Gastrointestinal dysfunction in multiple system atrophy.
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Anal Canal↗
Biomedical subjects
C J Mathias
Publications and source records attributed to C J Mathias.
Cardiovascular and catecholamine changes induced by supine exercise and upright posture in vasovagal syncope. Comparisons with normal subjects and subjects with sympathetic denervation.
The haemodynamic and catecholamine responses to supine leg exercise were studied in vasovagal syncope (n = 10), pure autonomic failure (n = 10) and in control (n = 10) subjects. With exercise, blood pressure increased in controls; with a smaller rise in vasovagal syncope, and a substantial fall in pure autonomic failure. Heart rate increased similarly in controls and vasovagal syncope, but less in pure autonomic failure. The increase in cardiac index was less in controls and pure autonomic failure than vasovagal syncope; the fall in systemic vascular resistance was greatest in pure autonomic failure, but also fell more in vasovagal syncope than controls. Plasma noradrenaline levels increased in controls; with a smaller rise in vasovagal syncope and no increase in pure autonomic failure. Plasma adrenaline levels increased in vasovagal syncope only. The blood pressure responses to standing before and after exercise were similar in controls and vasovagal syncope, with no postural blood pressure fall; in pure autonomic failure there was a greater postural blood pressure fall post exercise. In conclusion, with supine exercise, blood pressure rose in controls and vasovagal syncope, and fell in pure autonomic failure. Systemic vascular resistance fell more in vasovagal syncope and pure autonomic failure, than controls. Noradrenaline responses differed and adrenaline rose in vasovagal syncope only. Standing post exercise did not induce syncope in vasovagal syncope, but increased postural hypotension in pure autonomic failure. There are clear differences in response to exercise in vasovagal syncope and pure autonomic failure. The differences between vasovagal syncope and control subjects suggest an underlying abnormality which may predispose to vasodepression in subjects with vasovagal syncope.
Adult↗
QT interval and dispersion in primary autonomic failure.
OBJECTIVE: To investigate the role of the autonomic nervous system in determining QT interval and dispersion. PATIENTS AND METHODS: 32 patients with chronic primary (idiopathic) autonomic failure (19 men, mean age 60 years) and 21 normal controls (11 men, mean age 59) without symptoms of ischaemic heart disease were studied retrospectively. Autonomic failure was diagnosed by a combination of symptomatic postural hypotension, subnormal plasma noradrenaline response to head-up tilt, and abnormal cardiovascular responses to standing, Valsalva manoeuvre, mental stress, cutaneous cold, isometric exercise, and deep breathing. QT intervals were measured from surface electrocardiograms and QT dispersion was defined as maximum QT--minimum QT occurring in any of the 12 leads. RESULTS: Mean heart rate (RR intervals) was similar in patients with autonomic failure and controls (S2 lead: 865 (132) v 857 (108) ms, P = NS; V2 lead: 865 (130) v 868 (113) ms, P = NS). QT intervals measured from electrocardiogram leads S2 and V2 were significantly longer in patients than in controls (401 (40) v 376 (16) ms, P < 0.01; and 403 (41) v 381 (20) ms, P < 0.05 respectively). The mean maximum QT interval in any lead, which is the best estimate of the maximum duration of electrical systole, was significantly longer in the patients than in controls (417 (48) v 388 (23) ms, P < 0.005). Linear regression analysis of QT and RR intervals for both groups showed a significant difference between the slopes of the two regression lines (F = 8.4, P < 0.001). However, QT dispersions were similar between patients and controls. CONCLUSIONS: Patients with primary autonomic failure have prolongation of QT intervals, indicating that the autonomic nervous system is an important determinant of QT interval. However, QT dispersion does not seem to be affected by chronic primary autonomic denervation.
Autonomic Nervous System Diseases↗
Differences in cardiovascular responses to supine exercise and to standing after exercise in two clinical subgroups of Shy-Drager syndrome (multiple system atrophy).
BACKGROUND: In chronic autonomic failure of varying aetiologies, there are differences in the cardiovascular responses to supine leg exercise and to standing after exercise. Whether this occurs between the different subgroups with Shy-Drager syndrome (SDS) is unknown. METHODS: Fourteen patients with the cerebellar form (SDS-C) and 11 patients with parkinsonian features (SDS-P) were studied. RESULTS: Both groups had a similar degree of autonomic failure and postural hypotension. Their responses were compared with nine patients with idiopathic Parkinson's disease (IPD) and 15 normal subjects (controls), all with normal autonomic function. With supine exercise, blood pressure and heart rate rose similarly in controls and patients with IPD and there was no fall in blood pressure on standing after exercise. In both SDS groups there were abnormal responses to exercise: blood pressure fell in SDS-C, but did not fall or rise in SDS-P. Heart rate increased similarly in both SDS groups, calculated systemic vascular resistance fell similarly, but cardiac index rose more in SDS-P than SDS-C. Resting plasma noradrenaline concentrations were subnormal in both forms of SDS, and did not increase with exercise. Postural hypotension was enhanced after exercise to the same extent in SDS-C and SDS-P. CONCLUSIONS: The greater cardiovascular abnormalities in response to exercise in SDS-C suggests that cerebellar or brain stem autonomic pathways are impaired to a greater extent in SDS-C than in SDS-P. Pooling SDS subgroups, therefore, may obscure pathophysiological differences to certain stimuli. Clinically when postural hypotension is being assessed, separation of the subgroups may not be essential, as they responded similarly.
Adult↗
Autonomic nervous system disorders and erectile dysfunction.
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Autonomic Nervous System↗
Disorders affecting autonomic function in parkinsonian patients.
This chapter deals with certain aspects of autonomic dysfunction in parkinsonian patients. It provides a classification of autonomic disorders and a brief description of autonomic manifestations. An outline of autonomic investigations, including those to diagnose the Shy-Drager syndrome (multiple system atrophy), is provided. It concludes with comments on terminology and on whether the parkinsonian syndromes with autonomic failure comprise single or multiple entities.
Autonomic Nervous System Diseases↗
Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate.
UNLABELLED: The receptor-mediated endocytosis uptake pathway for the vitamin folate was investigated as a target for tumor-selective radiopharmaceutical delivery. The molecular target for this delivery mechanism is a membrane-associated folate binding protein (FBP) that is overexpressed by a variety of malignant cell lines. METHODS: The ability of a 67Ga-labeled deferoxamine-folate conjugate (67Ga-DF-folate) to target tumor cells in vivo was examined using an athymic mouse tumor model. Subcutaneous inoculation of approximately 4 X 10(6) folate-receptor-positive KB (human nasopharyngeal carcinoma) cells into athymic mice yielded approximately 0.20 g tumors in 15 days, at which time either 67Ga-DF-folate, 67Ga-deferoxamine (67Ga-DF) or 67Ga-citrate was administered by intravenous injection. RESULTS: The 67Ga-DF-folate conjugate showed marked tumor-specific deposition in vivo, with 1.0 +/- 0.3% of the injected dose (%ID) in tumor at 4 hr postinjection (equating to 5.2 +/- 1.5 %ID/g tumor; n = 3 mice). Corresponding tumor-to-background ratios at 4 hr postinjection were: tumor/blood = 409 +/- 195; tumor/muscle = 124 +/- 47; tumor/liver = 11 +/- 3; and tumor/kidney = 2.6+/-0.9. Tumor uptake of 67Ga-DF-folate conjugate was effectively blocked by co-injection of 2.4+/-1.0 mg free folate. In control experiments, 67Ga-citrate exhibited tumor uptake of 2.2 +/- 0.4% of the injected dose (10.9 +/- 0.2 %ID/g tumor), but very poor target-to-background contrast (tumor/blood = 0.84 +/- 0.19; tumor/muscle = 5.4 +/- 0.7; tumor/liver = 2.3 +/- 0.2; and tumor/kidney = 2.4 +/- 0.3). Unconjugated 67Ga-deferoxamine showed no tumor affinity. CONCLUSION: Receptor-mediated endocytosis of radiolabeled folate-conjugates may offer a suitable mechanism for selectively delivering radiopharmaceuticals to tumors for diagnostic imaging and/or radiation therapy.
Animals↗
Double-blind, parallel, comparative multicentre study of a new combination of diltiazem and hydrochlorothiazide with individual components in patients with mild or moderate hypertension.
OBJECTIVE: To compare the antihypertensive efficacy and tolerability of a new combination preparation of diltiazem (150 mg) and hydrochlorothiazide (12.5 mg) with the individual constituents in patients with mild/moderate hypertension. DESIGN: Multi-centre, double-blind, randomised parallel group study. PATIENTS: Seventy-one patients with essential hypertension were recruited to the study. TREATMENT: Following completion of the placebo run-in period 63 patients fulfilled the prerandomisation criteria and entered the 10 week treatment period. Patients were randomised to receive either the combination preparation (D 150 mg/H 12.5 mg), diltiazem (150 mg) or hydrochlorthiazide (12.5 mg). The dosage was increased in three patients who had not attained target blood pressure (BP) control after 6 weeks. OUTCOME MEASURES: Response to treatment assessed by change from baseline in clinic and 24 h ambulatory BP. RESULTS: The proportion of patients achieving target BP (a reduction in resting supine diastolic blood pressure (DBP) to below 90 mm Hg or a reduction of 10 mm Hg from baseline) was 80% in the combination group, 55% in the diltiazem group, and 38% in the hydrochlorothiazide group. The respective figures for reduction in supine DBP from baseline were 13.5 mm Hg, 11.2 mm Hg and 5.9 mm Hg. A similar treatment order appeared throughout each of the efficacy variables. BP control throughout the 24 h dosing interval was demonstrated by ambulatory BP monitoring. Each treatment was well tolerated. CONCLUSION: This study provides clear evidence of the efficacy of combination therapy with diltiazem and hydrochlorothiazide in the management of patients with hypertension.
Adolescent↗
Abnormal cardiovascular and catecholamine responses to supine exercise in human subjects with sympathetic dysfunction.
1. The cardiovascular and catecholamine responses to supine leg exercise were measured in fifteen normal subjects (controls) and in three groups with sympathetic dysfunction: fifteen with central failure (Shy-Drager syndrome; SDS), fifteen with peripheral failure (pure autonomic failure; PAF) and two with isolated dopamine beta-hydroxylase deficiency (DBH deficiency). 2. With exercise, blood pressure increased in controls, fell markedly in SDS and PAF and was unchanged in DBH deficiency. After exercise, blood pressure rapidly returned to baseline in controls, but remained low in SDS and PAF. With exercise, heart rate increased more in controls than SDS or PAF; the response varied in DBH deficiency. 3. With exercise, cardiac output increased similarly in controls, SDS and PAF, with a larger increase in DBH deficiency. Vascular resistance fell less in controls than SDS, PAF and DBH deficiency. 4. With exercise, plasma noradrenaline increased in controls only; plasma adrenaline remained unchanged in all groups. In DBH deficiency, plasma noradrenaline and adrenaline were undetectable, but plasma dopamine was elevated and rose further with exercise. 5. Supine exercise substantially lowered blood pressure in sympathetic failure due to SDS and PAF. In DBH deficiency blood pressure was unchanged; this lack of fall may have been due to vasoconstriction induced by dopamine and other substances released from otherwise intact sympathetic terminals, or to preserved cardiac vagal function.
Adult↗
Positron emission tomography studies on the dopaminergic system and striatal opioid binding in the olivopontocerebellar atrophy variant of multiple system atrophy.
Ten patients with sporadic olivopontocerebellar atrophy and autonomic failure were studied with positron emission tomography. Subjects underwent both an [11C]diprenorphine and an [18F]fluorodopa scan. The mean caudate-occipital uptake ratio for [11C]diprenorphine was significantly reduced to 88% and the putamen-occipital uptake ratio to 85% of the control values. Individually, 4 of the 10 patients had significantly reduced opioid binding in the putamen. Mean putamen [18F]fluorodopa uptake was significantly diminished (to 71% of the control mean); individually 7 patients had significantly reduced uptake. There was a significant positive correlation between putamen-occipital uptake ratios for [11C]diprenorphine and putamen uptake of [18F]fluorodopa. Our results suggest that subclinical nigrostriatal dysfunction is present in the majority of patients with sporadic olivopontocerebellar atrophy, in accordance with it being part of the spectrum of multiple system atrophy.
Autonomic Nervous System Diseases↗
Morphological overlap between corticobasal degeneration and Pick's disease: a clinicopathological report.
An 81-year-old woman died after a 3-year history of a progressive nondementing akinetic-rigid syndrome. Initially, there was a moderate response to levodopa treatment. Subsequently she developed postural tremor, loss of upward gaze, and frequent falls suggestive of Steele-Richardson-Olszewski syndrome (SROS). Macroscopical examination showed depigmentation of substantia nigra and locus ceruleus. Histology revealed occasional swollen achromatic neurons predominantly in frontal cortex, small cortical neurofibrillary tangles, brain stem basophil (corticobasal) inclusions, and Pick bodies. The coexistence of these histopathological markers raises questions concerning their specificity and the basis of a morphological distinction between corticobasal degeneration and Pick's disease.
Aged↗
The classification and nomenclature of autonomic disorders--ending chaos, resolving conflict and hopefully achieving clarity.
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Autonomic Nervous System Diseases↗
Effect of the somatostatin analogue, octreotide, on exercise-induced hypotension in human subjects with chronic sympathetic failure.
1. In autonomic failure, supine exercise lowers blood pressure and worsens postural hypotension. The somatostatin analogue, octreotide, reduces post-prandial and postural hypotension, but its effects on exercise-induced hypotension and on postural hypotension post-exercise are unknown. 2. Eighteen subjects with chronic sympathetic denervation were studied; 12 had pure autonomic failure and six had additional neurological features of the Shy-Drager syndrome. Haemodynamic, hormonal and biochemical changes were measured before, during and after incremental supine leg exercise on two occasions: on no treatment and after subcutaneous octreotide. Exercise was performed 120 min after octreotide in eight subjects and 60 min after octreotide in ten subjects. 3. Octreotide did not improve exercise-induced hypotension; the blood pressure fall was greater during exercise, but the blood pressure level was no different than without treatment. Heart rate, stroke distance, cardiac index and systemic vascular resistance were similar at rest and changed to the same degree with exercise on and off octreotide. After octreotide, resting levels of serum growth hormone, plasma noradrenaline, adrenaline and renin were unchanged, but glucose was higher and insulin was lower. There was no change in biochemical and hormone levels during exercise either off or on octreotide. 4. After octreotide, although the rate of blood pressure recovery was similar post-exercise, the levels of blood pressure were higher than in the non-treatment phase and postural hypotension was improved before and after exercise. 5. In conclusion, in primary autonomic failure, octreotide did not improve exercise-induced hypotension in the supine position, suggesting that octreotide-sensitive vasodilatory peptides do not contribute to the blood pressure fall.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Octreotide reduces alcohol-induced hypotension and orthostatic symptoms in primary autonomic failure.
Symptomatic postural hypotension is a major problem in patients with primary idiopathic autonomic failure, and ingestion of small quantities of alcohol may worsen the degree of postural hypotension. The proposed mechanisms include mesenteric vasodilation and release of vasodilatory gut peptides. We measured systemic, mesenteric, other regional vascular and biochemical responses to alcohol ingestion before and after pre-treatment with the somatostatin analogue Octreotide (which inhibits the release of a wide range of gut peptides normally released in response to food ingestion) in six patients with primary autonomic failure. Octreotide effectively prevented alcohol-induced hypotension and vasodilatation of the mesenteric vascular bed, with improvement of signs and symptoms of hypotension post-alcohol. This suggests that the mechanism of alcohol-induced symptomatic hypotension in autonomic failure is at least partly mediated by release of vasodilatatory gut peptides with resultant mesenteric vasodilatation.
Aged↗
Species-dependent binding of copper(II) bis(thiosemicarbazone) radiopharmaceuticals to serum albumin.
UNLABELLED: Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)-copper(II) (Cu-PTSM) is a generator-based PET radiopharmaceutical under investigation for use in evaluation of tissue perfusion. Despite promising results from animals, problems have been encountered in the use of 62Cu-PTSM to quantitate myocardial perfusion in humans at high flow rates, possibly due to species-dependent interactions of the tracer with serum albumin. METHODS: Ultrafiltration and plasma/erythrocyte partitioning studies were performed to assess the protein binding of 67Cu-labeled Cu-PTSM and six related copper(II) bis(thiosemicarbazone) complexes. RESULTS: These studies reveal significant interspecies variability in the strength of Cu-PTSM binding to serum albumin, with 67Cu-PTSM binding much more strongly to human albumin than to dog albumin. Most of the related Cu(II)-bis(thiosemicarbazone) complexes examined exhibit interspecies variability of albumin binding similar to that observed with Cu-PTSM. Two such complexes, Cu-ETS and Cu-n-PrTS, however, were identified that exhibit no preferential association with human serum albumin. CONCLUSION: Copper-62-PTSM exhibits substantial interspecies variability in the strength of its binding to serum albumin, which appears to explain the problems encountered in using animal data to predict 62Cu-PTSM behavior in humans. The 62Cu-ETS and 62Cu-n-PrTS complexes may be viable alternatives to 62Cu-PTSM for PET studies to evaluate quantitatively myocardial blood flow in humans.
Animals↗
Orthostatic hypotension: causes, mechanisms, and influencing factors.
Blood pressure homeostasis is particularly challenged by moving to an upright position. The autonomic nervous system, structural factors, infravascular volume, and circulating and local hormones influence the body's response to a change in posture. Disorders of the autonomic nervous system can result in orthostatic hypotension. Both neurogenic and nonneurogenic disorders can contribute, and distinguishing between the two causes is important for both diagnosis and management. It is also important to recognize various factors in daily life that influence orthostatic hypotension.
Hemodynamics↗
Postural hypotension enhanced by exercise in patients with chronic autonomic failure.
The effect of supine exercise on blood pressure (BP), measured while recumbent and after head-up postural change, was investigated in three groups with marked postural hypotension due to chronic autonomic failure: 15 with associated neurological impairment (Shy-Drager syndrome, SDS, multiple system atrophy); 15 with pure autonomic failure (PAF) and two with a deficiency of the enzyme dopamine beta hydroxylase (DBH deficiency). Fifteen normal subjects were controls. In controls, exercise increased supine BP, and there was no postural fall before or after exercise. In SDS and PAF, however, exercise produced a substantial fall in BP, which was greater in PAF. In both groups, BP fell to a lower level on standing after than before exercise. In DBH deficiency, there was little change in BP with exercise, but BP fell to a lower level on standing after exercise. In all three groups with autonomic failure, there were more symptoms of postural hypotension on standing after exercise. The influence of exercise on both supine and postural BP, therefore, should be considered in the clinical and laboratory assessment of autonomic dysfunction.
Aged↗
Effects of the peptide release inhibitor, octreotide, on daytime hypotension and on nocturnal hypertension in primary autonomic failure.
OBJECTIVE: To investigate the effects of the somatostatin analogue octreotide, which inhibits the release of various peptides, on 24-h ambulatory blood pressure profiles in subjects with primary (idiopathic) autonomic failure due to sympathetic denervation, and in particular to determine whether octreotide reduces daytime hypotension and whether it causes or accentuates nocturnal hypertension. SUBJECTS AND METHODS: Eighteen subjects with primary autonomic failure, confirmed by detailed physiological and biochemical autonomic tests, were studied in a randomized manner on two occasions, with and without octreotide treatment (1 mu g/kg body weight subcutaneously, twice a day at 0800 and 1800 h). Blood pressure was measured using the SpaceLabs 90207 system. This was connected at 0900 h with programmed recordings at 30-min intervals until 2300 h and at 60-min intervals until the next morning. There were additional subject-initiated recordings after 5 min each of lying, sitting and standing four times during the day, while sitting after lunch at noon and while standing following walking in the evening. Additional analyses included calculation of cumulative sum (cusum)-derived parameters and construction of cusum plots. RESULTS: After octreotide treatment, the overall mean daytime systolic/diastolic blood pressure (mmHg) was raised (123 +/- 2/77 +/- 1 without treatment versus 128 +/- 2/79 +/- 1 with treatment). There was a reduction in postural (supine versus standing: from 96 +/- 3/62 +/- 3 without treatment to 106 +/- 5/67 +/- 4 with treatment), postprandial (107 +/- 3/65 +/- 2 to 122 +/- 5/75 +/- 4) and exertion-induced (96 +/- 5/61 +/- 5 to 113 +/- 6/71 +/- 5) hypotension. Symptoms of hypotension were reduced by octreotide. Nocturnal blood pressure was lower after octreotide (139 +/- 3/84 +/- 1 versus 129 +/- 3/78 +/- 2). Analyses with the cusum technique further demonstrated blood pressure recovery during the day, with a reduction in the magnitude of change at night after octreotide treatment. CONCLUSIONS: In primary autonomic failure, 24-h ambulatory blood pressure profiles and cusum analyses indicate that octreotide has beneficial effects in reducing postural, postprandial and exertion-induced hypotension, without causing or increasing nocturnal hypertension.
Adult↗