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Biomedical subjects

C J Mathias

Publications and source records attributed to C J Mathias.

At least 127 records · Page 7Linked to original sources
PubMed1994

Structure-distribution relationships for metal-labeled myocardial imaging agents: comparison of a series of cationic gallium (III) complexes with hexadentate bis(salicylaldimine) ligands.

A series of 10 cationic gallium(III) complexes with hexadentate bis(salicylaldimine) ligands were synthesized, characterized, radiolabeled with 67Ga, and screened in a rat model to assess their potential as 68Ga radiopharmaceuticals for imaging the heart with positron emission tomography. The tris(salicylaldimine) ligand precursors were synthesized by condensation of either bis(3-aminopropyl)ethylenediamine (BAPEN) or bis(2,2-dimethyl-3-aminopropyl)ethylenediamine (DM-BAPEN) with 3 equiv of a salicylaldehyde derivative containing alkyl, alkoxy, or alkylamino substituents in the 4, 5, or 6 position of the aromatic ring. The cationic six-coordinate gallium(III) bis(salicylaldimine) complexes were obtained by reaction of these tris(salicylaldimines) with tris(acetylacetonato)gallium(III). X-ray crystallographic confirmation of the molecular structure of Ga[(4,6-(MeO)2sal)2DM-BAPEN]+I- shows the Ga cation to adopt a pseudo-octahedral N4O2 coordination sphere with a trans configuration. All of the 67Ga complexes are lipophilic with measured octanol/water partition coefficients (P) varying from log P = 0.84 to 3.00. These 67Ga-labeled complexes are all found to exhibit significant myocardial uptake following intravenous administration to rats (ranging from 0.34 to 1.08% of the injected dose in myocardium at 1 min postinjection) combined with the desired myocardial retention of tracer.

Animals↗
PubMed1994

Alcohol ingestion lowers supine blood pressure, causes splanchnic vasodilatation and worsens postural hypotension in primary autonomic failure.

Patients with pure autonomic failure (PAF) and multiple system atrophy (MSA) may complain of feeling light-headed after alcohol ingestion particularly on assumption of the upright posture. The reasons for this have not been investigated. We therefore studied the effects of oral alcohol (40% vodka in sugar-free orange juice) and placebo (juice only) on the systemic and regional (including superior mesenteric artery, SMA) blood flow in nine patients with PAF and six patients with MSA. After alcohol, there was a fall in supine blood pressure (BP) and vasodilatation in the SMA but no change in cardiac output, or forearm muscle and cutaneous blood flow in either PAF or MSA; BP fell further during head-up tilt with no changes in levels of plasma catecholamines. After placebo, there were no changes while supine. We conclude that alcohol lowers supine BP and dilates the SMA with no change in muscle or cutaneous blood flow. Alcohol also enhances the fall in BP during head-up tilt. This may explain the symptoms experienced by PAF and MSA patients after alcohol.

Adult↗
PubMed1994

Investigation of [67Ga]dimethylgallium(III) acetylacetonate as a potential radiopharmaceutical.

Carrier-added [67Ga]dimethylgallium(III) acetylacetonate, a four coordinate Ga complex with two hydrolytically-stable Ga-C bonds, was prepared at a specific activity of 2.8 mCi/mmol. The biodistribution of this tracer was determined following intravenous injection into rats as a 5% ethanol: 19% propylene glycol solution in saline. Although the myocardial levels of 67Ga were fairly constant over a 2 h time period (%ID/heart = 0.80 +/- 0.19, 0.67 +/- 0.04 and 0.62 +/- 0.07 at 1.30 and 120 min post-injection, respectively), somewhat slow clearance of activity from the blood would preclude the use of this organometallic gallium complex as a myocardial imaging agent.

Animals↗
PubMed1994

Evaluation of Cu-PTSM as a tracer of tumor perfusion: comparison with labeled microspheres in spontaneous canine neoplasms.

Copper-62-labeled Cu-PTSM is a promising generator-produced PET tracer for myocardial, cerebral and renal perfusion. To evaluate whether [62Cu]Cu-PTSM could also serve as a blood flow tracer in PET studies of tumor tissue, the tumor uptake of [62Cu]Cu-PTSM was examined in dogs with spontaneously-occurring soft-tissue neoplasms. Copper-67-labeled Cu-PTSM was administered intravenously to four anesthetized dogs, followed c. 5 min later by a left ventricular injection of 85Sr-labeled microspheres (15 microns) to provide an independent measure of tumor perfusion. Forty-seven tumors (average weight = 2.5 +/- 3.7 g) were obtained and sectioned into 80 samples. The correlation of 67Cu-PTSM uptake with regional renal perfusion was also examined in data from 395 tissue samples ranging in flow from 0.02 to 9.39 mL min-1 g-1. Rates of tumor perfusion assessed with 85Sr-labeled microspheres ranged from 0.011 to 3.0 mL min-1 g-1. No correlation was found between tumor size and the rate of tumor perfusion. However, an excellent linear correlation exists between tumor perfusion calculated from [62Cu]Cu-PTSM data and tumor perfusion measured with 85Sr-microspheres (r = 0.94 for 80 samples), suggesting that [62Cu]Cu-PTSM may be useful as a radiopharmaceutical for PET studies of tumor perfusion.

Animals↗
PubMed1994

High beta-adrenoceptor density on peripheral blood mononuclear cells in progressive multiple sclerosis: a manifestation of autonomic dysfunction?

In multiple sclerosis (MS) up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMCs) has been attributed to either autonomic dysfunction, inflammation or a combination of the two. We have compared secondary progressive MS patients with normal subjects (NS) and two models of autonomic dysfunction; pure autonomic failure (PAF) and multiple system atrophy (MSA, Shy-Drager syndrome). There was up-regulation of beta-adrenoceptors on PBMCs in MS and PAF patients but not in MSA patients. Only in PAF patients beta-adrenoceptor up-regulation was correlated with low plasma levels of noradrenaline (NA) and adrenaline (Ad). In addition to studies in the basal state, measurements also were made after the centrally acting sympatholytic agent clonidine. These were combined with haemodynamic and neurohormonal measurements. After clonidine, there was a fall in blood pressure in NS and MSA patients but not in MS and PAF patients; a rise in growth hormone (GH) in NS and PAF patients but not in MS and MSA patients; and an up-regulation in PBMCs beta-adrenoceptors in NS but not in MS, MSA and PAF patients. Up-regulation of beta-adrenoceptors on PBMCs in MS could be attributed to autonomic dysfunction but the disparity between MS and PAF patients when considering their plasma levels of NA and Ad argue against. Although the neurohormonal responses to clonidine and the physiological assessment of autonomic function in progressive MS patients, demonstrate central autonomic dysfunction resembling that of the MSA patients, the normal basal beta-adrenoceptor densities in the latter, suggests that the up-regulation of these receptors is independent of the central autonomic dysfunction in MS.

Adult↗
PubMed1994

High prevalence of autoantibodies to glutamic acid decarboxylase in long-standing IDDM is not a marker of symptomatic autonomic neuropathy.

Immune reactivity to the enzyme glutamic acid decarboxylase (GAD), a pancreatic islet autoantigen, is present at the diagnosis of insulin-dependent diabetes mellitus (IDDM). Because GAD is also highly expressed in the nervous system, we investigated the presence of autoantibodies to the isoform GAD65 in patients with diabetic neuropathy, which is a debilitating complication of the disease. We studied 39 patients with autonomic and somatic neuropathy, 28 patients matched for age and IDDM duration, and 13 patients with a shorter duration of IDDM, all with no diabetic complications, as well as 50 recently diagnosed diabetic patients, 23 neurologic patients with idiopathic autonomic failure unrelated to IDDM, and 72 healthy subjects. An immunoprecipitation radioligand assay was used to detect anti-GAD65 autoantibodies with in vitro transcribed and translated human islet GAD65 as antigen. Autoantibodies to GAD65 were present in 56% of the diabetic patients with neuropathy, 57% of the long-duration and 69% of the short-duration diabetic control subjects, 78% of the recently diagnosed patients, and 13% of the nondiabetic neuropathic patients. Among the diabetic patients with neuropathy, there was no correlation between the presence of anti-GAD65 antibodies and the presence of autoantibodies to sympathetic ganglia, vagus nerve, or adrenal medulla structures identified by immunofluorescence. Our study shows that anti-GAD65 antibodies are present in a high proportion of patients with diabetic neuropathy but are not exclusively associated with it, rendering it unlikely that they have a role as a disease marker or that they are pathogenetic.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Expression of beta-adrenoceptors on circulating mononuclear cells in hypertensives and normotensives before and after reduction of central sympathetic outflow by clonidine.

We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells (PBMCs) in normotensives (NT) and hypertensives (HT), before and after intravenous administration of 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 blood pressure and plasma noradrenaline (NA) and adrenaline (Ad) levels, with an increase in growth hormone (GH) levels, in both NT and HT. There was no difference in basal beta-adrenoceptor densities on PBMCs between NT and HT. After clonidine at 30 and 60 min, there was an increase in beta-adrenoceptor density associated with a low affinity in NT. In HT, no changes were observed. The increased beta-adrenoceptor densities on PBMCs in NT after clonidine, returned to baseline values after 2 h. Short term up-regulation of beta-adrenoceptors on PBMCs in NT after clonidine is accompanied by a fall in blood pressure (BP) and plasma levels of catecholamines. The changes may represent a compensatory mechanism reflecting a rapid externalization-activation of adrenoceptors residing on the internal surface of the membranes with a change of the coupling ability between the receptor and the catalytic component. In HT, although the haemodynamic and neurohormonal response to clonidine was similar to NT, short term upregulation of receptors did not occur. The lack of such response may mirror a form of regulatory dysfunction of beta-adrenoceptors in HT.

Aged↗
PubMed1993

Physiological assessment of aspects of autonomic function in patients with secondary progressive multiple sclerosis.

A detailed non-invasive study of systemic and regional haemodynamic responses to a range of autonomic tests which assess sympathetic and parasympathetic pathways (mental arithmetic, cutaneous cold, isometric exercise, deep breathing, Valsalva manoeuvre and head-up tilt) were performed in ten patients with secondary progressive multiple sclerosis and ten age- and sex-matched healthy normal subjects (controls). Blood pressure rose in controls during the pressor tests and was maintained during tilt. In six out of ten patients with multiple sclerosis blood pressure was unchanged during one or more of the three pressor tests, but was maintained in all during tilt. In the controls, superior mesenteric artery blood flow fell during pressor tests and head-up tilt. In multiple sclerosis patients, superior mesenteric artery blood flow did not change during pressor tests but fell during tilt. Cardiac index rose during isometric exercise and fell during head-up tilt in controls. Forearm blood flow rose during mental arithmetic in the controls only, but fell during tilt in both groups. Individual analysis indicated that of the ten multiple sclerosis patients, four had responses during the pressor tests similar to controls. Responses to deep breathing and to the Valsalva manoeuvre in controls and multiple sclerosis patients were similar. We conclude that some patients with an aggressive and disabling form of multiple sclerosis have selective autonomic dysfunction, in particular involving pressor responses, despite the lack of postural hypotension. The autonomic abnormality is likely to involve central autonomic interconnections rather than afferent or sympathetic efferent pathways. Further clarification of the nature, site and progression of these lesions is needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Development and validation of a solvent extraction technique for determination of Cu-PTSM in blood.

The partitioning of [67Cu]Cu-PTSM between plasma and red blood cells (RBC) was investigated in vitro with human, rat, pig and dog blood. Significant inter-species variability is observed in the plasma/RBC partitioning of tracer, ranging from c. 75% association with plasma in human blood to only c. 35% association with plasma in dog blood. This inter-species difference results from selective association of the [67Cu]Cu-PTSM tracer with human albumin. When [67Cu]Cu-PTSM is mixed with human blood in vitro at 37 degrees C the fraction of 67Cu-radioactivity that remains plasma-associated decreases with time, apparently due to the expected intracellular decomposition of the Cu-PTSM complex by RBC; however, this process is sufficiently slow that it should have limited influence on [62Cu]CU-PTSM biodistribution following intravenous injection. Octanol extraction of blood was found to be an effective technique for quantitating the amount of intact [67Cu]Cu-PTSM complex in blood samples. When imaging with [62Cu]Cu-PTSM, octanol extraction may be useful for determining the [62Cu]Cu-PTSM content of arterial blood samples to establish a true radiotracer input function.

Animals↗
PubMed1993

Titration of the in vivo uptake of 16 alpha-[18F]fluoroestradiol by target tissues in the rat: competition by tamoxifen, and implications for quantitating estrogen receptors in vivo and the use of animal models in receptor-binding radiopharmaceutical development.

We have measured in vivo the uptake of 16 alpha-[18F]estradiol (FES) by target tissues in the immature rat at increasing dose levels (obtained by dilution of [18F]FES with unlabeled estradiol). This was done to examine the binding capacity of target tissues in vivo and to determine whether the uptake in receptor-rich tissues was flow limited, as this has implications concerning the appropriateness of using receptor-rich tissues in experimental animals as models for FES uptake by receptor-poor breast tumors in humans. We also wanted to establish the dose level of the anti-estrogen tamoxifen required to block target tissue uptake of FES. We found that in untreated rats, specific uptake in the uterus saturated at c. 180 pmol/g, in the ovary at c. 54 pmol/g and in the muscle at c. 2 pmol/g. At an intermediate dose of tamoxifen (570 micrograms/kg), uptake saturated at somewhat lower levels, and at a high tamoxifen dose (1710 micrograms/kg), yet lower specific uptake was evident. In the FES titrations at low dose levels of FES, both the uterus and the ovaries, but not the muscle, showed characteristics of flow-limited uptake, i.e. the uptake-to-dose ratio reached a maximum level. This flow limitation suggests that only when receptor levels are sufficiently low will the FES uptake be related to receptor concentration. While receptor-rich tissues such as the rat uterus will show this flow limitation, the receptor concentration in most primary and metastatic human breast tumors is sufficiently low, so that the uptake should parallel receptor content. In in vivo distribution studies, target tissues (or tumors) with low receptor content will be more fully saturated and ligand more readily displaced. Also, uptake by secondary target tissues (i.e. those with a lower content of estrogen receptor, such as muscle, thymus and kidney) may be better models for assessing the effectiveness of new breast tumor imaging agents than uptake by receptor-rich tissues.

Animals↗
PubMed1993

Sympathetic nervous system disorders in man.

The sympathetic nervous system innervates most organs in the body and controls their function. A variety of disease processes, surgery or drugs can result in disordered sympathetic nerve function, which can be either localized or more generalized. Malfunction can result in either sympathetic underactivity (causing postural hypotension, impotence or anhidrosis) or overactivity (causing paroxysmal hypertension or hyperhidrosis). The investigation of sympathetic disorders depends upon the system and organs involved and should include, where relevant, investigation of the possible aetiological processes. The clinical features and management of some of the major disorders affecting the sympathetic nervous system, including the recently described syndrome of DBH deficiency, are described.

Dopamine beta-Hydroxylase↗
PubMed1993

Effects of oral alcohol on superior mesenteric artery blood flow in normal man, horizontal and tilted.

1. The cardiovascular effects of oral alcohol (0.5 g/kg body weight diluted to 300 ml in sugar-free orange juice) were compared with those of placebo in 10 normal subjects. Measurements were made while the subjects were supine and horizontal for 45 min and after 10 min of 45 degrees head-up tilt. 2. After alcohol, plasma alcohol levels rose from 1.9 +/- 1.3 to 61.6 +/- 6.5 mg/100 ml. After placebo, plasma alcohol levels did not increase. After alcohol and placebo, supine blood pressure was unchanged; heart rate, both supine and during tilt, rose after alcohol only. 3. After alcohol, superior mesenteric artery and digital skin blood flow increased and calculated vascular resistances fell. There was no change after placebo. 4. Forearm blood flow, forearm vascular resistance and cardiac index did not change in either phase, except for a fall in cardiac index during tilt but only after alcohol. 5. In conclusion, the acute ingestion of 0.5 g of alcohol/kg body weight in normal subjects raised heart rate and actively dilated the superior mesenteric artery and digital skin vessels. There was no effect on blood pressure, cardiac output and skeletal muscle vascular tone. During head-up tilt after alcohol, there was a tendency for blood pressure to fall with a compensatory rise in heart rate.

Adult↗
PubMed1993

The effect of captopril on the superior mesenteric artery and portal venous blood flow in normal man.

1. Measurements of superior mesenteric artery and portal venous blood flow were made non-invasively along with systemic and other regional (cardiac index, forearm and cutaneous blood flow) vascular responses to acute ingestion of the ACE inhibitor captopril (50 mg) or placebo (50 mg vitamin C), in 12 healthy subjects while supine and during head-up tilt. 2. After captopril, superior mesenteric artery and portal blood flow rose markedly with a reduction in superior mesenteric artery vascular resistance. Supine blood pressure was unchanged but cardiac index and forearm blood flow rose; during head-up tilt, blood pressure fell in some subjects. 3. There was a rise in levels of plasma renin activity and a fall in levels of plasma angiotensin II after captopril. After placebo, there were no significant changes in splanchnic blood flow, systemic or other regional responses and in biochemical measurements, while supine. 4. Our studies indicate that captopril is a potent dilator of the splanchnic vascular bed and suggest that this action may contribute to its therapeutic effects. The studies indicate a role for angiotensin II in the control of this large vascular bed although other agents (bradykinin, prostacyclin) may contribute.

Adult↗
PubMed1993

Post-exertion dizziness as the sole presenting symptom of autonomic failure.

An otherwise fit young man, leading an active life, whose only complaint at presentation was dizziness after extreme exertion is described. He was found later to have postural and exercise induced hypotension. Subsequently, he developed typical symptoms of autonomic failure, with postural dizziness, urinary abnormalities, and erectile failure. Progression of autonomic failure was documented on testing. A fall in blood pressure during or after exercise has been reported previously in pure autonomic failure, but a presentation with exercise induced symptoms alone is unusual.

Adult↗
PubMed1993

Cardiovascular and hormonal responses to liquid food challenge in idiopathic Parkinson's disease, multiple system atrophy, and pure autonomic failure.

We investigated the effect of a balanced liquid meal on blood pressure (BP) and heart rate (with patients supine and during head-up tilt), and on levels of plasma catecholamines, glucose, and insulin, in patients with idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA), pure autonomic failure (PAF), and in healthy subjects (controls). After food, supine BP fell in IPD, but to a greater extent in MSA and PAF. In controls, BP was unchanged. Head-up tilt did not lower BP in IPD and controls, but there was a postprandial fall to lower levels in both MSA and PAF. Plasma norepinephrine levels rose in IPD pre- and postprandially during tilt, but were unchanged in MSA and PAF. These data suggest that in IPD, food causes a smaller fall in supine BP than in MSA and PAF. In IPD, as in controls, food does not induce or unmask postural hypotension, unlike in MSA and PAF, in which BP falls to even lower levels. There are therefore differences in the responses to food ingestion between these groups. This may be of value in separation of these disorders at an early stage.

Adult↗