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R H Myers

Publications and source records attributed to R H Myers.

At least 19 recordsLinked to original sources
PubMed1996

Incomplete dominance of type III hyperlipoproteinemia is associated with the rare apolipoprotein E2 (Arg136-->Ser) variant in multigenerational pedigree studies.

In the process of screening apolipoprotein (apo) E genotypes in a population of subjects with lipid abnormalities, we have identified five subjects (one homozygote and four heterozygotes) with an abnormal 109 base pairs band following apo E restriction isotyping of amplified DNA with the restriction endonuclease CfoI. The polymerase chain reaction (PCR) products were cloned and their sequencing revealed a C-->A substitution at the first nucleotide of codon 136. This mutation resulted in an amino acid substitution Arg to Ser, previously described as apo E2 Christchurch. Family studies were carried out for four of the probands. In these kindreds, stepwise multiple regression analyses indicated that 78% of the cholesterol variability in men was predicted by body mass index, age and the rare apo E2 (Arg136-->Ser) variant. In women, age and the apo E2 (Arg136-->Ser variant predicted 54.9% of the variability in cholesterol levels. Linkage analysis suggested that the presence of the apo E2 (Arg136-->Ser) variant was linked with the occurrence of cholesterol enriched triglyceride rich lipoproteins and with an incomplete dominance of type III hyperlipoproteinemia. Our data indicates that this mutation may be a relatively common cause of dyslipidemia in the Spanish population.

Adult↗
PubMed1996

Absence of association or genetic linkage between the angiotensin-converting-enzyme gene and left ventricular mass.

BACKGROUND: Homozygous carries of the D allele of the angiotensin-converting-enzyme (ACE) gene have been reported to be at increased risk for various cardiovascular disorders, including left ventricular hypertrophy. We investigated the potential role of the ACE gene in influencing left ventricular mass. METHODS: Quantitative echocardiographic data and DNA samples were available for 2439 subjects from the Framingham Heart Study. ACE genotypes were determined by an assay based on the polymerase chain reaction. (The D allele of the ACE gene contains a deletion, whereas the I [insertion] allele does not.) Left ventricular mass and the prevalence of left ventricular hypertrophy, adjusted for clinical covariates, were analyzed according to genotype. Genetic linkage between the ACE locus and left ventricular mass was evaluated by quantitative analysis of pairs of siblings. RESULTS: The ACE genotype was associated neither with left ventricular mass nor with the prevalence of left ventricular hypertrophy. Mean (+/-SE) left ventricular mass (adjusted for sex) among subjects carrying the DD, DI, and II genotypes was 165+/-1.6, 165+/-1.3, and 166+/-2.0 g, respectively (P=0.90). The prevalence of left ventricular hypertrophy among the three genotype groups was 15.6 percent, 13.6 percent, and 15.6 percent, respectively (P=0.36), and the adjusted relative risk of left ventricular hypertrophy associated with the DD genotype was 1.10 (95 percent confidence interval, 0.86 to 1.19). Linkage analysis in 759 pairs of siblings using both the ACE D/I marker and a microsatellite polymorphism at the neighboring locus for the human growth hormone gene failed to support any role of ACE in influencing left ventricular mass. CONCLUSIONS: The ACE genotype showed no association with echocardiographically determined left ventricular mass, nor did it confer an increased risk of left ventricular hypertrophy. We found no appreciable role of the ACE gene in influencing left ventricular mass.

Adult↗
PubMed1996

Evidence of cortical metabolic dysfunction in early Huntington's disease by single-photon-emission computed tomography.

We compared perfusion of prefrontal, motor, and sensory cortices and basal ganglia in 29 Huntington's disease (HD) patients and nine controls. We found a significant reduction in perfusion in patients with HD of short (< 6 years, n = 10), medium (6-10 years, n = 8), and long duration (> 10 years, n = 11) compared with controls. Among short-duration patients, we observed decreases in cortical perfusion before evidence of atrophy on magnetic resonance imaging, suggesting that decreases in neuronal activity, as reflected by perfusion levels, precede gross structural changes. As expected, decreased perfusion was marked in basal ganglia. The extent of cortical perfusion correlated with clinical assessments of functional capabilities as well as with the duration of disease. Prefrontal perfusion correlated with cognitive measures, and motor cortical perfusion correlated with physical disability and activities of daily living scores. We found no significant clinical correlations with sensory cortical perfusion. Single-photon-emission computed tomography may be a sensitive method for assessing disease progression in clinical trials and pharmacologic intervention.

Adult↗
PubMed1996

Two-stage designs for the logistic regression model in single-agent bioassays.

In this paper we focus on the use of a two-stage procedure for logistic regression that emphasizes predicting response through the use of the Q-optimality criterion. The use of D-optimality in the first stage is primarily to allow best possible parameter estimates as one enters the second stage. However, it is important to understand that there are many ways to formulate the two-stage procedure. It may involve any optimality criterion in either stage. In fact, theoretically, one need not stop at two stages. It was our intention in this paper to demonstrate the potential in the two-stage procedure in cases in which good initial parameter estimates are not available. Those investigators who are interested in the software for the two-stage procedure described here should contact Dr. William R. Myers.

Animals↗
PubMed1996

Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study.

Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimer's disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established. We examined the association of apoE epsilon4 with AD and other dementias (mainly multi-infarct or dementia following stroke) in 1,030 persons aged 71 to 100 years in the population-based Framingham Study cohort. Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years. In comparison with persons without a 4 allele, the risk ration for AD was 3.7 (95% CI = 1.9 to 7.5) for apoE epsilon3/epsilon4 heterozygotes and 30.1 (95% CI = 10.7 to 84.4) for apoE epsilon4 homozygotes. ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD. One-half (n=21) of the 43 AD patients were either homozygous or heterozygous for apoE epsilon4. We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke. The risk ratio was 2.3 (95% CI = 0.9 to 6.1) for non-AD dementias among persons with apoE epsilon3/epsilon4. Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated. The low positive predictive value of this marker (0.10) suggest that use of apoE genotyping as a screening test for AD is not supported.

Adult↗
PubMed1995

Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum.

The CAG triplet repeat region of the Huntington's disease gene was amplified in 923 single sperm from three affected and two normal individuals. Average-size alleles (15-18 repeats) showed only three contraction mutations among 475 sperm (0.6%). A 30 repeat normal allele showed an 11% mutation frequency. The mutation frequency of a 36 repeat intermediate allele was 53% with 8% of all gametes having expansions which brought the allele size into the HD disease range (> or = 38 repeats). Disease alleles (38-51 repeats) showed a very high mutation frequency (92-99%). As repeat number increased there was a marked elevation in the frequency of expansions, in the mean number of repeats added per expansion and the size of the largest observed expansion. Contraction frequencies also appeared to increase with allele size but decreased as repeat number exceeded 36. Our sperm typing data are of a discrete nature rather than consisting of smears of PCR product from pooled sperm. This allowed the observed mutation frequency spectra to be compared to the distribution calculated using discrete stochastic models based on current molecular ideas of the expansion process. An excellent fit was found when the model specified that a random number of repeats are added during the progression of the polymerase through the repeated region.

Alleles↗
PubMed1994

Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study.

OBJECTIVE: To describe the association between apolipoprotein E alleles (epsilon 2, epsilon 3, and epsilon 4), dyslipidemias, and coronary heart disease (CHD). DESIGN: Cross-sectional prevalence study. SETTING AND PARTICIPANTS: Community-based sample of men (n = 1034) and women (n = 916) aged 40 to 77 years who are participating in a long-term study of cardiovascular disease. Study participants underwent fasting lipid measurements, coronary risk factor determinations, and a comprehensive evaluation for the presence of current or previous CHD. RESULTS: Compared with the epsilon 3 allele, the epsilon 4 allele was associated with elevated low-density lipoprotein cholesterol values (> or = 4.14 mmol/L [160 mg/dL]) in women, the epsilon 2 and epsilon 4 alleles were associated with moderately elevated triglyceride values (> or = 2.82 mmol/L [250 mg/dL]) in men, and the epsilon 2 allele was associated with severely elevated triglyceride values (> or = 5.64 mmol/L [500 mg/dL]) in men. The apolipoprotein E alleles were not associated with hypertension, obesity, smoking, or diabetes, but the epsilon 4 allele frequency was reduced in women after 60 years of age. The age-adjusted prevalence of CHD was associated with the epsilon 4 allele in both men (relative odds = 1.53, P = .04) and women (relative odds = 1.99, P = .05). In analyses for women and for both sexes combined, this relation persisted after adjustment by hypertension, smoking, obesity, diabetes, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. CONCLUSIONS: Apolipoprotein E alleles are important genetic markers for dyslipidemia and CHD. The estimated CHD odds associated with the epsilon 4 allele appears to be greater than that for any other known genetic lipid abnormality, and the association of the epsilon 4 allele with CHD remains significant in women and both sexes combined after adjustment by traditional coronary risk factors and lipids.

Adult↗
PubMed1994

A clinical genetic study of Parkinson's disease: evidence for dominant transmission.

We used a family history questionnaire, semi-structured interview, and personal examination of secondary cases to collect data on the prevalence of Parkinson's disease (PD) in relatives of patients seen consecutively for 1 year and assessed the proportion of secondary cases of PD as a function of pedigree completeness. Survival analysis methods were applied to estimate the lifetime risk and age-at-onset distribution of PD among first-degree relatives of probands. When we considered siblings of probands with affected parents, the cumulative risk increased significantly over siblings of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. We further analyzed 80 multicase families with two or more affected individuals. Age-adjusted segregation ratios approaching 0.5 and similar proportions of affected parents and siblings, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD.

Adolescent↗
PubMed1993

Segregation analysis for high density lipoprotein in the Berkeley data.

Transmission models for high density lipoprotein (HDL) were evaluated in the Berkeley data set through segregation analyses using S.A.G.E. These preliminary analyses indicate that among the models fitted, an additive model with non-Mendelian transmission probabilities provides a good fit for HDL, suggesting the possibility of a significant environmental component in the transmission of HDL. After adjustment for triglyceride, however, Mendelian models for a major gene seem to provide as good a fit as non-Mendelian models but the results do not permit distinction between a dominant model and an additive model.

California↗
PubMed1993

De novo expansion of a (CAG)n repeat in sporadic Huntington's disease.

Huntington's disease (HD) chromosomes contain an expanded unstable (CAG)n repeat in chromosome 4p16.3. We have examined nine families with potential de novo expression of the disease. With one exception, all of the affected individuals had 42 or more repeat units, well above the normal range. In four families, elderly unaffected relatives inherited the same chromosome as that containing the expanded repeat in the proband, but had repeat lengths of 34-38 units, spanning the gap between the normal and HD distributions. Thus, mutation to HD is usually associated with an expansion from an already large repeat.

Adult↗
PubMed1993

Gametic but not somatic instability of CAG repeat length in Huntington's disease.

Instability of a CAG repeat in 4p16.3 has been found in Huntington's disease (HD) chromosomes. Unlike a similar repeat in the fragile X syndrome, the expanded HD repeat showed no evidence of somatic instability in a comparison of blood, lymphoblast, and brain DNA from the same persons. Four pairs of monozygotic HD twins displayed identical CAG repeat lengths suggesting that repeat size is determined in gametogenesis. In contrast with the fragile X syndrome and with HD somatic tissue, mosaicism was readily detected as a diffuse spread of repeat lengths in DNA from HD sperm samples. Typically, the modal repeat size was larger in the sperm DNA than in corresponding lymphoblast DNA, with the greatest degree of gametic mosaicism coinciding with the longest somatic CAG repeats. These data indicate that the developmental timing of repeat instability appears to differ between HD and fragile X syndrome, and that the fundamental mechanisms leading to repeat expansion may therefore be distinct.

Adolescent↗
PubMed1993

Familial aggregation of stroke. The Framingham Study.

BACKGROUND AND PURPOSE: Family history is perceived to be an important risk factor for stroke despite conflicting published data. We examined patterns of familial aggregation of stroke among three generations using data from the Framingham Study. METHODS: Cox proportional hazards analyses, adjusting for known stroke risk factors, were used to examine familial concordance in three groups: (1) members of the original Framingham cohort using reported parental stroke death; (2) members of the Framingham Offspring Study and their parents (members of the original Framingham Study); and (3) sibships within the original Framingham cohort. RESULTS: We found no association between stroke or transient ischemic attack among original cohort members and their reported parental stroke death (n = 4933; relative risk [RR] = 1.07). Using verified cases of parental stroke or transient ischemic attack, the Offspring analyses revealed that both paternal (n = 1762; RR = 2.4; 95% confidence interval [CI], 0.96 to 6.03) and maternal (n = 2074; RR = 1.4; 95% CI, 0.60 to 3.25) histories were associated with an increased risk. Parental history of coronary heart disease was strongly associated with stroke or transient ischemic attack among Offspring Study members (RR = 3.33; 95% CI, 1.27 to 8.72). Sibling history of stroke or transient ischemic attack was not associated with stroke or transient ischemic attack among original cohort members, although a non-statistically significant increased risk associated with sibling history of atherothrombotic brain infarction was observed (RR = 1.8; 95% CI, 0.68 to 4.94). CONCLUSIONS: These analyses suggest that parental history of stroke may be a risk factor for stroke. As more stroke or transient ischemic attack events develop among the Offspring Study members, it will be valuable to reexamine these associations.

Adult↗
PubMed1993

Evidence for neuronal degeneration and dendritic plasticity in cortical pyramidal neurons of Huntington's disease: a quantitative Golgi study.

Aided by a computer microscope, the Eutectic Neuron Tracing System, we performed a quantitative analysis of 59 rapid Golgi-impregnated pyramidal neurons from the third and fifth prefrontal cortical layers (P III and P V neurons) in tissue sections obtained from seven autopsied Huntington's disease (HD) patients (grades 2 through 4) and 59 corresponding cells from eight age-matched control cases. Relative to controls, P III HD neurons had a significant increase in the number of primary dendritic segments arising from soma, total dendritic length, and total surface area. The HD cells also had significantly more dendritic branches at three intervals of measurement in a Sholl diagram (100 microns, 200 microns, and 400 microns from the soma) and a significant increase in the number of dendritic branching points. The dendritic spine density in P III HD neurons was comparable to that of control subjects and significantly lower than that in P V HD cells. The total number and the total density of dendritic swellings were significantly increased in both P III and P V neurons, being most numerous in grades 2 and 3 cases. Rare withered cells with shrunken dendritic trees, harboring few spines and numerous varicosities on their dendritic shafts, were present in HD but not in control cases. Thus, while a small fraction of prefrontal cortical pyramidals degenerates in HD, the plasticity of the remaining pyramidal neurons, evidenced as an orderly augmentation of the dendritic tree, may represent a compensatory response sufficient to maintain relatively normal metabolic function of the cortex in most adult-onset cases.

Adult↗
PubMed1993

The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD.

We evaluated the hypothesis that Huntington disease (HD) is influenced by the normal HD allele by comparing transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring. Analysis of information from 21 sibships in 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent. Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset. These findings suggest that the expression of HD is modulated by the normal HD allele or by a closely linked locus.

Adolescent↗
PubMed1992

Family patterns of coronary heart disease mortality: the Framingham Longevity Study.

Family patterns for age at death were examined in a 40 year follow-up of 5209 men and women (2900 deceased, 2309 living) in the Framingham Study and their parents. Age at death of both mothers and fathers was significantly older for surviving offspring when compared to decreased offspring (p less than 0.0001). When longevity was assessed according to cause of death in the offspring, parental age at death was a significant predictor of death by coronary heart disease (CHD), but not for stroke or cancer. Multiple regression analysis for offspring with sudden CHD death revealed that mother's age at death was a significant predictor of age at sudden CHD death (p less than 0.0003) whereas father's age at death was a significant predictor of age at death in non-sudden CHD death (p less than 0.004). Life table analysis showed longest survival rates associated with both parents surviving to age 75 or older followed by mother only surviving to age 75 or older, then father only, and shortest survival with neither parent surviving to age 75. Longevity appears to be more strongly associated with maternal death age than parental death age. Proportional hazards analysis of risk factors associated with CHD revealed that systolic blood pressure, sex of the individual, and cigarette smoking were the most significant predictors of death age. These findings suggest that familial similarities for death age may be mediated primarily through shared CHD risk factors within families, either genetic or non-genetic.

Adult↗
PubMed1992

Evidence of presymptomatic cognitive decline in Huntington's disease.

Asymptomatic persons at risk for Huntington's disease (HD) (N = 28) were assessed with neuropsychological, psychiatric, and neurologic tests while undergoing genetic linkage studies to determine their probability of carrying the HD gene. Those participants who were subsequently identified as probable gene carriers did not differ on neurologic or psychiatric examination from those subsequently identified as probable noncarriers. Neuropsychological data are presented for a subset of participants free of other conditions (such as alcoholism) putting them at risk for cognitive deficits. Among these subjects, probable gene carriers were inferior to probable noncarriers on the neuropsychological battery as a whole and on several individual tests involving learning and memory. The results suggest the presence of cognitive decline prior to identifiable motor impairments in HD.

Adult↗