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Biomedical subjects

R J Polinsky

Publications and source records attributed to R J Polinsky.

At least 37 records · Page 2Linked to original sources
PubMed1991

Central and peripheral effects of arecoline in patients with autonomic failure.

Increased plasma adrenalin (A) levels following arecoline in normal subjects and patients with multiple system atrophy (MSA) may result from nicotinic adrenal stimulation. Lack of this response in patients with pure autonomic failure (PAF) is consistent with peripheral sympathetic dysfunction. The mechanisms underlying diminished plasma corticotropin (ACTH) responses to arecoline may differ in patients with autonomic failure. Hypothalamic, cholinergic degeneration could prevent the response in MSA whereas patients with PAF do not manifest the normal increase in A which may be required to elicit an ACTH response. The appearance and exacerbation of tremor, vertigo, and pathological affect in the MSA group suggest that some central cholinergic receptors remain functional.

Adrenocorticotropic Hormone↗
PubMed1991

Sudomotor function in autonomic failure.

We measured sweat production to direct gland stimulation with intradermal methacholine in patients with autonomic failure and in normal subjects. The sympathetic skin response (SSR) to electrical stimulation was assessed in some of the same subjects. Patients with pure autonomic failure (PAF) and multiple system atrophy (MSA) produced significantly less sweat than controls. None of the patients manifested greater than normal sweat production. Impaired sweat gland function does not differentiate MSA and PAF. The SSR did not correlate with sweat response to methacholine. An SSR can occur in the absence of normal sweat gland function. The diminished production of sweat in response to intradermal methacholine in PAF suggests that human sweat glands do not develop chronic denervation supersensitivity. Intradermal methacholine is a simple method to assess sweat gland function.

Adult↗
PubMed1991

Beta-receptor sensitivity in autonomic failure.

We examined the cardiovascular, plasma norepinephrine (NE), and plasma renin (PRA) responses to isoproterenol infusion in patients with autonomic failure and in normal subjects. Slopes of the blood pressure response/dose relationships were more negative in patients with multiple system atrophy and pure autonomic failure (PAF) than in normal subjects, consistent with impaired baroreflex modulation. A shift to the left in patients with PAF suggests beta-adrenergic receptor supersensitivity. In normal subjects, the increase in plasma NE and PRA was proportional to the log of the plasma isoproterenol level. Isoproterenol infusion did not increase plasma NE or PRA in either patient group despite a reduction in mean blood pressure. Reflexive cardiovascular and renal mechanisms appear to play a role in eliciting the plasma NE and PRA responses to isoproterenol infusion in normal subjects.

Autonomic Nervous System Diseases↗
PubMed1990

Clinical autonomic neuropharmacology.

Autonomic failure can be divided into peripheral and central dysfunction on the basis of pharmacologic characteristics of the disorders. Low plasma NE levels, impaired neuronal uptake, and adrenergic receptor supersensitivity distinguish patients with PAF from those with MSA, who have defective baroreflex modulation of blood pressure and CNS neurotransmitter dysfunction. An increased understanding of neurotransmitter metabolism and function in patients with chronic autonomic failure has led to a variety of rational therapeutic approaches. Much progress has been achieved in the management of orthostatic hypotension, the most disabling feature of autonomic dysfunction. Treatment of the parkinsonian features in MSA is limited by pharmacologic sensitivity and autonomic failure. Elucidation of the neurochemical and pharmacologic abnormalities in these disorders suggests new therapeutic avenues for the future.

Autonomic Nervous System Diseases↗
PubMed1989

HLA in autonomic failure.

We did not find a significant association between HLA antigens and pure autonomic failure or multiple system atrophy with autonomic failure. HLA-A32, specifically, did not occur with increased frequency in either group of patients. Our results do not support an HLA contribution in these disorders of the autonomic nervous system as reported by other investigators.

Autonomic Nervous System Diseases↗
PubMed1989

Patterns of plasma levels of catechols in neurogenic orthostatic hypotension.

Patients with neurogenic orthostatic hypotension can have deficits in sympathetic neural function at any of several levels of the sympathetic neuraxis. We determined whether patterns of plasma levels of dopa, norepinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid would distinguish patients with orthostatic hypotension associated with multiple system atrophy, pure autonomic failure, or deficiency of dopamine-beta-hydroxylase. Plasma levels of catechols were normal in most patients with multiple system atrophy, consistent with relatively intact peripheral sympathetic neurons; in contrast, most patients with pure autonomic failure had decreased levels of all four catechols, consistent with degenerative loss of sympathetic nerve endings. Patients with deficiency of dopamine-beta-hydroxylase had increased levels of dopa and dihydroxyphenylacetic acid and markedly decreased levels of norepinephrine and dihydroxyphenylglycol, suggesting compensatory increases in sympathetic nerve activity in the absence of norepinephrine biosynthesis. Subgroups of patients with pure autonomic failure or multiple system atrophy had low levels of norepinephrine with normal levels of dopa, dihydroxyphenylglycol, and dihydroxyphenylacetic acid, consistent with normal catecholamine biosynthesis and decreased postganglionic sympathetic nerve traffic or decreased exocytotic release from sympathetic nerve endings. The results demonstrate the value of examining patterns of plasma levels of catechols to elucidate mechanisms of neurogenic orthostatic hypotension.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Decreased DNA repair in familial Alzheimer's disease.

Alterations in the capacity of a cell to repair DNA lesions play an important role in a number of human diseases. We and others have demonstrated defective DNA repair of alkylation damage in cells from patients with Alzheimer's disease. It has been hypothesized that this defect is related to the cause of Alzheimer's disease and results in the accumulation of lesions in the central nervous system neurons. One prediction of this hypothesis is that in dominantly inherited Alzheimer's disease, the repair defect will be present in half of the offspring of affected patients long before they develop symptoms of the disease. In order to test the hypothesis that decreased DNA repair is responsible for familial Alzheimer's disease and their at-risk offspring we have studied DNA repair in these individuals after exposure of lymphoblasts to alkylating agents. Our results indicate that cell lines from affected patients repair significantly less damage in 3 h than cell lines from healthy controls. A small number of at-risk individuals were also studied and some of these had lower levels of repair, although more cell lines from individuals in this group must be studied. These findings provide further support for defective DNA repair playing a role in the pathogenesis of Alzheimer's disease.

Adult↗
PubMed1989

Molecular genetics of familial Alzheimer's disease.

The molecular genetic strategies aimed at isolating and characterizing the defective gene(s) in familial Alzheimer's disease, the inherent limitations of the techniques and recent progress in the field are reviewed. Three independent groups have found an apparent linkage to chromosome 21 but two other groups have not, suggesting that familial Alzheimer's disease may be etiologically heterogeneous.

Alzheimer Disease↗
PubMed1989

Changes in blood pressure and plasma noradrenaline in short-term hypothyroidism.

Thirteen patients who had undergone thyroidectomy for thyroid cancer stopped thyroid hormone replacement prior to follow-up radioactive iodine scans. Thyroxine was replaced by triiodothyronine (T3) for 4 weeks and T3 was stopped 2 weeks before the scan and 16 to 19 days before blood pressure measurement and venipuncture for obtaining plasma noradrenaline samples. During this time, a small but significant decrease in systolic blood pressure occurred, both supine and standing, while the corresponding plasma noradrenaline levels increased significantly. These findings indicate that the acute cardiovascular effect of brief thyroid hormone withdrawal is a decrease in blood pressure rather than the increase often observed in chronic hypothyroidism, and that plasma noradrenaline levels may increase much sooner than previously reported after onset of hypothyroidism.

Adult↗
PubMed1989

Molecular genetics of familial Alzheimer's disease.

A proportion of cases of Alzheimer disease show familial aggregation with a pattern of vertical transmission compatible with autosomal dominant inheritance. Isolation of the genetic defect causing this form of Alzheimer disease, which may elucidate the biochemical mechanisms underlying the pathogenesis of the Alzheimer disease phenotype, can theoretically be achieved by first defining the chromosomal location of the disease gene(s) by classical genetic linkage studies in large families segregating this disorder. Subsequently, other cloning strategies can be applied to isolate the disease gene from the chromosomal region showing tight linkage to the disease phenotype. This paper reports some recent results of such studies, and discusses some of the potential confounding events which must be considered when approaching inherited neuropsychiatric disorders using these strategies.

Alzheimer Disease↗
PubMed1989

CSF acetylcholinesterase levels are reduced in multiple system atrophy with autonomic failure.

Diminished CSF levels of acetylcholinesterase in patients with multiple system atrophy attended by autonomic failure suggest that CNS cholinergic involvement may occur in this disorder. The lack of correlation between the low enzyme levels and low CSF levels of monoamine metabolites in these patients indicates that the acetylcholinesterase reduction is not directly related to disruption in these neurotransmitter systems. Normal CSF acetylcholinesterase levels in those patients with pure autonomic failure are consistent with functional integrity of central cholinergic pathways and support a pathophysiologic involvement limited to the peripheral nervous system.

Acetylcholinesterase↗
PubMed1989

DNA repair deficiency for alkylation damage in cells from Alzheimer's disease patients.

We have shown that fibroblasts, lymphocytes and lymphoblasts from patients with Alzheimer's disease (AD) are deficient in the repair of DNA damage induced by the alkylating agents methylmethane sulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Unscheduled DNA synthesis and alkaline elution studies of DNA repair using human skin fibroblasts obtained from patients coming to autopsy have shown that the cells from autopsy confirmed cases of AD have lower levels of DNA repair synthesis after exposure to varying concentrations of either MMS or MNNG. Lymphoblasts derived from individuals with dominantly inherited AD have also been used to study DNA repair. Alkaline elution analysis of DNA repair after exposure to 200 uM MMS or 6 uM MNNG indicates that there is significantly less repair in the lymphoblasts from AD patients. When healthy control cell lines repaired and cell lines from AD patients were exposed to MMS or MNNG respectively significantly less repair occurred in the AD cells. After studying five at risk individuals results indicate that cell lines from two of these people have low levels of DNA repair and three lines have normal repair. These findings support the hypothesis of a DNA repair deficiency in familial AD. Monocytes from healthy control subjects and putative AD patients were analyzed for mutant frequency and DNA repair capacity. Results of unscheduled DNA synthesis experiments using monocytes from 7 healthy controls and 9 presumed AD patients indicates that there is a decreased ability of AD cells to repair MMS and MNNG induced DNA damage.

Alkylating Agents↗
PubMed1988

Relationship between urinary excretion of homovanillic acid and norepinephrine metabolites in normal subjects and patients with orthostatic hypotension.

Patients with neurogenic orthostatic hypotension due to multiple system atrophy (MSA) or pure autonomic failure (PAF) excrete lower amounts of homovanillic acid (HVA) than do normal subjects. There is a highly significant correlation between the rates of excretion of HVA and norepinephrine metabolites. The regression line relating excretion of the dopamine and norepinephrine metabolites suggests that about one third of dopamine formed in noradrenergic neurons is converted to norepinephrine and the remainder metabolized, mainly to HVA. About one fourth of urinary HVA appears to be derived from a source independent of norepinephrine; this source is probably brain dopaminergic neurons.

Atrophy↗
PubMed1988

Gastrin responses in patients with adrenergic insufficiency.

High basal gastrin levels in pure autonomic failure could result from peripheral vagus nerve involvement, whereas the increased response during hypoglycaemia may reflect adrenergic supersensitivity. A reduced gastrin increment in multiple system atrophy was found following insulin-hypoglycaemia and is consistent with decreased gastrin release secondary to diminished central sympathetic nervous system activation in the absence of peripheral denervation supersensitivity.

Adult↗
PubMed1988

Low lumbar CSF levels of homovanillic acid and 5-hydroxyindoleacetic acid in multiple system atrophy with autonomic failure.

Low lumbar CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in patients with multiple system atrophy attended by autonomic failure (MSA) reflect decreased activity in central dopaminergic and serotonergic pathways. These neurochemical changes are consistent with the neuropathological involvement in MSA and distinguish such patients from those with pure autonomic failure who have normal CSF metabolite levels.

Adult↗
PubMed1987

Absence of duplication of chromosome 21 genes in familial and sporadic Alzheimer's disease.

The possibility that Alzheimer's disease (AD) is caused by overexpression or duplication of one or more genes on chromosome 21 has been raised by the observation of AD-like neuropathologic changes in individuals with Down syndrome and by the mapping of both the defect for familial AD and the amyloid beta protein gene to this autosome. Possible duplication on chromosome 21 was investigated in both familial and sporadic AD by means of restriction fragment length polymorphisms for the amyloid and SODI loci, as well as for DNA markers in the vicinity of the familial AD defect and in the critical Down syndrome region of chromosome 21. No evidence of increased DNA dosage was observed in either brain or leukocytes of patients with inherited or sporadic forms of AD. Duplication of these regions is therefore not a frequent event in either form of AD. Furthermore, no significant allelic association was detected between AD and any of the loci, including the amyloid and SODI genes, providing no support for the hypothesis that defects in these specific genes are the primary cause of AD.

Alleles↗
PubMed1987

The genetic defect causing familial Alzheimer's disease maps on chromosome 21.

Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.

Alzheimer Disease↗