Biomedical subjects
Publications and source records attributed to L L Heston.
This article considers the molecular aspects, population genetics, and familial versus nonfamilial aspects of Huntington's disease, Alzheimer's disease, Down's syndrome, and Pick's disease. Single-family pedigree studies are discussed.
We studied the effect of the same genetic but different environmental factors on total immunoglobulin and specific antibody levels in twins reared apart. Sera were analyzed from 26 monozygotic (MZ) and 10 dizygotic (DZ) twin pairs, who were separated on average 2 mo after birth and reared apart. Total IgM, IgG, and IgA were measured by single radial diffusion. Specific antibodies of each isotype to tetanus toxoid, and to polyvalent and type 14 pneumococcal capsular polysaccharides were measured by a solid-phase antigen-enzyme-labeled anti-Ig immunoassay. One-way analysis of variance showed intrapair total Ig and antibody levels to be more highly correlated in MZ compared with DZ twins. Our results indicate that genetic factors are more important than environment in regulating these humoral immune responses.
Neuropathologic and neurochemical studies of older adults with Down's syndrome and those with Alzheimer's disease reveal striking similarities. Genetic studies indicate that near relatives of patients with Alzheimer's disease are at increased risk of developing Alzheimer's disease, and the risk appears to be age specific. These families with familial Alzheimer's disease have also been found to have a high incidence of Down's syndrome. Neurochemical data suggest that a cholinergic deficiency must be present for dementia to develop, and serial assessments of brain metabolic function with positron emission tomography in Alzheimer's disease have shown that the parietal lobe has reductions in metabolic function before the onset of neuropsychologic deficits in this brain region. Neuropsychologic testing indicates that patients with Down's syndrome over 35 years old have poorer cognitive skills than do younger patients. Brain metabolic function is excessively reduced in the demented adults with Down's syndrome.
The typical neuropathological features of Alzheimer's disease, plaques and tangles, appear in virtually all patients with Down's Syndrome after the age of 40. Clinically, changes in cognitive performance and behavior appear to correlate with these neuropathological changes, although a satisfactory operational definition of dementia in a context of mental retardation is not available. It is unknown whether the cholinergic losses in the nucleus basalis, which are a feature of early onset Alzheimer's disease, also occur late in Down's syndrome. Two family studies have supported a greater than expected incidence of Down's cases among relatives of probands dying with Alzheimer-type dementia, but the association is not strong. It is noteworthy that in both studies, phenotypically normal carriers of the rare 15/21 translocation had severe early onset dementia, although this translocation is responsible for less than 0.4 per cent of Down's cases. An increased incidence of dementia among carriers of the more common 14/21 translocation has not been reported. In any case, it is proposed that a gene product originating from the long arm of chromosome 21 (21q) is necessary for Alzheimer-type pathology, since a segregating gene could not be responsible for the 100 per cent incidence of these changes among 21q trisomics.
The ages at onset of illness for 39 cases of Pick's and 201 cases of Alzheimer's dementia from two series of unselected cases are presented and analyzed. The frequency of Pick's disease peaks in the sixth decade of life and then decreases, whereas Alzheimer's dementia increases steadily through adult life. At least to age 70 years Pick's and other disorders that cannot reliably be separated from Alzheimer's dementia except by autopsy comprise a significant proportion of dementias. Neuropathological diagnoses are essential for most research in dementing illnesses.
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Relatives of 125 probands, who had dementia of the Alzheimer type as proved by autopsy, were subjects of a genetic investigation. The relatives exhibited an excess of dementing illness consistent with genetic transmission. Risk to relatives decreased sharply as severity of the proband's illness decreased. Also, when compared with a control group and the general population, the relatives had excesses of Down's syndrome, lymphoma, and immune diatheses. These associated conditions also were more likely to be present when the proband had severe illness. Mortality at all ages was increased among the relatives.
The hormonal response to human skin fibroblasts after exposure to beta-adrenergic agonists, prostaglandin E1 (PGE1), and cholera toxin was monitored by intracellular cyclic AMP accumulation. Down syndrome (DS; trisomy 21) cells had an approximately 10-fold greater response to beta-adrenergic agonists than did either normal diploid skin fibroblasts or other aneusomic fibroblast strains (trisomy 13, 18, and 22). The altered response in DS fibroblasts was specific for beta-adrenergic agonists, because treatment of DS or control cells with PGE1 or cholera toxin resulted in the same degree of cyclic AMP accumulation. Experiments with 3-isobutyl-1-methylxanthine, a cyclic nucleotide phosphodiesterase inhibitor, indicated that the increased response of DS fibroblasts was not primarily a function of altered cyclic AMP degradation. Monosomy 21 cells responded less than normal diploid fibroblasts to stimulation by the beta-adrenergic agonist isoproterenol. These findings suggest that genetic information on chromosome 21 participates in regulating the beta-adrenergic response of human fibroblasts.
By comparing MMPI profiles of sedative-dependent subjects during pentobarbital self-administration with comparable subjects during drug abstinence, the present study has found that self-administration tends to increase rather than decrease indicators of personal distress (MMPI scale scores). This finding agrees fully with other studies of drug effects on mood of drug-dependent subjects. (This finding should disturb only those who equate reinforcement with euphoria and other pleasurable states. Those familiar with the concept of reinforcement understand that reinforcement deals only with behavior and implies nothing about corresponding subjective states). Only scores on the Hypomania scale of the MMPI were found to correlate significantly with amount of daily drug intake, and this relationship occurred primarily in females. Scores on the Depression scale were correlated significantly with the daily pattern of drug-taking behavior. However, in neither case is it known whether the relationship reflects influences of personality factors on drug-taking behavior, or influences of drug-taking behavior on the obtained personality measures. Other research will be needed to answer this question. Clinically depressed individuals may constitute a special sub-group of subjects in which scores on many MMPI scales are related to daily amount of drug intake. Studies of human drug self-administration provide an excellent opportunity for more detailed research into these and other clinical research questions.
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Partial purification of soluble guanylate cyclase on DEAE-Sephacel yields two separate peaks of guanylate cyclase activity. After 10-fold purification of the soluble enzyme, guanylate cyclase is markedly inhibited by micromolar concentrations of dopamine (I50 = 0.2 microM). Dopamine inhibition is observed whether the reaction is conducted with Mn2+ or with Mg2+, under atmosphere or N2(g), and using enzyme from either peak from the DEAE-Sephacel column. Other catecholamines also inhibit partially purified guanylate cyclase with an order of potency at 1 microM of: dopamine = L-DOPA > norepinephrine = isoproterenol = adrenochrome > epinephrine. The structural requirements for inhibition are two free hydroxyl groups on the phenyl ring and an ethylamine side chain. Dopamine also inhibits the Triton X-100-solubilized microsomal guanylate cyclase after partial purification on DEAE-Sephacel. Neither chlorpromazine, propranolol, nor phentolamine at 20 microM effectively block the dopamine inhibition of partially purified soluble guanylate cyclase. Micromolar concentrations of the reducing agents dithiothreitol and glutathione also inhibit partially purified guanylate cyclase, but unlike these agents, catecholamines can inhibit whether added in the reduced or the oxidized forms. Inhibition of enzyme activity by micromolar concentrations of dopamine, adrenochrome, or dithiothreitol is rapidly reversed by dilution and the dopamine inhibition is competitive with MgGTP. Inhibition does not appear to involve covalent binding or to result from the ability of catecholamines to reduce the concentrations of oxygen or free radicals in solution.
Relatives of 12 probands who had severe dementia associated with Parkinson's disease were studied. A high risk for Parkinson's disease was found among relatives but only one instance of dementia. The high risk to relatives and the dementia of the probands appeared to be related to the overall severity of the Parkinsonian illness.
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The families of 11 probands with Pick's disease as determined by histopathological examination, were investigated by interview and acquisition of medical records. The estimated morbid risk was 0.25 +/- 0.08 for parents and 0.07 +/- 0.07 for siblings or probands. Further analyses are presented that seek associations between morbid risk and age, sex and age of onset. Data needed for genetic counseling are included.