituitary surgery, and 1 with ectopic ACTH syndrome. After HDD (2 mg every 6 h for 48 h), 21 of the 44 pituitary cases met the stringent more than 90% suppression criterion. Twenty-three of the 44 pituitary cases also underwent CRH testing; 16 of 23 met a stringent response criterion of a more than 50% serum cortisol rise. For HDD and CRH testing combined, 8 of 23 fulfilled both stringent criteria, 10 of 23 had discordant results, and 5 of 23 failed to fulfil either of the stringent criteria for pituitary dependency. IPSS was performed in all 44 of the proven pituitary cases; 36 had petrosal/peripheral ACTH ratios of 2.0 or more without CRH stimulation. Thus, in patients with proven pituitary disease, stringent response criteria to HDD and CRH testing were fulfilled by only 48% and 70%, respectively. IPSS, which gave direct evidence of pituitary ACTH secretion in 82% of the cases, is therefore considered necessary in a significant proportion of cases.

Adolescent↗
PubMed2000

Different patterns of allelic loss (loss of heterozygosity) in recurrent human pituitary tumors provide evidence for multiclonal origins.

Sporadic human pituitary tumors are benign adenomas of monoclonal origin. This implies that they arise from de novo somatic mutation(s) within a single pituitary cell. The availability of original and recurrent/regrown tumors from the same patient allowed testing of the prediction that recurrent/regrown tumors have identical genetic abnormalities as the original tumor sample. We used PCR amplification, from archival slide-extracted DNA, to allelotype microsatellite polymorphisms as an indication of clonality and confirmed this by X chromosome inactivation analysis in samples from women. Tumors from 33 of 49 (67%) patients with two or more specimens showed loss of heterozygosity (LOH) of at least one marker in at least one of their samples. Two patterns of LOH were observed. In pattern A in 14 of 33 (42%) of patients, the LOH pattern of the first tumor was preserved in the second recurrent sample, with some recurrent tumors also showing additional LOH. In these patients, the original and second tumors are presumed to arise from the same original clone with or without progressive accumulation of LOH. In pattern B [19 of 33 (58%) patients], LOH seen in the first tumor was not preserved in the second or subsequent tumors, as evidenced by retention of heterozygosity compared with the first tumor. The simplest explanation is that the second tumor, although still monoclonal, arises from another independently abnormal clone. This was confirmed by X chromosome inactivation analysis in all 11 women where this was informative. These results show that initial and recurrent tumors, of a benign tumor type, are frequently derived from separate independent clones. This suggests that either: (a) more than one abnormal clone is present from the outset though only one dominates; or (b) several clones arise independently at different times. In both scenarios, the initiating event(s) that predisposes to transformation might result in multiclonal hyperplasia, possibly as a consequence of exogenous stimulation.

Adolescent↗
PubMed1999

Low dose bendrofluazide (1.25 mg) effectively lowers blood pressure over 24 h: results of a randomized, double-blind, placebo-controlled crossover study.

Previous studies indicate that low dose bendrofluazide (1.25 mg/day) has no deleterious effect on insulin sensitivity in contrast to conventional doses. To evaluate the antihypertensive effect of 1.25 mg bendrofluazide across 24 h, we studied 12 subjects in a randomized, double blind, cross-over trial, comprising 8 weeks of either 1.25 mg/day bendrofluazide or placebo. Twenty-four-hour blood pressure averages were significantly lower after bendrofluazide compared with placebo (systolic 125 +/- 4 v 136 +/- 3 mm Hg, P < .005; diastolic: 78 +/- 2 v 85 +/- 2 mm Hg, P < .01). Trough:peak ratios were 0.67 +/- 0.07 for systolic and 0.72 +/- 0.15 for diastolic blood pressure reduction. In conclusion, 1.25 mg bendrofluazide daily produced a useful antihypertensive effect across the full 24-h period.

Aged↗
PubMed1999

Results of a European multicentre study with Sandostatin LAR in acromegalic patients. Sandostatin LAR Group.

A European multicentre, open-label 12-month study with Sandostatin LAR administered intramuscularly at 4-week intervals was initiated in 151 acromegalics responsive to octreotide. All patients received 3 injections of the 20 mg dose, following which the dose was adjusted to 10 mg in patients with mean 4-hour GH serum concentrations below 1 microgram/L (N: 29) and to 30 mg in patients with concentrations above 5 micrograms/L (N: 22). The GH level suppression was significant in the 20 mg dose group (p < 0.01) and for all 151 patients (p < 0.004), and was consistently maintained in all patients for the duration of the study. The suppression of the mean serum GH concentration to below 2.5 micrograms/L was recorded in 69.8% of patients at the endpoint treatment with Sandostatin LAR and 65.8% during prior treatment with Sandostatin s.c. A consistent suppression of serum IGF-I levels was also achieved. The number of patients with headache, fatigue, perspiration, joint pains and paresthesias had decreased significantly (p < 0.05) after the 6t]h injection of Sandostatin LAR vs. previous s.c. treatment. No patient discontinued the study because of drug-related adverse events. The most frequently reported adverse events were mild diarrhea, abdominal pain and flatulence. The local tolerability was very good. No impairment of safety hematology, biochemistry and thyroid function tests and no increased incidence of gallstone formation was recorded. Well tolerated and at least as efficacious as the s.c. formulation, Sandostatin LAR might become an alternative primary treatment to pituitary surgery and radiotherapy.

Acromegaly↗
PubMed1999

Comparison of monthly intramuscular injections of Sandostatin LAR with multiple subcutaneous injections of octreotide in the treatment of acromegaly; effects on growth hormone and other markers of growth hormone secretion.

OBJECTIVE: To compare the effects of monthly intra-muscular injections of a long acting preparation of octreotide, Sandostatin LAR, with multiple daily subcutaneous injections of octreotide and to study the interrelationships between mean 24 h growth hormone profile, serum total and free IGF-1 levels, 24 h urinary growth hormone levels and serum IGFBP-3. DESIGN: Patients were assessed by 24 h GH profile off octreotide or any other GH modifying drug therapy; on subcutaneous octreotide (200-600 micrograms daily in divided doses for six weeks); and 28 days after the second of two injections of Sandostatin LAR (20 mg by intra-muscular injection) administered 28 days apart. Serum total and free IGF-1, serum IGFBP-3 and 24 h urinary GH were also measured on each occasion. RESULTS: Sandostatin LAR was well tolerated. None of the patients reported any adverse effect and all completed the study uneventfully. Mean GH off treatment was 10.1 +/- 3.0 micrograms/l falling equally significantly (P < 0.05) during therapy with subcutaneous octreotide to 3.0 +/- 0.7 micrograms/l and Sandostatin LAR to 2.8 +/- 0.7 micrograms/l. Fasting 0900 h GH was significantly reduced (P < 0.05) on Sandostatin LAR (3.0 +/- 0.7 micrograms/l) compared with subcutaneous octreotide (5.1 +/- 1.2 micrograms/l). Mean total IGF-1 off treatment was 658.6 +/- 56.1 micrograms/l and was reduced to a comparable extent with subcutaneous octreotide and Sandostatin LAR (466.0 +/- 59.7 and 448.6 +/- 59.5 micrograms/l respectively; both P < 0.05). Free IGF-1 off treatment was 3.1 +/- 0.6 micrograms/l and was reduced equally by subcutaneous octreotide and Sandostatin LAR (1.2 +/- 0.2 and 1.2 +/- 0.2 micrograms/l; both P < 0.05). IGFBP-3 was reduced to a greater extent during Sandostatin LAR than during subcutaneous octreotide (4518.2 +/- 247.3 vs 5132.8 +/- 280.7 micrograms/l; P < 0.05). Twenty-four hour urinary GH excretion was reduced to a comparable extent with both therapies. Highly significant positive correlations were found between mean 24 h GH levels and free IGF-1 (r = 0.66, P < 0.0001) and 24 h urinary GH excretion (r = 0.94, P < 0.0001). The relationships between mean 24 h GH levels and total IGF-1 and IGFBP-3 although significant showed less powerful correlations. CONCLUSIONS: These results suggest that Sandostatin LAR is well tolerated and as effective as subcutaneous octreotide. In addition, urinary growth hormone and serum free IGF-1 may prove valuable for outpatient follow-up of acromegalic patients, as both correlate well with mean 24 h serum growth hormone levels.

Acromegaly↗
PubMed1999

A comparison of the naloxone test with the insulin stress test in patients following transsphenoidal surgery.

OBJECTIVE: To study the reliability of the naloxone test in assessing the hypothalamic-pituitary-adrenal (HPA) axis in patients following transsphenoidal pituitary surgery, by comparison with the insulin stress test (IST). Also, to establish a normal range for the response to naloxone in healthy controls. DESIGN: All patients had the IST performed, soluble insulin 0.1-0.3 U/kg (usually 0.15 U/kg) being administered intravenously, followed by venous sampling for plasma glucose and serum cortisol at 0, 15, 30, 45, 60, 75 and 90 minutes. Naloxone (125 micrograms/kg body weight) was similarly administered to all patients 6 days later, with sampling at -15, 0, 15, 30, 45, 60, 90 and 120 minutes for plasma glucose, serum cortisol and plasma ACTH. The naloxone test was also performed on control subjects using an identical protocol. SUBJECTS: Twenty patients (11F/9M) aged 48.8 +/- 2.8 years (mean +/- SE) 4-6 weeks following transsphenoidal pituitary surgery. Twelve normal healthy control subjects (6F/6M) aged 31.5 +/- 3.0 years. MEASUREMENTS: Serum cortisol was measured by radioimmunoassay and plasma ACTH by immunoradiometric assay. RESULTS: Adequate hypoglycaemia (< or = 2.0 mmol/l) was achieved in all patients. Peak cortisol was > 550 nmol/l in 17 subjects (range: 572-867 nmol/l) and a subnormal response observed in 3 (peak cortisol 163-498 nmol/l). In the 17 patients with a normal cortisol response to hypoglycaemia the response to naloxone was extremely variable, with serum cortisol falling in 4 and an increment of < or = 100 nmol/l in 6 others. In the 3 patients who failed the IST, two responded to naloxone and one did not. In normal controls, 3 of the 12 had little or no response to naloxone. CONCLUSIONS: As the naloxone test fails to produce a response in all normal subjects it is impossible to define a 'normal' response. The numerous discrepancies with the IST in patients are further evidence of the test's lack of reliability in assessing the HPA-axis and it is consequently not a viable alternative to traditional dynamic methods such as the IST.

Adrenocorticotropic Hormone↗
PubMed1999

Comparison of effects of captopril used either alone or in combination with a thiazide diuretic on insulin action in hypertensive Type 2 diabetic patients: a double-blind crossover study.

AIMS: It has been suggested that the adverse metabolic effects of antihypertensive therapy offset some of the benefits of blood pressure reduction. It has also been suggested that angiotensin converting enzyme (ACE) inhibitors reduce insulin resistance and that, if used together with thiazide diuretics, the adverse effects of thiazides on insulin sensitivity may be eliminated. We examined the effects on insulin sensitivity of captopril either alone or in combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients. METHODS: Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomized, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendrofluazide (CB) (2.5 mg). RESULTS: Blood pressure was lower following CB compared to C (128/82 vs. 144/ 88 mmHg; P<0.005) and both were lower than baseline (162/101 mmHg; P < 0.001). CB resulted in a significant increase in fasting plasma glucose compared to C (9.7+/-0.8 vs. 8.5+/-0.6 mmol/; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (22.3+/-2.4 vs. 27.4+/-4.2 mol x kg(-1) x min(-1); P < 0.05). Suppression of endogenous glucose production was reduced after CB compared to baseline (4.0+/-0.6 vs. 2.4+/-0.5 mol x kg(-1) x min(-1); P< 0.05). CONCLUSIONS: Combination of bendrofluazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.

Antihypertensive Agents↗
PubMed1999

Endothelial function in offspring of Type 1 diabetic patients with and without diabetic nephropathy.

AIMS: Familial aggregation of diabetes and nephropathy has been observed in several populations. Various interpretations have included underlying genetic mechanisms possibly mediated by a predisposition to hypertension. Endothelial dysfunction is now recognized as central to these conditions and offers a unifying mechanism to explain the disease aggregation. To test this hypothesis, we have examined endothelial function in healthy subjects at differing risks for diabetic nephropathy. METHODS: Endothelial function was assessed in 12 healthy offspring (nine male (M)/three female (F); age 25.8+/-1.2 years, mean +/- SEM) of parents with Type 1 diabetes mellitus (DM) and end-stage renal disease compared with 12 control offspring (9 M/3 F; age 26.3+/-1.3 years) of parents with long duration (>20 years) Type 1 DM but without evidence of nephropathy. Forearm blood flow responses to brachial artery infusion of acetylcholine (endothelium-dependent), sodium nitroprusside (endothelium-independent), noradrenaline and the competitive inhibitor of basal nitric oxide release N(G)-monomethyl-L-arginine were assessed using venous occlusion plethysmography. RESULTS: There were no significant differences between the groups in von Willebrand factor, fasting plasma glucose (4.2+/-0.1 vs. 4.0+/-0.2 mmol/l) or in 24-h ambulatory blood pressure. Similarly, the groups did not differ in vasodilation to acetylcholine (P = 0.75) and sodium nitroprusside (P = 0.79) or in vasoconstriction to noradrenaline (P = 0.45) and N(G)-monomethyl-L-arginine (P = 0.30). CONCLUSION: These data do not support a role for endothelial dysfunction in the familial aggregation of diabetic nephropathy.

Adult↗
PubMed1999

Accuracy of CT scanning and adrenal vein sampling in the pre-operative localization of aldosterone-secreting adrenal adenomas.

In primary hyperaldosteronism, it is important to distinguish between unilateral and bilateral disease, as management strategies differ. In the period 1983-95, we identified 34 patients with primary hyperaldosteronism. Following further investigations, a diagnosis of aldosterone-secreting adenoma was made in 17 patients, and surgery was performed. Computed tomography clearly localized an apparent adenoma (discrete adenoma=1 cm diameter; normal contralateral gland) in only 10 of these patients (59%); two of these 'adenomas' were subsequently shown to be hyperplastic glands without adenomas. Histological examination showed adrenal adenomas in the remaining 15 patients. An 'adenoma' also appeared to be clearly localized in 3/17 patients later classified as having bilateral adrenal hyperplasia by adrenal vein sampling. CT scanning, therefore clearly localizes adenomas in only 50% of histologically proven cases, and can also produce misleading results. Adrenal vein sampling results altered our management approach in one third of cases. On the basis of our detailed results we would recommend surgery if there is clear evidence of unilateral aldosterone secretion along with CT findings which may not be strictly localizing but are in keeping with the dominant side on adrenal vein sampling. The decision to refer for surgery in primary hyperaldosteronism can be difficult, and we would caution against too heavy a reliance on CT results when recommending adrenalectomy, and suggest that adrenal vein sampling should remain a routine part of the investigation of patients with primary hyperaldosteronism.

Adenoma↗
PubMed1999

Is whole-lung CT scanning still necessary in all cases of ACTH-dependent Cushing's syndrome in the era of petrosal sinus sampling?

We reviewed 31 patients in whom both bilateral inferior petrosal sinus sampling without CRH stimulation, and a CT scan of the lungs were done. Twenty-five had normal lung CT scans, of whom 23 had a higher inferior petrosal sinus: peripheral ACTH ratio > or = 1.5. After careful follow-up, none was subsequently shown to have ectopic ACTH syndrome. Six had abnormal lung CT scans, of whom two had ratios > or = 1.5. In these two patients, other investigations suggested pituitary disease, and pituitary surgery led to apparent cure. Of the remaining four patients, who had ratios < 1.5, two had incidental lung findings, and pituitary abnormalities were demonstrated at pituitary surgery. The third underwent bilateral adrenalectomy, and no evidence of ectopic ACTH syndrome has emerged as yet after 4 years follow-up. The fourth had a small-cell carcinoma of the lung, confirmed histologically. Our series suggests that whole-lung CT scanning is only necessary in cases of ACTH-dependent Cushing's syndrome where bilateral inferior petrosal sinus sampling has not demonstrated a significant increase in petrosal sinus ACTH levels as compared with the peripheral level. Thus, in our experience the test is now only necessary in those patients (approximately 25%) where the ratio is < or = 1.5.

ACTH Syndrome, Ectopic↗
PubMed1999

Relationship of endothelial function to birth weight in humans.

OBJECTIVE: Low birth weight has been associated with hyperlipidemia, hypertension, diabetes, and coronary heart disease in adult life, but the precise mechanism is debated. The endothelium is thought to play a pivotal role in each of the above conditions with abnormalities being detectable before the development of overt disease. To investigate the possibility that endothelium has a role in mediating the excessive risk of adult vascular disease associated with low birth weight, endothelial function was assessed in young healthy adults who were either of low or normal birth weight at term. RESEARCH DESIGN AND METHODS: Twelve low birth weight (2.2 +/- 0.05 kg, mean +/- SEM) subjects (six men/six women; age 28 +/- 0.2 years) and twelve age- and sex-matched normal birth weight (3.3 +/- 0.07 kg) control subjects were studied. The L-arginine-nitric oxide pathway was assessed in the forearm vascular bed by using venous occlusion plethysmography during intra-arterial brachial infusion of acetylcholine, sodium nitroprusside, norepinephrine, and NG-monomethyl-L-arginine (L-NMMA). Von Willebrand factor, a noninvasive marker of endothelial dysfunction, was also measured. Comparisons were made using Student's t test. RESULTS: Von Willebrand factor was significantly elevated in low birth weight compared with normal birth weight subjects (136.9 +/- 12.7 vs. 95.6 +/- 9.5%; P = 0.016). The groups did not differ in the responses to acetylcholine (P = 0.76), sodium nitroprusside (P = 0.84), norepinephrine (P = 0.21), or L-NMMA (P = 0.35). CONCLUSIONS: The finding of elevated von Willebrand factor in low birth weight subjects is suggestive of endothelial cell injury but does not appear to be associated with dysfunction of the L-arginine-nitric oxide pathway.

Acetylcholine↗
PubMed1999

Basal nitric oxide production is impaired in offspring of patients with essential hypertension.

There is considerable evidence that endothelium-dependent nitric oxide (NO)-mediated vasodilatation in response to acetylcholine is impaired in essential hypertension, whereas the endothelium-independent response to sodium nitroprusside is normal. More limited data have suggested that there is also reduced vasoconstriction in response to N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of basal NO release. As it is not known whether endothelial dysfunction in hypertension, if indeed present, is a cause or consequence of the condition, we have studied the normotensive offspring of parents with essential hypertension. Both basal and stimulated vascular responses were examined in 12 normotensive offspring [mean age (+/-S.E.M.) 26.1+/-1.4 years] of parents with essential hypertension and compared with those in 12 age-matched offspring (mean age 25.6+/-1.1 years) of normotensive subjects. Forearm blood flow was measured simultaneously in both arms by venous occlusion plethysmography, both at baseline and during intra-arterial brachial infusion of increasing doses of acetylcholine, sodium nitroprusside, noradrenaline and L-NMMA. There were no significant differences between the groups in the responses to acetylcholine, sodium nitroprusside or noradrenaline. In contrast, the vasoconstrictor response to L-NMMA was significantly blunted in the offspring of hypertensive parents compared with that in the offspring of normotensive parents (P=0.005). Thus endothelial dysfunction, as demonstrated by impaired basal production of NO, is present in subjects at high risk of essential hypertension, and does not occur simply as a consequence of the condition.

Acetylcholine↗
PubMed1998

Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study.

Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10-year prospective natural history study of 432 newly diagnosed diabetic patients aged 40-69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2-4, 67 patients in years 5-7, and 51 patients in years 8-10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta-cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta-cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups.

Adult↗