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Biomedical subjects

K O Ash

Publications and source records attributed to K O Ash.

At least 37 records · Page 2Linked to original sources
PubMed1988

Genetic and epidemiological studies on electrolyte transport systems in hypertension.

In recent years several different tests of cations in human cells have been studied to detect and to define possible roles in the development of essential hypertension. The goal of this report is to summarize what has been learned in genetic and epidemiological studies of human populations. The seven tests reviewed in greatest detail include sodium-lithium countertransport, intraerythrocytic sodium, sodium (or lithium)-potassium cotransport, lithium leak, sodium-potassium ATPase pump, sodium pump sites (ouabain binding), and circulating sodium pump inhibitor ('digoxin-like factor' in some studies). Countertransport, intraerythrocytic sodium and cotransport consistently show different values in hypertensives compared to normotensives and even in normotensives with a positive family history of hypertension when compared to controls without a positive family history. Thorough genetic studies have been carried out only for sodium-lithium countertransport and intraerythrocytic sodium. Both of these tests are highly heritable with a combination of both polygenic and major gene effects. Cotransport, leak, and pump sites also seem to be quite significantly heritable whereas the ATPase pump activity and the circulating pump inhibitor seem to be largely determined by nongenetic factors. Some of the most dramatic changes in these tests have been observed during pregnancy. Significant increases are seen in countertransport, cotransport, ouabain binding sites, and digoxin-like factor. Oral contraceptives also seem to affect at least cotransport. Plasma triglyceride level and body weight are some of the strongest correlates of countertransport, cotransport, and lithium leak. Cotransport increases with higher dietary sodium intake and decreases with the use of the diuretic medication. In the current developmental stage these tests have several significant limitations. In most population studies there is a considerable overlap of test values between persons with high and normal blood pressure. There are substantial variations in the methods used by different laboratories for the same tests. They are expensive, complex and usually must be done on fresh cells. There are conflicts between the results of several different reported studies that could be due to the way in which their subjects were selected, the effects of medications or other uncontrolled variables, or even due to the differences in laboratory methodologies.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Transport↗
PubMed1988

Hypertension and sodium-lithium countertransport in Utah pedigrees: evidence for major-locus inheritance.

Likelihood analysis was used to test for evidence that an allele at a major locus elevates rates of sodium-lithium countertransport (SLC) in a sample of 1,989 members of 89 Utah pedigrees. The pedigrees were ascertained through two or three sibs who died of stroke before age 74 years (stroke pedigrees), through hypertensive and normotensive probands of the Salt Lake Center of the Hypertension Detection and Followup Program (HDFP pedigrees), or through men who suffered a myocardial infarction before age 55 years (coronary pedigrees). Major-locus inheritance could be rejected in the total sample; transmission probability estimates of tau1 = .972, tau2 = .520, tau3 = .185 differed significantly from Mendelian transmission specified by tau1 = 1, tau2 = 1/2, tau3 = 0. However, heterogeneity between ascertainment groups was significant (chi2(18) = 40.06, P less than .01) and justified analysis within subsets of the sample. In the stroke pedigrees, evidence of major-locus inheritance was not found; polygenic heritability was estimated as .647. In the HDFP pedigrees, estimates of tau1 = .987, tau2 = .430, tau3 = .506 differed significantly from Mendelian transmission; the inferred model consisted of a mixture of two distributions incompatible with both Mendelian and environmental transmission but compatible with polygenic inheritance within distributions. In the coronary pedigrees, the hypothesis of Mendelian transmission could not be rejected. In the coronary pedigrees, the evidence supported an incompletely recessive allele with a frequency of .227 which elevated the level of SLC to a mean of .530 mmol/liter RBC/h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Preliminary evidence for genetic determination of intraerythrocytic sodium concentration in Utah pedigrees.

Intraerythrocytic sodium concentration has been reported to be increased in hypertensive individuals and some of their normotensive relatives. We investigated the "familiality" of this trait in 572 nonhypertensive subjects from 34 Utah kindreds. Most of these kindreds were selected because of a high incidence of hypertension, heart attack, or stroke. Intraerythrocytic sodium concentration was correlated with the sex of the subject and suprailiac skinfold thickness. Intraerythrocytic sodium concentration was adjusted by linear regression for these 2 factors. The residual values were positively correlated in parent-offspring pairs and among sibs, both those presumed to be living together and those presumed to be living apart. The spouse-spouse correlation was not significant. Pedigree analysis suggested a mixed major-gene/polygenic model of inheritance, but these data did not allow us to distinguish between dominant and recessive inheritance for the major gene component. Total heritability due to both major-gene and polygenic components was estimated to be 90-95%; the proportion of the total variance due to polygenes was estimated to be 60-75%. These results suggest that further study of the relationship between the inheritance of intraerythrocytic sodium and the pathophysiology of hypertension is warranted.

Epidemiologic Methods↗
PubMed1987

Familial correlations from genes and shared environment for urine, plasma, and intraerythrocytic sodium.

Spouse-spouse, sib-sib, and parent-offspring correlations were calculated for urinary, plasma, and intracellular sodium levels on over 1,900 persons aged 3-86 years in 98 Utah kindreds. For 36 hours prior to their clinic visit, 31% of the sample was salt-loaded with salt tablets, while the rest followed their normal diet. For those on their normal diet, urine creatine-, age-, and sex-adjusted urinary sodium excretion from a timed 12-hour overnight sample showed similar and significant correlations between spouses (r = .29), sibs less than 20 years old (r = .38), and parent-offspring pairs for offspring less than 20 years old (r = .29). This contrasted with the lower correlations between sibs 20 years of age and older (r = .10) and parent-offspring pairs for offspring 20 years of age and older (r = .13), presumed to live in different households. Adult plasma sodium sib-sib (r = .13) and parent-offspring (r = .15) correlations were similar to the urinary sodium correlations, while the spouse-spouse (r = .48), the sib-sib (r = .64), and the parent-offspring (r = .63) correlations for those presumed to live in the same household nearly doubled. Intracellular sodium correlations for the adult sibs (r = .32) and offspring (r = .36) were over twice as large as for urinary or plasma sodium, although the spouse-spouse correlation (r = .37) remained large also.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Genetic studies of cation tests and hypertension.

Several tests of cation concentration and transport are being studied among members of large Utah pedigrees as part of a study of the genetic and environmental determinants of essential hypertension. Corrected urinary sodium excretion and plasma sodium concentration correlated well in spouses and siblings (r = 0.21-0.54, p less than 0.001), suggesting the effects of shared family environment (e.g., sodium intake). Intraerythrocytic sodium concentration and sodium-lithium countertransport showed no significant correlation in spouses and very significant correlations between siblings and between parents and offspring (r = 0.34-0.58, p less than 0.001), suggesting mostly genetic determination. Using maximum likelihood tests of different genetic models, both sodium-lithium countertransport and intraerythrocytic sodium showed predominantly polygenic determination (H2 = 70%) and some possible major gene determinants (H2 = 18-25%) for a total heritability of 89 to 95% for these characteristics. These data suggest both genes and shared family environment contribute to the familiality of cation tests. They also illustrate the need and utility of quantitative methods for objective analysis of pedigree data.

Adult↗
PubMed1986

Erythrocyte cation transport activities as a function of cell age.

Erythrocyte cation transport systems were evaluated on cell fractions from 17 subjects. Density centrifugation was used to separate washed red cells into fractions enriched with younger and older cells; the cell age differences in these fractions were verified by reticulocyte counts (means are 3.5% for younger cell fractions and 0.7% for older cell fractions). Red cell age has a pronounced effect on several cation transport activities. The older cell fractions had increases in lithium-potassium cotransport (p less than 0.001), the rate constant for the lithium-potassium cotransport (p less than 0.001) and cellular cation permeability. The older cells had decreases in the number of ouabain binding sites (p less than 0.001), the rate constant for sodium efflux via the sodium-potassium adenosine triphosphatase pumps (p less than 0.001) and the sodium-lithium countertransport (p less than 0.025). In subjects with markedly different cell ages, these effects should be considered when evaluating red cell cation transport activities.

Adolescent↗
PubMed1986

Evidence that men with familial hypercholesterolemia can avoid early coronary death. An analysis of 77 gene carriers in four Utah pedigrees.

To study the genetic influence on serum cholesterol levels and early coronary heart disease, 1,134 individuals were screened from 18 Utah pedigrees. In most pedigrees, serum cholesterol appeared to be a purely polygenic trait, with 54% heritability. In four pedigrees with dominant familial hypercholesterolemia, male heterozygotes had a mean serum cholesterol level of 352 mg/dL, myocardial infarction at an average age of 42 years, and coronary death at an average age of 45 years. An informative pedigree structure allowed the identification of four ancestral males born before 1880 who carried this lethal gene and survived to ages 62, 68, 72, and 81 years. This suggests that some healthy life-style factors protected these men against the expression of a gene that has led to coronary disease by age 45 years in all of their heterozygous great-grandsons. One heterozygote showed a drop in serum cholesterol level from 426 to 248 mg/dL, with strict adherence to a low-fat diet without drugs. These observations should help encourage physicians to try harder to identify and help such individuals.

Adult↗
PubMed1986

A re-examination of major locus hypotheses for high density lipoprotein cholesterol level using 2,170 persons screened in 55 Utah pedigrees.

A dominant major locus (allele frequency of .0025 +/- .0014), resulting in low levels of high density lipoprotein cholesterol (HDL-C), was revealed by likelihood analysis on 2,170 persons in 55 Utah pedigrees. This allele was expressed through HDL-C levels ranging from 20 to 30 mg/dl in seven persons in two pedigrees. Early coronary heart disease was associated with the allele in one pedigree, but not in the other. In the pedigree without associated heart disease, HDL subfractions HDL2 and HDL3 were both low in individuals with the low HDL-C allele. No other major locus determining either high or low levels of HDL-C was identified in our sample. Polygenic heritability as part of the mixed model was estimated as .561 +/- .035.

Adolescent↗
PubMed1986

Associations of three erythrocyte cation transport systems with plasma lipids in Utah subjects.

To investigate the pathophysiology of essential hypertension, detailed biochemical and clinical variables were collected and analyzed for 2091 Utah subjects aged 3 to 83 years. Three different measurements of erythrocyte cation transport were obtained: Na+-Li+ countertransport, Li+-K+ cotransport, and furosemide-insensitive Li+ efflux into MgCl2. Total plasma cholesterol, triglycerides, and high density lipoprotein cholesterol levels were obtained from fasting subjects. Levels of high density lipoprotein subfractions 2 and 3 were also obtained from 350 subjects. Standardized data collection also included blood pressure, height, weight, and presence or absence of a diagnosis or treatment of essential hypertension. In univariate analyses of all 1420 adults, each of the three transport systems showed the same significant correlations with triglyceride levels (r = 0.33-0.35, p less than 0.0001), high density lipoprotein concentration (r = -0.19 to -0.21, p less than 0.001), and weight (r = 0.22-0.28, p less than 0.0001). In multivariate regression analyses, values for each transport system were significantly higher in hypertensive subjects; values for triglycerides, high density lipoprotein, and usually, the high density lipoprotein subfractions continued to have strong significant independent associations with all three transport systems; and weight remained significantly related only to Na+-Li+ countertransport. In separate logistic regressions, plasma triglyceride levels (positively, p less than 0.001) and high density lipoprotein subfraction 3 levels (inversely, p less than 0.03) were associated with hypertension itself. In multivariate analyses among 671 children, high density lipoprotein and high density lipoprotein subfraction 3 levels showed significant (p less than 0.05) inverse correlations with Na+-Li+ countertransport and furosemide-insensitive Li+ efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Evidence for environmental familiality of kallikrein excretion in Utah kindreds.

In investigating the role of urinary kallikrein in the pathophysiology of hypertension, we measured 12-hour kallikrein excretion in 1,100 persons in 68 Utah kindreds. The kallikrein excretion was statistically adjusted to account for variations in body size and urine output. Adjusted kallikrein excretion was greater in youths than in adults and correlated with potassium excretion and sodium excretion in persons with normal blood pressure. It was decreased in normotensive subjects with strong family histories of stroke and hypertension, but was not significantly different in adults with hypertension. Adjusted kallikrein excretion was correlated between pairs of siblings, parent-offspring pairs and spouses. Our results indicate that kallikrein excretion is a familial variable, with the familiality due more to shared environmental than genetic factors.

Adolescent↗
PubMed1986

Formic and lactic acidosis in a fatal case of methanol intoxication.

A 33-year-old white man was admitted to the University of Utah Hospital after about 30 h of various symptoms, including blurred vision and (eventually) severe left flank and back pain. Upon admission, his serum pH was 6.80 and serum bicarbonate concentration (calculated from pCO2 and pH) was 3.9 mmol/L. The etiology for the acidosis became apparent 10 h after admission, when assay of the serum prepared from a blood specimen obtained at admission revealed a methanol concentration of 74 mmol/L (2.4 g/L). At this time the patient was placed on hemodialysis and intravenously infused with sodium bicarbonate. The methanol concentration in serum had decreased to 21 mmol/L 2 h later. Formate and lactate concentrations were, respectively, 10 and 23 mmol/L in serum sampled 4.5 h after hospitalization, at which time serum pH was 6.91 and bicarbonate concentration 7 mmol/L. The patient eventually died with extensive neuropathy.

Acid-Base Equilibrium↗
PubMed1985

Urinary kallikrein: assay validation and physiological variability.

Decreased urinary kallikrein (UK) output has been suggested as a preclinical indicator of essential hypertension. In preparation for UK studies in hypertension prone Utah kindreds, we assessed selected UK assay parameters and physiological variability. Precision for the colorimetric kallikrein assay was quite acceptable, coefficient of variation (CV) less than 5% within run and 14% day-to-day at a concentration of 9.5 TU/l. The mean recovery was 105% and assay results were correlated with results from the 3H-TAME esterase method, r = 0.990. Urine specimens were stable at room temperature for up to 4 days, frozen at -20 degrees C for 6 weeks, or frozen at -80 degrees C after Sephadex treatment for a year. UK output varied significantly throughout the day with excretion highest in the morning. Urine collections at 10.00, 12.00 and 14.00 had significantly (p less than 0.05) more UK than the overnight collection. Intra- and inter-individual variations were of the same magnitude, mean 20%. In children UK output increased with age until the adult levels were reached at age 15. Male and female values were similar. Smoking; consumption of alcohol, coffee, tea, cola of chocolate; and female hormone medications did not significantly influence the 12-hour UK output in the 1110 caucasian subjects.

Adolescent↗
PubMed1985

Effects of household sharing on high density lipoprotein and its subfractions.

Household effects accounted for significant proportions of the observed variance of high density lipoprotein cholesterol (HDL-C) and subfractions HDL2 and HDL3. It was found that 19.3% of HDL-C variance could be attributed to a juvenile sib effect (under age 18); 17.4% of HDL2 variance could be attributed to a sib effect (of any age); and 22.1% and 32.6% of the HDL3 variance could be attributed to a parent-offspring effect and a sib effect (of any age), respectively. In addition, additive genetic effects accounted for 56.5%, 37.3%, and 28.3% of the variances of HDL-C, HDL2, and HDL3, respectively. These are maximum likelihood estimates obtained using a variance components model on 2,149 HDL-C levels measured on members of 54 Utah pedigrees, and 337 HDL2 and HDL3 levels measured on a subset of 14 pedigrees.

Adult↗
PubMed1985

The relationship of lithium-potassium cotransport and the passive lithium leak to hypertension in Utah subjects.

Rate constants for lithium-potassium cotransport (kLPC) and the lithium efflux into MgCl2 with furosemide (passive lithium leak) along with sodium-lithium countertransport (SLC) were measured in erythrocytes from 351 normotensive adults age 18 and over, 220 youth under age 18 and in 27 hypertensives. The kLPC was significantly higher in the hypertensives than the adult normotensives with means and standard deviations of 13.9 +/- 9.2 vs. 8.7 +/- 5.9 10(-3)/hr (p less than 0.01). Adjusting for the significant weight (p = 0.014) and sex (p = 0.066, normotensive males higher than females) associations with kLPC in an analysis of covariance, increased the significant difference between the hypertensives and normotensives (p = 0.0004). The passive lithium leak rate constant was also higher in hypertensives than normotensives (20.2 +/- 7.6 vs. 15.5 +/- 5.3 10(-3)/hr, p less than 0.01). Weight (p=0.0003), but not sex, was related to the leak but did not account for the difference between hypertensives and normotensives (p = 0.0009). Mean blood pressure was positively associated with the lithium leak but not the kLPC or SLC values in a multivariate regression.

Adolescent↗
PubMed1984

Hemodialysis does not affect erythrocyte sodium-lithium countertransport.

Sodium-lithium countertransport measurements on erythrocytes are currently of interest because some hypertensive subjects and their relatives have abnormally high values. Woods et al [1] reported that red cells taken from dialysis patients after hemodialysis had significantly lower sodium-lithium countertransport than before dialysis. They suggested that sodium-lithium countertransport is influenced by 'a dialyzable plasma factor'. We conducted experiments to further evaluate their observations relating to the 'dialyzable plasma factor'. However, we have been unable to confirm their findings. Neither an effect of hemodialysis on sodium-lithium countertransport in erythrocytes from maintenance dialysis patients nor any effect of dialysis on normal erythrocytes in vitro was evident. Our results do not support the existence of a dialyzable plasma factor affecting sodium-lithium countertransport.

Adult↗