Search PubMed⌕ Search

Biomedical subjects

J M Connell

Publications and source records attributed to J M Connell.

At least 73 records · Page 4Linked to original sources
PubMed1997

Specific insulin assays, insulin sensitivity and blood pressure.

Serum insulin concentrations have been used as markers of insulin resistance in population studies examining the relationship between insulin resistance and blood pressure, but the relationship is variable among studies. We hypothesized that differences in cross-reactivity of insulin assays with proinsulin and its split/des-amino products might account for the variation. We therefore examined fasting and post-glucose load serum insulin concentrations (determined by both specific and conventional assays), insulin sensitivity (measured by the euglycaemic clamp technique), and blood pressure, in a group of 56 diabetic (NIDDM) and non-diabetic subjects. Insulin concentrations as measured by the two methods were highly correlated (r = 0.97, p < 0.0001), and the relationships among serum insulin concentrations, insulin sensitivity and blood pressure were independent of assay method; for example, in non-diabetic subjects the univariate correlation between log10AUC insulin and insulin sensitivity index was similar with both methods [r = -0.81 vs. r = -0.82, p < 0.0001 (specific vs. conventional assay)]. Discrepancies between studies in the relationship between serum insulin concentrations and blood pressure are unlikely to be due to cross-reactivity of conventional insulin assays with proinsulin-like molecules.

Adult↗
PubMed1997

The euglycaemic hyperinsulinaemic clamp: an evaluation of current methodology.

1. The recognition of the role of insulin resistance in disease states and the recent development of new drugs that modify insulin-dependent metabolism has led to increased use of the euglycaemic hyperinsulinaemic clamp to measure in vivo insulin sensitivity, but several key aspects of the technique are poorly documented in the literature. 2. We have evaluated the reproducibility and intersubject variation of measurements of insulin sensitivity in groups of insulin-sensitive and insulin-resistant subjects and assessed the effects of hand warning on haemodynamic and metabolic responses. 3. Subjects participated in one of two protocols: (i) 18 healthy male volunteers and 18 patients with hypertension and glucose intolerance were clamped on two occasions, 1 week apart with measurements of insulin sensitivity (M) derived after 120 and 180 min of hyperinsulinaemia; and (ii) six healthy volunteers were clamped on one occasion with simultaneous sampling of antecubital and 'arterialized' (dorsal hand) venous blood for comparison of plasma glucose concentrations and oxygen saturation and a further six volunteers were clamped on two occasions with and without the use of hand warming. 4. Measurements of M derived after 120 min (M120) and 180 min (M180) of hyperinsulinaemia were reproducible: the coefficients of repeatability (mg/kg per min) of M120 and M180 were 1.0 and 0.9 for volunteers and 1.0 and 1.0 for the patient group, respectively. The intersubject variation in insulin stimulus was high: coefficients of variation for M180 were 22% for volunteers compared with 38% for the patient group. In volunteers compared with the patient group, hand warming significantly increased venous oxygen saturations (95 +/- 2 vs 79 +/- 18%, respectively) and glucose concentrations (5.2 +/- 0.2 vs 4.5 +/- 0.4 mmol/L, respectively) and measurements of M were significantly higher using arterialized compared with antecubital venous blood. However, local hand warming was associated with systemic vasodilatation: blood pressure decreased (e.g. 6 mmHg diastolic; P < 0.05) with a compensatory increase in heart rate (8 b.p.m.). 5. In conclusion, clamps of 120 and 180 min duration yielded measurements of M that were reproducible. The technique is much more robust when used in the context of a crossover design because of the significant (20-40%) intersubject variation in M, even among apparently homogeneous male volunteers. Hand warming effectively arterializes venous blood and gives significantly higher M values, but induces systemic vasodilation, which may confound measurements of M.

Adult↗
PubMed1997

The effect of nebulized albuterol on the activity of the renin-angiotensin system in asthma.

STUDY OBJECTIVE: We have previously described activation of the renin-angiotensin system (RAS) in acute severe asthma and have also reported activation of the RAS in normal subjects by single doses of nebulized beta 2-agonists. In the present study, we have examined the effect of single and multiple doses of nebulized albuterol on the activity of the RAS in mild asthma. DESIGN: Eight patients with mild asthma were studied. The effect of single and multiple doses of nebulized albuterol (5 mg) on the activity of the RAS was compared with that of placebo using a randomized, double-blind crossover study design. Nebulized drugs were administered at time 0 and 30 min. MEASUREMENTS: Plasma renin, angiotensin II (Ang II), and serum potassium levels were measured at baseline following a short rest, and thereafter at intervals up to 150 min. RESULTS: Renin levels increased after both the single (S) and double (D) nebulized doses of albuterol and were significantly greater than placebo at 30 min after S, and at 45 and 120 min after D. Plasma Ang II level also increased after S and D and was significantly greater than placebo at 30 and 45 min after S, and at 30 min and all timepoints thereafter following D. In addition, the effect of D was significantly greater than S at 45 min. CONCLUSIONS: These results confirm that there is activation of the RAS in asthmatic subjects by single doses of nebulized beta 2-agonists and that repeated dosing with nebulized albuterol has further, additive effects on plasma Ang II levels. It therefore seems likely that these agents are contributing to activation of the RAS in acute asthma, although the exact clinical significance of these transient changes in plasma Ang II levels in asthma is at present unclear.

Adrenergic beta-Agonists↗
PubMed1996

Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease.

BACKGROUND: Insulin sensitivity varies up to threefold in apparently healthy individuals, but the mechanism for this is unknown. We have examined the hypothesis that vascular endothelial nitric oxide production and insulin sensitivity are directly related in humans. METHODS AND RESULTS: Nineteen healthy male subjects were studied on 3 separate days 1 week apart during which time they underwent measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (soluble insulin 1.5 mU . kg-1 . min-1) and measurement of in vivo basal and stimulated endothelial nitric oxide production by forearm venous occlusion plethysmography. There was a correlation between insulin sensitivity and forearm vasoconstrictor responses to NG-monomethyl-L-arginine, the substrate inhibitor of nitric oxide synthase (r = .52, P < .05). No correlations were observed between insulin sensitivity and noradrenaline, acetylcholine, or sodium nitroprusside responses. CONCLUSIONS: Endothelial nitric oxide synthesis and insulin sensitivity are positively related in healthy humans, which suggests a direct physiological link.

Acetylcholine↗
PubMed1996

Potential confounding effect of hand-warming on the measurement of insulin sensitivity.

1. Hand-warming is employed during metabolic studies to "arterialize' venous blood, but also has systemic haemodynamic effects. Study 1 aimed to determine if hand-warming affects the value for whole-body insulin sensitivity derived from the hyperinsulinaemic euglycaemic clamp technique. Study 2 was designed to assess the effect of hand-warming on contralateral forearm blood flow. 2. In study 1, eight healthy male subjects attended for four modified euglycaemic clamp studies, during which the right hand was placed in a heated-air hand box (55 degrees C), and the glucose infusion rate was adjusted according to blood samples from a cannula in either an ipsilateral dorsal hand vein or a contralateral antecubital vein with the box switched either on or off. In study 2, five healthy subjects attended two study days when the effect of 2 h of hand-warming (or control) on contralateral forewarm blood flow was measured. 3. Study 1; when clamps were performed according to samples taken from the contralateral antecubital vein, insulin sensitivity values were significantly lower during box-on versus box-off clamps (mean +/- SD 10.2 +/- 3.0 versus 13.0 +/- 3.8 mg min-1 kg-1, P < 0.05, 95% confidence interval -0.2, -5.3). When clamps were performed according to samples taken from the ipsilateral hand, there was no difference in insulin sensitivity during box-on versus box-off clamps (9.2 +/- 2.1 versus 9.0 +/- 1.7 mg min-1 kg-1, P not significant, 95% confidence interval -0.5, +0.9). There was a mean increase in heart rate of 6 beats/min in the box-on conditions (P < 0.05, analysis of variance). Study 2; forearm blood flow in the contralateral arm during hand-warming was significantly higher than in the control condition (P < 0.05, analysis of variance), although heart rate was similar on both study days. 4. Hand-warming had a detectable effect on insulin sensitivity when clamps were performed according to samples withdrawn from the contralateral arm, but no measurable effect when clamps were performed in the conventional manner. In addition, hand-warming increased heart rate during hyperinsulinaemia and contralateral FBF under basal conditions. These findings raise concern about unwanted (potentially confounding) systemic haemodynamic effects of hand-warming on the measurement of insulin sensitivity and insulin-mediated vasodilation.

Blood Glucose↗
PubMed1996

11 beta-Hydroxylase activity in glucocorticoid suppressible hyperaldosteronism: lessons for essential hypertension?

Corticosteroid 11 beta-hydroxylation is catalysed by 11 beta-hydroxylase and aldosterone synthase. Using plasma steroid ratios, the level of this process in patients with glucocorticoid-suppressible hyperaldosteronism (GSH) was compared with that in unaffected control subjects and in patients with Conn's syndrome. Based on both 11-deoxycortisol:cortisol (S:F) and 11-deoxycorticosterone:corticosterone (DOC:B) ratios, patients with GSH showed impaired resting 11 beta-hydroxylase activity. In GSH, but not in the other groups, the S:F ratio was significantly correlated with basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all these patient groups, suggesting a common partial deficiency. The results also indicate that 11 beta-hydroxylation may be rate-limiting in normal subjects. In control subjects and patients with Conn's syndrome, the DOC:B ratio was not affected by ACTH. However, in GSH patients, this ratio fell markedly, indicating an increased efficiency of 11 beta-hydroxylation of DOC (but not S). This may be due to the activation by ACTH of the zona fasciculata chimaeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone and DOC concentrations, appeared to be more sensitive to ACTH in GSH than the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in the condition, and may contribute to the phenotypic variability.

Adrenocorticotropic Hormone↗
PubMed1996

Corticosteroids in essential hypertension: multiple candidate loci and phenotypic variation.

1. The role of genetically determined changes in adrenal steroid production, metabolism and action in the pathogenesis of cardiovascular disease in man is considered by studying three loci that are important in corticosteroid function. 2. Variation at the glucocorticoid receptor locus can be identified as a biallelic restriction fragment length polymorphism (Bcl1); subjects with contrasting genotypes show altered skin vasoconstrictor responses to topically applied budesonide without any significant change in leucocyte receptor binding characteristics. 3. In a case control study of patients with essential hypertension, we have shown evidence of reduced 11 beta-hydroxysteroid dehydrogenase activity, with an elevated ratio of cortisol to cortisone metabolites in urine. 4. The genes encoding 11 beta-hydroxylase and aldosterone synthase are highly homologous. Studies in the Milan hypertensive rat show variation at this locus, which may account for the increased steroid synthesis noted in the hypertensive strain; in man, a chimaeric gene comprising 5' regulatory regions from 11 beta-hydroxylase and 3' coding sequence from aldosterone synthase accounts for the autosomal dominant condition Dexamethasone Suppressible Hyperaldosteronism. Variation in the precise location of the crossover site between the two genes does not account for the observed phenotypic heterogeneity in this condition. 5. Measurement of basal plasma steroid levels in subjects with essential hypertension show an increased ratio of 11-deoxycortisol/cortisol, consistent with reduced activity of 11 beta-hydroxylase in the zona fasciculata. 6. In summary, three loci involved in corticosteroid synthesis, metabolism and action can independently affect cardiovascular phenotypes; their roles in determining pathophysiological changes, including hypertension, remain to be studied.

Adrenal Cortex Hormones↗
PubMed1996

Sodium status, corticosteroid metabolism and blood pressure in normal human subjects and in a patient with abnormal salt appetite.

1. A patient with severe hypertension was found to have mildly impaired 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activity on the basis of urinary steroid metabolite ratios, low plasma aldosterone, angiotensin II and renin levels and marginally low levels of plasma potassium. 2. The patient also had a compulsively high salt intake. 3. We tested the hypothesis that high salt intake may affect 11 beta-HSD activity. 4. High salt intake in normal subjects did not significantly alter either blood pressure or 11 beta-HSD activity. 5. We suggest that the potentially small hypertensive effect of the partial enzyme deficiency in our patient, also reported in patients with essential hypertension, has been markedly amplified by the very high salt intake.

Adrenal Cortex Hormones↗
PubMed1996

The role of genetic polymorphisms of angiotensin-converting enzyme in the progression of renal diseases.

The renin-angiotensin system is likely to be important in the progression of renal diseases because of its effect on tissue hemodynamics and glomerular cell function. Recent evidence from small studies has suggested a possible role for the genetic determinants of angiotensin converting enzyme activity in the rate of progression of renal failure. We studied the effect of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene on the rate of renal function deterioration in 822 patients with a variety of renal diseases. We found that the slope of the reciprocal serum creatinine-versus-time plot was steeper in patients homozygous for the deletion allele (DD) compared with those homozygous for the insertion allele (II) (P = .015). When patients with similar renal function at presentation (creatinine < 200 mumol/L) were compared, II homozygotes had significantly improved renal survival (P = .039). Separate analyses of patients with glomerular diseases and tubulointerstitial diseases demonstrated an effect of this genotype in glomerular diseases only. These data provide further evidence of the possible role of the angiotensin-converting enzyme gene in the rate of progression of renal failure, although further studies are required to evaluate the role of this and other proposed candidate genes in renal diseases.

Adolescent↗
PubMed1996

Altered 11 beta-hydroxylase activity in glucocorticoid-suppressible hyperaldosteronism.

Corticosteroid 11 beta-hydroxylation is catalyzed by 11 beta-hydroxylase and aldosterone synthase. Using plasma steroid ratios, the level of this process in patients with glucocorticoid-suppressible hyperaldosteronism (GSH) was compared with that in unaffected control subjects and patients with Conn's syndrome. Based on both 11-deoxycortisol/cortisol (S:F) and 11-deoxycorticosterone/corticosterone (DOC:B) ratios, patients with GSH showed impaired resting 11 beta-hydroxylase activity. In GSH, but not in the other groups, the S:F ratio was significantly correlated with the basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all of these patient groups, suggesting a common partial deficiency. The results also indicate that 11 beta-hydroxylation may be rate limiting in normal subjects. In control subjects and patients with Conn's syndrome, the DOC:B ratio was not affected by ACTH. However, in GSH patients, this ratio fell markedly, indicating an increased efficiency of 11 beta-hydroxylation of DOC (but not S). This may be due to the activation by ACTH of the zona fasciculata chimeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone, and DOC concentrations appeared to be more sensitive to ACTH in GSH than in the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in this condition and may contribute to the phenotype variability.

Adrenal Cortex Neoplasms↗
PubMed1996

Mistyping of the human angiotensin-converting enzyme gene polymorphism: frequency, causes and possible methods to avoid errors in typing.

A polymorphism of the gene encoding the human angiotensin I-converting enzyme (ACE), which is defined by an insertion/deletion polymorphism in intron 16, has been identified as a candidate genetic locus in the development of cardiovascular and renal disease. We have demonstrated that the accuracy of ACE genotyping is critically dependent on the strategy of the PCR used in typing. Of 1238 individuals genotyped by a standard method, 335 were typed as DD, 645 as DI and 258 as II. However, when DD individuals were retyped using modified methods (including either 5% dimethyl sulphoxide, or a 'hot start') 35 of the original 335 samples (10.5%) were retyped as DI. In approximately half of these mistyped samples, PCR amplification was assessed as inefficient by the absence of a third faint heteroduplex band in a control ID sample: when the assay was repeated without any modifications, the mistyped samples were correctly genotyped. In the remainder, mistyping persisted. In these cases, the use of a third 'nested' PCR primer specific for the I allele was required for successful genotyping, providing a more reliable strategy without the need for further modification to the PCR technique. Our results suggest that the triple primer approach is the method of choice for accurate ACE genotyping.

Dimethyl Sulfoxide↗
PubMed1995

Polymorphisms in angiotensin-converting-enzyme gene and progression of IgA nephropathy.

We have investigated the influence of the functional insertion (I) and deletion (D) polymorphism in intron 16 of the gene for angiotensin-converting enzyme (ACE) in a retrospective study of 100 patients with IgA nephropathy. There was no difference in genotype frequency compared with normal subjects. However, patients homozygous for the D allele tended to present at an earlier age (medians: DD, 33; ID, 34; II, 42 years) and to require renal replacement therapy at a younger age (medians 37, 42, and 48 years, respectively). The rate of progression was significantly worse in patients homozygous for the D allele. The DD genotype is associated with increased severity of disease in patients with IgA nephropathy.

Adult↗
PubMed1995

Colonic adenocarcinoma associated ectopic ACTH secretion: a case history.

A 57-year-old woman developed features of Cushing's syndrome after resection of a Duke's C adenocarcinoma of the sigmoid colon. Biochemical and endocrine investigation indicated ectopic production of adrenocorticotrophic hormone (ACTH) as the cause for her condition. Hepatic metastases were detected by computed tomography (CT) scan. Histology of the original tumour displayed neuroendocrine characteristics but no definite evidence of ACTH synthesis. Treatment was instituted to control her hypercortisolism, and chemotherapy initiated to reduce the production of ectopic hormone. A clinical, biochemical and radiological response was obtained with complete resolution of her Cushing's syndrome. The tumour relapsed after several months with distant metastases, but no further endocrine abnormality was noted. A review of ectopic ACTH producing adenocarcinoma is given along with a discussion of the major pathological and therapeutic features of the case.

ACTH Syndrome, Ectopic↗
PubMed1995

Glucocorticoid-suppressible hyperaldosteronism: effects of crossover site and parental origin of chimaeric gene on phenotypic expression.

1. Genetic analysis of five kindreds with glucocorticoid-suppressible hyperaldosteronism, four of whom had not been subjected to any previous genetic analysis, revealed three different crossover breakpoints within the five kindreds clustered in the exon 3-intron 4 region of the chimaeric gene. The site of the crossover point had no effect on blood pressure within the kindreds studied. 2. The gene causing glucocorticoid-suppressible hyperaldosteronism was in strong linkage disequilibrium with an allele of a newly described restriction enzyme polymorphism of the aldosterone synthase gene promoter region, suggesting a possible role for this allele in the development of the chimaeric gene. 3. A novel observation on subjects inheriting glucocorticoid-suppressible hyperaldosteronism from their mothers showed that they had significantly higher plasma aldosterone concentrations and mean arterial blood pressures than those inheriting glucocorticoid-suppressible hyperaldosteronism from their fathers. 4. These results raise the possibility that chronic exposure in utero to elevated plasma aldosterone concentrations may result in the permanent programming of mineralocorticoid-dependent blood pressure regulatory mechanisms, which is amplified in later life by the elevated plasma aldosterone concentrations found in glucocorticoid-suppressible hyperaldosteronism.

Adolescent↗