Search PubMed⌕ Search

Biomedical subjects

C J Mathias

Publications and source records attributed to C J Mathias.

At least 55 records · Page 3Linked to original sources
PubMed2000

Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans.

1. States of peripheral autonomic arousal accompany emotional behaviour, physical exercise and cognitive effort, and their central representation may influence decision making and the regulation of social and emotional behaviours. However, the cerebral functional neuroanatomy representing and mediating peripheral autonomic responses in humans is poorly understood. 2. Six healthy volunteer subjects underwent H215O positron emission tomography (PET) scanning while performing isometric exercise and mental arithmetic stressor tasks, and during corresponding control tasks. Mean arterial blood pressure (MAP) and heart rate (HR) were monitored during scanning. 3. Data were analysed using statistical parametric mapping (SPM99). Conjunction analyses were used to determine significant changes in regional cerebral blood flow (rCBF) during states of cardiovascular arousal common to both exercise and mental stressor tasks. 4. Exercise and mental stressor tasks, relative to their control tasks, were associated with significantly (P < 0.001) increased MAP and HR. Significant common activations (increased rCBF) were observed in cerebellar vermis, brainstem and right anterior cingulate. In both exercise and mental stress tasks, increased rCBF in cerebellar vermis, right anterior cingulate and right insula covaried with MAP; rCBF in pons, cerebellum and right insula covaried with HR. Cardiovascular arousal in both categorical and covariance analyses was associated with decreased rCBF in prefrontal and medial temporal regions. 5. Neural responses in discrete brain regions accompany peripheral cardiovascular arousal. We provide evidence for the involvement of areas previously implicated in cognitive and emotional behaviours in the representation of peripheral autonomic states, consistent with a functional organization that produces integrated cardiovascular response patterns in the service of volitional and emotional behaviours.

Adult↗
PubMed2000

Differentiation of atypical parkinsonian syndromes with routine MRI.

OBJECTIVE: To evaluate the use of routine MRI in differentiating between patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD) and control subjects. METHODS: Two neuroradiologists rated blindly and independently axial T2-weighted and proton density MR images of 54 patients with MSA, 35 patients with PSP, 5 patients with CBD, and 44 control subjects. RESULTS: More than 70% of patients with PSP and more than 80% of patients with cerebellar predominant MSA could be classified correctly with 0.5-T or 1.5-T scans, and no patient in these groups was misclassified. In the remaining patients an unequivocal differentiation could not be made. However, only approximately 50% of patients with parkinsonism-predominant MSA could be classified correctly, and 19% of them (all of whom had had 0.5-T scans) were misclassified. CONCLUSIONS: Characteristic findings on routine MRI, either 1.5 T or 0.5 T, can contribute to the identification of MSA and PSP. However, in a minority of patients no unequivocal diagnosis can be made using MRI findings alone.

Adult↗
PubMed2000

Familial vasovagal syncope and pseudosyncope: observations in a case with both natural and adopted siblings.

This report describes an 11-year-old girl with recurrent syncope beginning at the age of 2 1/2 years. Her paternal grandmother, father, and three of her five natural siblings had similar symptoms, often linked to emotional upsets. There were three adopted children from a single family, and none of these had syncope. Prior to referral there was an increase in attacks, some with convulsions, but with no other features of epilepsy. Vasovagal syncope was confirmed. However, continuous electroencephalogram, blood pressure, and heart rate recordings during attacks indicated that in some episodes there was neither cardiovascular change nor epileptiform activity, implying feigned syncope (pseudosyncope) with pseudoseizures. A psychological origin was sought, found, and in part rectified. The separation of vasovagal syncope from pseudosyncope, in the context of the family history, is discussed.

Adolescent↗
PubMed2000

Physiological, pharmacological and neurohormonal assessment of autonomic function in progressive supranuclear palsy.

The clinical features of progressive supranuclear palsy (PSP) overlap with other parkinsonian syndromes, including multiple system atrophy (MSA). Autonomic dysfunction is a characteristic of MSA, but has also been described in PSP. We therefore report results from a series of physiological studies of cardiovascular autonomic function in 35 PSP and 20 MSA subjects, and 26 age-matched healthy control subjects. The response to growth hormone-clonidine testing, a neuropharmacological assessment of central adrenoceptor function, was also assessed in 14 PSP and 10 MSA subjects, and compared with 10 controls. None was on medication which may have affected the results. Orthostatic hypotension did not occur in PSP subjects or controls, unlike MSA subjects. Overall there was no evidence of sympathetic vasoconstrictor failure in PSP subjects, unlike MSA subjects, although the pressor response to mental arithmetic was reduced. Cardiac parasympathetic function was affected in only a minority (three of 35) of PSP subjects and was abnormal in MSA subjects. After clonidine administration, growth hormone rose in PSP subjects (median increase 4.3; interquartile range 1.8-7.8 mU/l) and controls, unlike MSA subjects (0.9; 0.3-2.4 mU/l; P < 0.005, Mann-Whitney U-test). In conclusion, in PSP subjects, responses to both physiological and pharmacological tests provided evidence against widespread autonomic dysfunction; this differed markedly from MSA subjects. Thus, cardiovascular autonomic dysfunction should be an exclusionary feature in the diagnosis of PSP.

Adrenergic alpha-Agonists↗
PubMed2000

Performance of a 62Zn/62Cu generator in clinical trials of PET perfusion agent 62Cu-PTSM.

UNLABELLED: The 62Zn/62Cu PET generator can be inexpensively produced and distributed from a single production site operating under typical good manufacturing practice guidelines. It therefore has the potential to greatly facilitate development of clinically practical PET. We report generator performance in a study in which 62Cu-pyruvaldehyde-bis(n4-methylthiosemicarbazone (PTSM) myocardial perfusion imaging is compared with 99mTc-sestamibi in the diagnosis of coronary artery disease. The 62Zn/62Cu generator is an improved version of a previously reported system that employs automated synthesis of 62Cu-PTSM. With this approach, the cumbersome step of 18C purification has been eliminated. METHODS: The 62Zn (9.3 h half-life) parent isotope is prepared by proton bombardment of natural copper at 33 MeV. A typical target irradiated with 37.5 microA/h is delivered by 12:00 PM on the day it is to be processed. Purified 62Zn obtained from the target is loaded onto the generator column in 2 mol/L HCl. The generator is eluted using an internal three-channel peristaltic pump, which delivers 2.25 mL eluant (1.8 mol/L NaCl, 0.2 mol/L HCl) through the generator column to elute the 62Cu in 40 s. The same pump simultaneously pumps an equal volume of buffer (0.4 mol/L NaOAc) and 1 mL ligand solution (2 ppm PTSM, 2% EtOH) passing it through a septum into a 35-cc syringe preloaded with 28 mL sterile water. This solution is thoroughly mixed by agitation of the syringe and injected as a bolus through a 0.2 microm filter. The generator is eluted twice before shipping, providing quality assurance samples, and shipped to the clinical site by overnight delivery. Complete quality assurance testing is performed the evening before the generator reaches the clinical site. RESULTS: A total of 34 generators have been produced and shipped to 2 clinical sites for a phase III Food and Drug Administration study. The load activity on the generators at 8:00 AM the day of clinical use was 1.7+/-0.2 GBq (46.7+/-5.6 mCi), and yield was 72%+/-16%. Breakthrough of 62Zn was undetectable by high-purity germanium spectroscopy for all units. Radiochemical purity was 95.4%+/-2.4%. Volume delivered, pH, sterility, and bacterial endotoxin tests yielded passing results on all generators. The entire process of generator production, from target receipt to generator shipment, took less than 6 h and cost approximately $1000, including shipping charges and cyclotron cost. A total of 68 patients were injected with 2 62Cu-PTSM doses, with a mean injected activity of 0.8+/-0.2 GBq (20.5+/-5.3 mCi) with no adverse side effects. CONCLUSION: Results of this work confirm that the 62Zn/62Cu generator is an easily produced, transportable, and inexpensive source of PET radiopharmaceuticals, which can expand the field of clinical PET imaging by providing radiopharmaceuticals to sites not associated with cyclotrons.

Clinical Trials, Phase III as Topic↗
PubMed1999

Superior mesenteric artery dilatation alone does not account for glucose-induced hypotension in human sympathetic denervation.

Haemodynamic and hormonal effects of two oral isovolaemic, isoosmotic solutions of 0.5 g/kg and 1.0 g/kg glucose were studied in 10 humans with sympathetic denervation due to primary autonomic failure (AF). Measurements were made supine for 60 min, and also after 5 min 45 head-up tilt, before and 60 min after glucose. There was a similar fall in blood pressure (BP) after each dose, after 0.5 g/kg from 160+/-12 / 87+/-6 to 143+/-13 / 76+/-6 mm Hg, P < 0.05 and after 1.0 g/kg from 160+/-13 / 90+/-6 to 136+/-9 / 76+/-5 mm Hg, P < 0.05. Heart rate, cardiac index and forearm muscle blood flow did not change after either dose. After 0.5 g/kg, superior mesenteric artery blood flow was unchanged but rose significantly after 1.0 g/kg, from 243 (169-395) to 722 (227-982) ml/min, P < 0.05, 15 min after ingestion. BP fell further on tilt 60 min after each dose, but there was no difference between doses. Plasma glucose was higher after 1.0 g/kg but plasma insulin was similar after each dose. Thus, in AF with sympathetic denervation there was no dose-related effect of glucose on supine or postural hypotension. Supine hypotension after glucose was not attributable solely to increased splanchnic blood flow; other factors, including dilatation in other vascular beds may have contributed.

Adult↗
PubMed1999

Consensus statement on the diagnosis of multiple system atrophy.

We report the results of a consensus conference on the diagnosis of multiple system atrophy (MSA). We describe the clinical features of the disease, which include four domains: autonomic failure/urinary dysfunction, parkinsonism and cerebellar ataxia, and corticospinal dysfunction. We set criteria to define the relative importance of these features. The diagnosis of possible MSA requires one criterion plus two features from separate other domains. The diagnosis of probable MSA requires the criterion for autonomic failure/urinary dysfunction plus poorly levodopa responsive parkinsonism or cerebellar ataxia. The diagnosis of definite MSA requires pathological confirmation.

Autonomic Nervous System Diseases↗
PubMed1999

Selegiline-induced postural hypotension in Parkinson's disease: a longitudinal study on the effects of drug withdrawal.

OBJECTIVES: The United Kingdom Parkinson's Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinson's disease (PD) randomized to receive 10 mg selegiline per day and L-dopa compared with those taking L-dopa alone. Recently, we found that therapy with selegiline and L-dopa was associated with selective systolic orthostatic hypotension which was abolished by withdrawal of selegiline. This unwanted effect on postural blood pressure was not the result of underlying autonomic failure. The aims of this study were to confirm our previous findings in a separate cohort of patients and to determine the time course of the cardiovascular consequences of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension. METHODS: The cardiovascular responses to standing and head-up tilt were studied repeatedly in PD patients receiving selegiline and as the drug was withdrawn. RESULTS: Head-up tilt caused systolic orthostatic hypotension which was marked in six of 20 PD patients on selegiline, one of whom lost consciousness with unrecordable blood pressures. A lesser degree of orthostatic hypotension occurred with standing. Orthostatic hypotension was ameliorated 4 days after withdrawal of selegiline and totally abolished 7 days after discontinuation of the drug. Stopping selegiline also significantly reduced the supine systolic and diastolic blood pressures consistent with a previously undescribed supine pressor action. CONCLUSION: This study confirms our previous finding that selegiline in combination with L-dopa is associated with selective orthostatic hypotension. The possibilities that these cardiovascular findings might be the result of non-selective inhibition of monoamine oxidase or of amphetamine and metamphetamine are discussed.

Aged↗
PubMed1999

Neuroendocrine responses to levodopa in multiple system atrophy (MSA).

Hypothalamic dopaminergic pathways are involved in the regulation of growth hormone and prolactin release from the anterior pituitary. Neuroendocrine studies in patients with multiple system atrophy (MSA), in whom there is a reported loss of hypothalamic dopamine, are few and contradictory. We therefore studied the neuroendocrine responses to 250 mg levodopa (plus 25 mg carbidopa) in subjects with MSA (n = 15), and compared them with age- and sex-matched healthy control subjects (n = 8). There were no significant differences in basal or post-levodopa levels of growth hormone (GH), growth hormone-releasing hormone (GHRH), glucose, insulin-like growth factor (IGF-1), or thyroid-stimulating hormone (TSH) between the groups. In patients with MSA, basal levels of prolactin were elevated (21.1 +/- 5.2 ng/mL [mean +/-standard error]) compared with control subjects (12.1 +/- 1.7, p <0.05), and after L-dopa there was increased variability in prolactin response with less suppression compared with control subjects. In conclusion, in patients with MSA, the GHRH and GH responses to L-dopa were preserved and were similar to responses in age-matched control subjects. In contrast, there was impaired dopaminergic suppression of prolactin secretion. In patients with MSA this may represent a selective dysfunction, rather than generalized loss, of tubero-infundibular dopaminergic neurones.

Adult↗
PubMed1999

Contribution of nitric oxide to exercise-induced hypotension in human sympathetic denervation.

The cardiovascular, catecholamine, and nitrate/nitrite (NO) responses to bicycle exercise were measured in 14 normal subjects (controls) and two groups with sympathetic denervation; 14 with peripheral autonomic failure (pure autonomic failure [PAF]); and 13 with central autonomic failure (multiple system atrophy [MSA]). With exercise, blood pressure increased in control subjects by 40 +/- 7/24 +/- 5 mm Hg (p < 0.001) and fell in PAF by 24 +/- 8/24 +/- 5 mm Hg (p < 0.02 and p < 0.007) and MSA by 31 +/- 7/11 +/- 3 mm Hg (p < 0.005 and p < 0.04). With exercise, the increase in heart rate was greater in control subjects (60 +/- 3 to 111 +/- 4/min; p < 0.0001) than in PAF (69 +/- 3 to 86 +/- 4/min; p < 0.0001) and MSA (70 +/- 4 to 90 +/- 4; p < 0.001). Resting plasma noradrenaline levels were similar in controls (291 +/- 51 pg ml(-1)) and MSA (257 +/- 49 pg ml(-1)), but lower in PAF (82 +/- 14 pg ml(-1)). With exercise, plasma noradrenaline increased in controls but was unchanged in PAF and MSA. Resting NOx was similar in controls (50 +/- 5 nmol/L; range, 23.3-87.6 nmol/L) and PAF patients (59+/-8 nmol/l; range, 19.3-116.4 nmol/L), but was higher in MSA patients (87 +/-14 nmol/L; p <0.025, range 15.4-157.2 nmol/L). With exercise, NOx was unchanged in control subjects and increased by 10% and 17% in PAF and MSA, respectively; these changes were not statistically significant. This study suggests that circulating changes in NOx levels do not exert a major role in exercise-induced hypotension in subjects with sympathetic denervation.

Autonomic Nervous System Diseases↗
PubMed1999

Abnormal suppression of arginine-vasopressin by clonidine in multiple system atrophy.

In normal man, the centrally active alpha2-adrenoceptor agonist clonidine reduces arginine-vasopressin (AVP) secretion, probably by presynaptic inhibition of noradrenergic neuron terminals in the supraoptic nucleus. A lesion of noradrenergic pathways in animals abolishes this response to clonidine. At postmortem in multiple system atrophy (MSA) there is marked loss of hypothalamic noradrenergic innervation. We hypothesized that the AVP response to clonidine in MSA may be abnormal and therefore studied the AVP response to clonidine (2 microg/ kg iv) in 10 subjects with MSA and compared them to six healthy age-matched control subjects. Basal levels of AVP were similar in controls and MSA. Following clonidine there was a significantly greater fall in controls than MSA (-47 +/- 4% vs -25 +/- 6%; p < 0.05). There was a similar fall in mean arterial pressure (MAP) and plasma catecholamines in both groups, with no change in plasma osmolarity, excluding these as a contributary factor. In conclusion, there is an abnormal AVP response to clonidine in MSA, which probably represents loss of functional noradrenergic innervation of the supraoptic nucleus.

Adrenergic alpha-Agonists↗
PubMed1999

Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy.

The symptoms caused by or relating to orthostatic hypotension (over 20 mmHg systolic blood pressure) were evaluated using a questionnaire in 72 patients with primary chronic autonomic failure, 32 of whom had pure autonomic failure (PAF, and 40 multiple system atrophy (MSA). The most common posturally related symptoms were dizziness (84% PAF, 83% MSA), syncope (91% PAF, 45% MSA), visual disturbances (75% PAF, 53% MSA) and suboccipital/paracervical 'coat-hanger' neck pain (8 l% PAF, 53% MSA). Chest pain occurred mainly in patients with PAF (44% PAF, 13% MSA). Improvement occurred with sitting or lying flat. Non-specific symptoms (weakness, lethargy and fatigue) were common in both groups (91% PAF, 85% MSA); six patients (one PAF, five MSA) had these symptoms only. Postural symptoms (mainly dizziness and neck pain) were worse in the morning and with warm temperature, straining, exertion, arm movements and food ingestion; they were more common in PAF. Compensatory autonomic symptoms, such as palpitations and sweating, did not occur in either group. In conclusion, orthostatic hypotension caused symptoms of cerebral hypoperfusion (syncope, dizziness and visual disturbances); neck pain, presumably due to muscle hypoperfusion, also occurred frequently. These symptoms were exacerbated by various factors in daily life and were relieved by returning to the horizontal. Non-specific symptoms (such as fatigue) also were common. In MSA, despite substantial orthostatic hypotension, fewer patients had syncope, visual disturbance and neck pain; the reasons for this are unclear. Lack of these features does not exclude the need to assess and investigate orthostatic hypotension and possible autonomic failure.

Adaptation, Physiological↗
PubMed1999

Receptor-mediated targeting of 67Ga-deferoxamine-folate to folate-receptor-positive human KB tumor xenografts.

The radiochemical synthesis and stability of 67Ga-deferoxamine-folate ([67Ga]Ga-DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations > or =2.5 microg/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [67Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor-positive KB tumors were found to concentrate the 67Ga radiolabel in a dose-dependent fashion, consistent with saturable involvement of the folate receptor in mediating tumor accumulation of the radiopharmaceutical.

Animals↗
PubMed1999

Synthesis and evaluation of copper radiopharmaceuticals with mixed bis(thiosemicarbazone) ligands.

Four "mixed" bis(thiosemicarbazone) derivatives of pyruvaldehyde were synthesized that incorporate two dissimilar thiosemicarbazone functions. The corresponding [67Cu]copper(II) complexes were prepared and evaluated as possible copper radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands, CH3C[=NNHC(S)NHMe]CH[=NNHC(S)NHEt] (1), CH3C[=NNHC(S)NHMe] CH[=NNHC(S)NEt2] (2), CH3C[=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)5] (3), and CH3C [=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)6] (4), were obtained by reaction of the appropriate thiosemicarbazide derivative with pyruvaldehyde-2-N4-methylthiosemicarbazone (CH3C[=NNHC(S) NHMe]CHO). The 67Cu-labeled copper(II) complexes of ligands 1-4 were prepared and screened in a rat model to assess the potential of each chelate as a 62Cu-radiopharmaceutical for imaging with positron emission tomography. The 67Cu-complexes of ligands 1-4 exhibit significant uptake into the brain and heart 1 min following intravenous administration to rats. For the 67Cu-complexes of ligands 2, 3, and 4, the cerebral and myocardial uptake of 67Cu is two-to-threefold lower at 2 h than at 1 min postinjection, due to significant biological clearance of these 67Cu-chelates. However, the 67Cu-complex of 1 affords cerebral and myocardial uptake and retention comparable to that of [67Cu]Cu-PTSM in this model. Although the kinetics of this new agent appear attractive, ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu-complex of ligand 1, like Cu-PTSM, interacts more strongly with human albumin than dog albumin. Thus, this new agent would appear to offer no advantage over Cu-PTSM as a 62Cu-labeled tracer for evaluation of regional tissue perfusion.

Animals↗