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Biomedical subjects

C J Mathias

Publications and source records attributed to C J Mathias.

At least 19 recordsLinked to original sources
PubMed1992

Growth hormone response to clonidine in central and peripheral primary autonomic failure.

Patients with primary autonomic failure may have either pure autonomic failure (PAF) or multiple system atrophy (MSA) in which there is additional neurological involvement. Distinction between PAF and MSA at an early stage is important because a wide range of complications is associated with MSA, which has a poor response to drug therapy and a less favourable prognosis. We have investigated the growth hormone (GH) releasing effects of clonidine in patients with PAF and MSA to see whether this hormonal response could serve as a neuroendocrine marker to distinguish between the groups. Age-matched normal subjects were studied as controls. Both groups of patients had severe postural hypotension due to primary sympathetic failure of presumed central origin in MSA and peripheral origin in PAF. After clonidine, plasma GH concentrations increased in controls and PAF, with no change in MSA. Changes in plasma glucose and insulin concentrations were similar in all groups. Clonidine, therefore, stimulates growth hormone release in PAF but not MSA and may serve as a neuroendocrine marker in differentiating patients with MSA and a central autonomic defect from those with PAF with a peripheral defect.

Adult↗
PubMed1992

Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography.

Equilibrium striatal: cerebellar 11C-raclopride (RAC) uptake ratios reflect the density of striatal dopamine D2 binding sites. Using positron emission tomographic scanning we have measured striatal RAC uptake in 6 untreated patients with Parkinson's disease (PD), 5 chronically treated patients with PD and a fluctuating response to L-dopa, 10 patients with striatonigral degeneration (SND), and 9 patients with progressive supranuclear palsy (PSP). Regional cerebral blood flow was determined also, with C15O2. Mean striatal: cerebellar RAC uptake was not significantly different from normal in untreated patients with PD, though 2 of these 6 patients showed significantly increased putamen tracer binding. Mean caudate and putamen: cerebellar RAC uptake ratios of the group with PD and a fluctuating response to L-dopa were significantly reduced by 30% and 18%, respectively. The patients with SND had lesser, but significant, 10% and 11% decreases in mean caudate and putamen: cerebellar RAC uptake ratios, respectively, whereas patients with PSP showed 24% and 9% reductions in caudate and putamen: cerebellar RAC binding. Striatal and frontal blood flow were significantly reduced in patients with PSP, but not in patients with PD or SND. In conclusion, striatal D2 binding potential is normal or raised in untreated patients with PD, but reduced in patients with PD and a fluctuating response to L-dopa. Patients with SND and PSP show a decrease in striatal RAC binding, but to a lesser extent than patients with PD and a fluctuating response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Up-regulation of beta-adrenoceptors on circulating mononuclear cells after reduction of central sympathetic outflow by clonidine in normal subjects.

Short term regulation of beta-adrenoceptors in peripheral blood mononuclear cells after sympathetic activation has been previously documented in normal individuals but changes after a central reduction in sympathetic activity are not known. We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells in normal subjects, before and after intravenous clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine there was a decrease in plasma levels of noradrenaline and adrenaline, and an increase in growth hormone. There was up-regulation of beta-adrenergic receptors on peripheral blood mononuclear cells 30 and 60 min after clonidine which was related to the fall in blood pressure, noradrenaline and adrenaline levels and to the increase in growth hormone levels. The affinity of the receptors was decreased. Return to baseline values was observed after 2 h. Intracellular production of cAMP after isoproterenol stimulation demonstrated that the up-regulation was not functional. Our studies indicate short term up-regulation of beta-adrenoceptors in peripheral blood mononuclear cells after clonidine. These observations after a reduction in sympathetic activity may be of importance if they mirror the pattern of redistribution of adrenoceptors, which are present in a wide range of tissues.

Adult↗
PubMed1992

Increased gut parasympathetic activity and chronic diarrhoea in a patient with the acquired immunodeficiency syndrome.

A 25-year-old homosexual man with a 2-year history of watery diarrhoea and a 20 kg weight loss is described. He had been diagnosed HIV-1 antibody positive 6 years previously. Investigations excluded opportunist pathogens and other known causes of diarrhoea. A range of anti-diarrhoeal medication had been unsuccessful. Plasma levels of gastrointestinal and pancreatic peptides were normal and treatment with the somatostatin analogue, octreotide, which inhibits release of pancreatic/gut peptides, did not provide any benefit. Cardiovascular autonomic function tests revealed blunted pressor responses but no other abnormalities. Gastric emptying studies with a technetium labelled meal indicated rapid gastric emptying time. This was slowed by the anticholinergic drug, atropine. This suggested increased parasympathetic activity to the gut. He was, therefore, treated with the anti-cholinergic agent, propantheline bromide, which reduced the frequency and volume of stools. He put on weight and has remained well since. This case highlights the diagnostic challenge in HIV-associated chronic diarrhoea, the case for investigations of autonomic function, and the need for a therapeutic trial of anticholinergic drugs, when other measures have failed.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Fluorine-substituted corticosteroids: synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain.

We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11 beta-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.

Adrenal Cortex Hormones↗
PubMed1992

Differential responses in superior mesenteric artery blood flow may explain the variant pressor responses to clonidine in two groups with sympathetic denervation.

1. Measurement of superior mesenteric artery blood flow along with systemic and regional haemodynamic changes in blood pressure, heart rate, cardiac index, forearm blood flow, digital skin blood flow and index finger temperature were made before and after administration of clonidine (2 micrograms/kg body weight intravenously) in 10 patients with multiple-system atrophy, 10 patients with pure autonomic failure and 15 age-matched healthy control subjects. 2. After clonidine, blood pressure fell in patients with multiple-system atrophy and control subjects but not in patients with pure autonomic failure. 3. Resting superior mesenteric artery blood flow was similar in patients with multiple-system atrophy and control subjects, but was higher in patients with pure autonomic failure. The fall in blood pressure after clonidine was accompanied by active dilatation of the superior mesenteric artery in patients with multiple-system atrophy and control subjects. This did not occur in patients with pure autonomic failure. 4. After clonidine, there was a fall in cardiac index in patients with multiple-system atrophy. 5. After clonidine, changes in other haemodynamic parameters were not significant in any group, except for a fall in forearm blood flow and a rise in index finger temperature in control subjects. 6. We conclude that after clonidine there are differential superior mesenteric artery blood flow responses in the two groups with autonomic failure (multiple-system atrophy and pure autonomic failure). These may relate to differences in the site of the sympathetic lesion, which is considered to be mainly central in multiple-system atrophy but peripheral in pure autonomic failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Abnormality of superior mesenteric artery blood flow responses in human sympathetic failure.

1. Systemic and regional haemodynamic responses, including superior mesenteric artery blood flow, were measured during stimuli which increase sympatho-neural activity in age-matched normal subjects (controls) and in two groups of patients with sympathetic failure (pure autonomic failure and multiple system atrophy). The stimuli included the pressor tests (mental arithmetic, cutaneous cold and isometric exercise) and head-up tilt. 2. In the controls, the blood pressure did not rise in some during mental arithmetic, but rose in all subjects during cutaneous cold and isometric exercise and was maintained during head-up tilt. In sympathetic failure patients, blood pressure was unchanged during each pressor test and fell during head-up tilt. 3. In the controls, superior mesenteric artery blood flow did not fall significantly during mental arithmetic but fell (with a corresponding rise in calculated superior mesenteric artery vascular resistance), during cutaneous cold, isometric exercise and head-up tilt. In sympathetic failure patients, there were no changes in superior mesenteric artery blood flow and vascular resistance during the pressor tests and head-up tilt. 4. There were no changes in cardiac index or forearm blood flow during each pressor test in both controls and patients. Cardiac index fell and forearm vascular resistance rose during head-up tilt in the controls only. 5. In conclusion, active constriction of the superior mesenteric artery occurs in normal subjects during sympatho-neural activation induced by stimuli such as cutaneous cold, isometric exercise and head-up tilt. This does not occur in patients with sympathetic failure and probably contributes to postural hypotension, emphasizing the role of the splanchnic vascular bed in overall blood pressure control. This study confirms the necessity of integrity of sympathetic pathways in the neural control of the splanchnic vascular bed.

Adult↗
PubMed1992

The cardiovascular, endocrine and renal response of tetraplegic and paraplegic subjects to dietary sodium restriction.

1. The effects of change from a high to low sodium diet upon renal sodium and water excretion and hormone responses were studied in patients with dissociated sympathetic control (DS, tetraplegic) and controls with sympathetic control largely intact (IS, paraplegic). 2. Total and fractional urinary sodium excretion fell in response to sodium restriction in both groups, but the fall in fractional sodium excretion was greater in the DS group compared with the IS group (DS, 1.34 +/- 0.12 to 0.42 +/- 0.05%; IS, 0.96 +/- 0.08 to 0.52 +/- 0.06%). 3. Supine mean arterial pressure fell during the low salt period in the DS group (80.2 +/- 2.7 to 74.4 +/- 2.3 mmHg) but was unaffected by salt restriction in the IS group (101 +/- 2.3 to 98.8 +/- 2.7 mmHg). In the DS group, creatinine clearance remained constant throughout the low salt period (103.7 +/- 7.9 to 98.3 +/- 9.7 ml min-1), but fell during salt restriction in the IS group (101.4 +/- 8.5 to 83.2 +/- 5 ml min-1). 4. Plasma renin activity was lower during salt loading in DS subjects but increased more rapidly and to higher levels in response to salt restriction (DS, 1021 +/- 142 to 4439 +/- 355; IS, 1765 +/- 269 to 3683 +/- 465 pg angiotensin I ml-1 h-1). Plasma atrial natriuretic peptide concentration was higher in the DS group during salt loading and salt restriction (DS, 37.6 +/- 5.6 to 22 +/- 3.8; IS, 20.2 +/- 2.3 to 11 +/- 1.6 pg ml-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

New autonomic and sensory neuropathy with loss of adrenergic sympathetic function and sensory neuropeptides.

A 30-year-old woman with longstanding dizziness was found to have a severe postural fall in blood pressure and a reduced skin axon-reflex flare response. Autonomic tests indicated selective impairment of adrenergic sympathetic function. Plasma noradrenaline, adrenaline, dopamine, and dopamine beta hydroxylase were undetectable. Skin biopsy specimens showed loss of tyrosine hydroxylase and neuropeptide Y (markers of adrenergic sympathetic fibres) and of substance P and calcitonin gene-related peptide (sensory neuropeptides). A sural nerve biopsy specimen showed severe depletion of unmyelinated fibres. The constellation of losses were compatible with nerve growth factor (NGF) deprivation, which was confirmed on assay. This new syndrome may be explained by loss of trophic action of NGF.

Adrenergic Fibers↗
PubMed1991

The sympathetic nervous system in hypertension due to unilateral renal artery stenosis in man.

The contribution of neurogenic mechanisms in maintaining hypertension was investigated in 13 patients with unilateral renal artery stenosis (twelve with normal, one with grossly elevated plasma renin levels) by determining the haemodynamic and hormonal responses to the centrally acting sympatholytic agent, clonidine. The same patients were studied after captopril to determine the dependency of their blood pressure on the direct peripheral effects of angiotensin-II. Sixteen patients with essential hypertension (normal plasma renin) were additionally studied after clonidine. After clonidine, blood pressure fell markedly in patients with renal artery stenosis (17 +/- 3%) and essential hypertension (18 +/- 2%). In both groups, clonidine lowered cardiac output by a reduction in stroke volume and heart rate; forearm vascular resistance was unchanged but digital skin vascular resistance fell. Plasma noradrenaline levels were normal in both groups and fell after clonidine; plasma renin activity and aldosterone levels were unchanged. After captopril, blood pressure fell minimally (5 +/- 3%) in renal artery stenosis patients; cardiac output fell and forearm and digital skin vascular resistance were unchanged. Plasma renin activity rose, plasma aldosterone fell and plasma noradrenaline was unchanged after captopril. In the patient with grossly elevated renin levels, blood pressure fell minimally (6%) after clonidine, but unlike others fell profoundly (37%) after captopril. We conclude that, in the majority of our renal artery stenosis patients, despite the elevated blood pressure, sympathetic nervous activity was not reduced. Central neurogenic mechanisms appear to play an important role in maintaining raised blood pressure. In the same patients the peripheral effects of angiotensin-II did not maintain vascular tone or hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Noninvasive quantification of superior mesenteric artery blood flow during sympathoneural activation in normal subjects.

The role of the splanchnic circulation in normal subjects during sympathoneural activation induced by stimuli which either raise (mental arithmetic, cold pressor test, isometric exercise) or maintain (head-up tilt) blood pressure has been studied by measuring superior mesenteric artery blood flow using a noninvasive Doppler ultrasound method in 18 normal subjects. Cardiac, systemic and regional haemodynamic changes were simultaneously studied. Blood pressure rose with the pressor tests and was maintained with head-up tilt. There was a significant fall in superior mesenteric artery blood flow with a rise in vascular resistance during each stimulus indicating active constriction. In six subjects, after 2 months measurements were repeated in an identical study. Superior mesenteric artery blood flow measurements in this study were closely correlated with the initial results. These changes, in a large vascular bed, are likely to be of importance in the overall haemodynamic response during sympathoneural stimuli which either raise or maintain blood pressure.

Adult↗
PubMed1991

The effects of the somatostatin analogue, octreotide, on postural hypotension, before and after food ingestion, in primary autonomic failure.

The effects of the somatostatin analogue, octreotide on postural hypotension have been compared with placebo, before and after food ingestion in two groups with primary autonomic failure; patients with pure autonomic failure, and patients with additional neurological involvement as part of multiple system atrophy. After placebo, supine blood pressure was unchanged, but after octreotide, it rose in both groups. Octreotide reduced pre-prandial postural and supine post-prandial hypotension in both pure autonomic failure and multiple system atrophy patients. Postural hypotension post-prandially was considerably worse after placebo; this was reduced after octreotide. Plasma noradrenaline and adrenaline levels remained unchanged. Plasma glucose levels rose higher and faster after placebo. Insulin levels were similar in both groups at rest, but rose higher in patients with pure autonomic failure after placebo. After octreotide, the insulin response in both groups was suppressed. We conclude that octreotide prevents post-prandial hypotension in both groups with primary autonomic failure and additionally reduces postural hypotension both before and after food ingestion. The greater rise in insulin levels in patients with pure autonomic failure suggests that insulin may be a contributing factor to the more severe post-prandial hypotension observed in this group of patients.

Adult↗
PubMed1991

Value of non-invasive continuous blood pressure monitoring in the detection of carotid sinus hypersensitivity.

A patient with recurrent episodes of dizziness and blackouts is described. Detailed cardiac and neurological investigations were normal. Autonomic assessment excluded postural hypotension and confirmed normal sympathetic vasoconstrictor function. Cardiac parasympathetic function in response to deep breathing, hyperventilation and ocular pressure was normal. Left carotid sinus massage only reproducibly lowered blood pressure with minimal change in heart rate. This occurred mainly during head-up tilt. The fall in blood pressure was not affected by the muscarinic blocker atropine, or the peptide release inhibitor, octreotide. A diagnosis of left carotid sinus hypersensitivity of the vasodepressor variety was made. Left carotid sinus denervation was performed. This successfully prevented further episodes of dizziness and blackouts. The ability to measure beat-to-beat blood pressure non-invasively was of particular importance in diagnosis, and in the assessment of management options in this patient.

Blood Pressure Determination↗
PubMed1991

Investigation of copper-PTSM as a PET tracer for tumor blood flow.

Copper-PTSM has been shown in previous studies to act as a fluid microsphere and to be useful in quantitating blood flow in brain, myocardium, and kidneys. In this study we have evaluated this agent as a PET tumor blood flow agent. 64Cu- or 67Cu-labeled Cu-PTSM was administered (i.v.) to Golden Syrian hamsters with colorectal carcinoma cell implants (GW39). One minute prior to sacrifice (10-60 min after Cu-PTSM was administered) 125I-iodoantipyrine (125I-IAP), an agent known to measure tumor blood flow, was administered intravenously by a 3-stage, 1 min ramp infusion. Following sacrifice, samples of tumor and brain were removed (within 40s) and the tumor and brain levels of Cu-PTSM and iodoantipyrine determined. Since the brain uptake of both Cu-PTSM and IAP is perfusion rate limited, the brain was used as a reference organ to normalize tumor levels of the two tracers. The plot of Cu-PTSM versus 125I-IAP tumor/brain ratios showed a good linear correlation (r value of 0.97), suggesting that Cu-PTSM could be used to quantify tumor blood flow. Since the mechanism of Cu-PTSM trapping is likely to be due to glutathione levels in the tissue, and because tumor tissue glutathione levels might vary, the temporal uptake of Cu-PTSM was investigated by PET imaging both the tumor-bearing hamsters and approximately 300 g Copenhagen rats bearing R3227 prostate tumors. The tumors were clearly visualized and the retained copper radioactivity in the tumor was constant over the 30 min imaging period.

Animals↗
PubMed1991

Positron labeled muscarinic acetylcholine receptor antagonist: 2- and 4-[18F]fluorodexetimide. Syntheses and biodistribution.

Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexetimide (4-FDEX), were prepared and evaluated in vivo as possible agents for the study of the muscarinic acetylcholine receptor (mAChR) with PET. Two synthetic approaches, a 2-step reductive alkylation procedure and a 4-step alkylation approach, were investigated. The alkylation approach with higher overall radiochemical yields was used to prepare 2- and 4-FDEX for biodistribution studies. The overall synthesis time for both compounds was 2.5 h and the overall radiochemical yield at end-of-synthesis was 12%. The specific activity was found to be greater than 600 mCi/mumol. Biodistribution studies of 2-FDEX in rats produced striatum-to-cerebellum and cortex-to-cerebellum ratios of 8.6 +/- 1.1 and 8.4 +/- 1.0 at 1 h after injection, and 12.1 +/- 2.1 and 10.7 +/- 2.2 at 3 h, respectively. Substantial radioactivity detected in bone indicated the in vivo defluorination of 2-FDEX. The striatum-to-cerebellum ratio for 4-FDEX was slightly lower at 1 h (5.9 +/- 0.9) but equally high at 3 h (12.3 +/- 2.0) when compared to 2-FDEX, and there was little bone uptake. The uptake of both 2-FDEX and 4-FDEX into mAChR rich brain regions (e.g. striatum, cortex) was blocked by a dose of dexetimide (5 mg/kg). Our results suggest 4-FDEX is a potential PET agent for study mAChR in vivo.

Acetylcholine↗
PubMed1991

Evaluation of two new bifunctional chelates for radiolabeling a parathyroid-specific monoclonal antibody with In-111.

BB5-G1, a monoclonal antibody specific for human parathyroid cell membrane antigen was conjugated with two new ligands, BrMe2HBED and Br phi HBED and radiolabeled with 111In. We have compared the biodistribution of 111In-labeled BB5 using the new ligands to conventionally labeled (125I-labeled and 111In-DTPA-labeled) BB5 in a nude mouse model. Both 111In-BrMe2HBED-BB5 and 111In-Br phi HBED-BB5 attained high parathyroid-to-blood and parathyroid-to-muscle ratios by 72-96 h. 111In-Br phi HBED-BB5 showed lower %ID/g than 111In-BrMe2HBED-BB5 in the clearance organs, the liver and kidney; renal activity had cleared significantly by 120 h. This work suggests that 111In-Br phi HBED-BB5 offers improved in vitro behavior and may be useful as a radiopharmaceutical for localizing parathyroid tissue.

Animals↗