A population genetic study of six VNTR loci in three ethnically defined populations.

To investigate the population genetic characteristics of VNTR polymorphisms in human populations, we have studied the allele frequency distribution of six VNTR loci (D1S57, RB1, D1S77, D1S61, alpha-globin 5'HVR, D1S76) in three well-defined populations (Kachari of Northeast India; Dogrib Indian of Canada; and New Guinea Highlander of Papua New Guinea). Even though the number of alleles sampled is limited, 48 to 92 alleles per locus per population, significant variation is noticed in the number of alleles per locus for all the populations. Using alternate summary measures, we have observed that genotype distributions at the six VNTR loci apparently conform to their respective Hardy-Weinberg predictions. Multilocus genotype profiles of the individuals in each of the three populations suggest that the VNTR alleles are independently segregating with the exception of the two linked loci D1S76 and D1S77. Lack of fit of all VNTR loci to one particular model of mutational change, either the Infinite Allele Model or the Stepwise Mutation Model, suggests more than one mechanism for production of new VNTR alleles. This study also indicates that increased heterozygosity at VNTR loci in comparison to protein and blood group loci may lead to more accurate estimates of genetic distance.     

Heterogeneity of apolipoprotein E polymorphism in different Mexican populations

Mexico has approximately 100 million inhabitants. Most of the urban Mexican population has been considered mestizo (Indian and Spanish descent), whereas the Indian population predominates in rural areas and small towns in the countryside. In this study we analyzed the apolipoprotein E (APOE) polymorphism in Guadalajara (the second largest metropolitan area of Mexico) and its surrounding areas, two adjoining states (Nayarit and Durango), and an Indian town (Huichol Indians) from western Mexico. APOE*3 was the most common allele, and APOE*3/*3 was the most common genotype in all populations studied. Guadalajara revealed the highest frequency of the APOE*2 allele (7.8%); the frequency decreased in the rural area (4.4%), followed by Nayarit (1.6%), and was absent in Durango and in the Huichols. On the contrary, the lowest frequency of the APOE*4 allele was in Guadalajara (8.4%); the frequency increased in the rural area (9.3%), in Nayarit and Durango (11.5% and 11.7%), and reached a high frequency in the Huichol Indians (28%). The distribution of the APOE allele in the western population of Mexico is similar to those described in Mexican American migrants living in the United States but is different from those populations living in Mexico City. This study shows the heterogeneity of the Mexican population, where the frequency of the APOE*2 allele is higher in Guadalajara than in other urban areas of Mexico and is similar to frequencies described in the Caucasian population. On the contrary, the Huichols revealed the highest frequency of the APOE*4 allele in Mexico and in the Americas. This information could be useful for the study of dyslipidemias associated with chronic diseases and as markers of ethnic variation in the Americas.     

Heterogeneity in genetic admixture across different regions of Argentina

The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63–68%), 31% Indigenous American (28–33%) and 4% African (3–4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73–79%; Northeast (NEA) 54%, 95%CI: 49–58%; Northwest (NWA) 33%, 95%CI: 21–41%; South 54%, 95%CI: 49–59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75–86%) versus 68% (95%CI: 58–77%), p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88–94%) compared to 54% (95%CI: 51–57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population.     

Heterogeneity of macrophage populations in human lymphoid tissue and peripheral blood

Human lymphoid tissue and peripheral blood leukocytes were stained with six monoclonal antibodies directed against monocyte/macrophage populations. The staining pattern described by each of these monoclonal reagents was compared with the distribution of morphologically distinguishable tissue macrophages. The results show that there exists considerable heterogeneity of tissue macrophages based on the expression of surface and/or cytoplasmic antigens; furthermore, the distribution of cells bearing particular antigenic determinants is associated with distinct regions in normal lymphoid tissue. Double staining methods demonstrated that these antibodies bind to different, as well as to identical, macrophage populations. OKM-1 antibody binds predominantly to sinus histiocytes and tingible body macrophages. The Leu M-1 reagent stains interdigitating reticulum cells, while the KiM-4 antibody labels follicular dendritic cells. Leu M-3 antibody identifies cells predominantly in the germinal center, and histiocytes lining the sinuses. Both CM-1 and BRL-M.1 appear to stain tissue macrophages distributed throughout the lymphoid tissue.     

Estimation of allele frequencies in ethnically heterogeneous populations

A method for reconstructing allele frequencies characteristic of an original ethnically homogeneous population before the start of migration processes is described. Information on both the ethnic group studied and offspring of interethnic marriages is used to estimate the allele frequencies. This makes it possible to increase the informativeness of the sample, which, in the case of ethnic heterogeneity, depends not only on allele frequencies and the total sample size, but also on the ethnic structure of the sample. The problem of estimating allele frequency in an ethnically heterogeneous sample has been solved analytically for diallelic loci. It has been demonstrated that, if offspring of interethnic marriages with the same degree of outbreeding is added to a sample of the ethnic group studied, the sample informativeness does not change. To utilize the information contained in the phenotypes of the offspring of interethnic marriages, representatives of the population from which migration occurs should be included into the sample. The size of the sample ensuring the preassigned accuracy of estimation is minimized at a certain ratio between the numbers of the offspring of interethnic marriages and the "immigrants." To analyze polyallelic loci, a software package has been developed that allows estimating allele frequencies, determining the errors of these estimates, and planning the sample ensuring the preassigned accuracy of estimation. The package is available free at http://mga.bionet.bionet.nsc.ru/PopMixed/PopMixed.html.     

Heterogeneity of ribosomal populations in Escherichia coli cells grown in different media

Summary In order to establish whether ribosomes exhibit heterogeneity with respect to their protein pattern in vivo, E. coli cells were grown in rich or minimal medium and labeled with ¹⁴C and ³H amino acid mixture, respectively. After harvesting, the cells from the different media were mixed, the differently labeled ribosomes isolated and the ribosomal proteins separated. For each protein the ratio of ¹⁴C to ³H was determined and used as an indication of whether differences exist in ribosomal populations synthesized under different growth conditions.With respect to their ratio the ribosomal proteins can be classified as follows: Many of the proteins have a ratio of 1, i. e. they are present in the same amount in both preparations. The ratios for about 30% of the proteins differ only slightly from 1 whereas three proteins namely S6, S21 and L12 have ratios of 2.5 and 3.1 respectively. This means that ribosomal populations isolated from cells grown in rich medium contain these three proteins in two to three fold greater amounts compared to those synthesized in minimal medium.The relevance of these results with respect to the occurrence of heterogeneous ribosomal populations in vivo is discussed.Paper Nr. 36 on Ribosomal Proteins. Preceding paper is by H. J. Weber, Mol. Gen. Genetics 119, 233–248 (1972).     

Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification

Control of blood pressure and of blood flow is essential for maintenance of homeostasis. The hemodynamic state is adjusted by intrinsic, neural, and hormonal mechanisms to optimize adaptation to internal and environmental challenges. In the last decade, many studies showed that modification of the mouse genome may alter the capacity of cardiovascular control systems to respond to homeostatic challenges or even bring about a permanent pathophysiological state. This review discusses the progress that has been made in understanding of autonomic cardiovascular control mechanisms from studies in genetically modified mice. First, from a physiological perspective, we describe how basic hemodynamic function can be measured in conscious conditions in mice. Second, we focus on the integrative role of autonomic nerves in control of blood pressure in the mouse, and finally, we depict the opportunities and insights provided by genetic modification in this area.     

Heterogeneity of peripheral blood monocyte populations in human immunodeficiency virus-1 seropositive patients

Abstract Monocytes from human immunodeficiency virus (HIV) patients have an increased heterogeneity of phenotype and function. In a study of 120 HIV patients we have demonstrated that they have normal monocyte differential counts but that with progression of the disease an increasing proportion of monocytes show phenotypic and functional evidence for activation or maturation. A proportion of the monocytes are larger, with increased expression of CD11b, HLA-DR, CD45 and CD16. Concomitantly there was increased expression of TNF-α, high constitutive synthesis of PGE2 and high plasma IL-6 levels. This suggested that there exist a more dynamic situation of recuitment, activation and maturation of peripheral blood monocytes driven by HIV infection which results in a broader phenotypic profile.     

Heterogeneity of human natural killer cell populations.

Natural killing (NK) in human donors was determined by the ability of peripheral blood subpopulations to lyse the myeloid target, K562, in a 2 to 4 hr ⁵¹Cr release assay. The most active cell was a non-T cell which passed through nylon columns (representing 10 to 25% of column passed cells). A second column passed cell population, with characteristics of T lymphocytes (75 to 90% of column passed cells), was also capable of mediating natural killing. Non-T cells which were retained by the nylon columns (45 to 55% of adherent cells) lacked NK activity. However, nylon adherent T cells (45 to 55% of adherent cells) were consistently active in NK assays, illustrating an important subset of NK effector cell often overlooked. Both column passed and adherent T cells were further separated according to their ability to bind IgG or IgM immune complexes, showing that those mediating NK have receptors for IgG (Tγ+) but not for IgM (Tμ+).     

Graviceptive control of blood pressure in man

The purpose of the study was to demonstrate a rapid 'graviceptive' influence on blood pressure in man. Subjects, sitting in an electrically powered car, made discrete head tilts, some of which were unpredictably accompanied by transient linear accelerations of the car i) with head tilting to align with the direction of the resulting inertial force vector (gravity + car acceleration) so that the graviceptors were not stimulated; ii) with head tilting in the opposite direction 'misaligning' which stimulated the graviceptors but otherwise maintained similarity of other sensory inputs. Stimuli were dispensed in a balanced, cross over, repeated measures design on 8 normal males. Recordings were made of arterial blood pressure in the left radial artery, the electrocardiogram and plethysmographic responses in the right hand first digit. Comparisons of 10s pre-stimulus baseline with 10s post stimulus responses. Misaligned head tilts provoked highly significant peak increases in systolic (7.6-9.4 mm Hg) and diastolic (5-6 mm Hg) BP and average BP over 10s was significantly raised. Head tilts maintaining alignment with the inertial force vector provoked raised systolic BP by 4-6 mm Hg for only one or two heartbeats. Head movements alone caused a slight lowering of BP. Effects were evident within 1-2 heartbeats of the acceleration onset. The results demonstrate that the graviceptors have a direct influence on BP in normal man. They also help to explain the profound vaso-vagal symptoms of patients with vertigo and why patients with autoregulatory impairment may be further compromised by uncontrolled accelerating and braking when they are transported in an ambulance.     

Twenty-four-hour blood pressure control: an intraarterial review.

Intraarterial blood pressure monitoring has shown the circadian rhythm of blood pressure control. Blood pressures tend to be highest in the morning before falling gradually during the day to a nadir at 3:00 a.m. There is a slight rise in the late afternoon that may correspond to patients' attendance at hospital for calibration of the equipment. There is a small rise in the blood pressure before awakening, and after arousal there is a rise in blood pressure to the peak level of the morning. In this article, we examine the effect of a variety of antihypertensive agents on this rhythm. In general, beta-adrenoceptor blockers appear to have less effect on nocturnal blood pressure and surge in pressure after arousal, while vasodilators, particularly alpha-adrenoceptor blockers, have a pronounced effect. These findings indicate that the rise in blood pressure before awakening and the rapid rise upon arousal appear to be due to increased alpha-adrenoceptor activity.     

The sympathetic control of blood pressure

Hypertension - the chronic elevation of blood pressure - is a major human health problem. In most cases, the root cause of the disease remains unknown, but there is mounting evidence that many forms of hypertension are initiated and maintained by an elevated sympathetic tone. This review examines how the sympathetic tone to cardiovascular organs is generated, and discusses how elevated sympathetic tone can contribute to hypertension.     

Effects of elements in human blood pressure control

This review enumerates and discusses the elements involved in the control of human blood pressure via a historical evolutionary form. The older and most recent element literature presentations were researched using MEDLINE and a manual review of documents cited. Independent data extraction and cross-referencing was performed. Of the 28 known elements that can influence blood pressure, 15 were found to be involved in human blood pressure regulation. The elements were divided into four groups: electrolyte, composed of sodium, potassium, calcium, and magnesium; metal, which included zinc, copper, and iron; toxic, made up of lead, mercury, cadmium, barium, thallium, arsenic; miscellaneous (lithium and selenium). Evolutionary historical data, possible mechanisms of actions, and interactions between elements that have been shown to influence blood pressure are discussed. Controversy exists over the therapeutic use of elements to alter blood pressure but is absent in the case of the toxic group where preventive control is a proven public health matter. The significance of these 15 elements in the regulation of human blood pressure has been established and ongoing studies will continue to reinforce their influence and importance.     

Fenofibrate lowers blood pressure in two genetic models of hypertension

Fenofibrate, a commonly used lipid lowering drug, induces the expression of the gene coding for cytochrome P450-4A, whose major product is 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a potassium channel antagonist, could increase or decrease blood pressure (BP). We studied the effects of four weeks of oral fenofibrate on BP, urine output (UVol), plasma renin activity (PRA), and urine protein excretion in young (4-5 weeks) stroke prone spontaneously hypertensive rats (SHRSP), older (25 weeks) SHRSP, Dahl salt sensitive rats (Dahl S) on a high salt diet, Dahl S rats on a normal salt diet, and normotensive Sprague-Dawley (SD) rats. Fenofibrate prevented the increase in BP in 4-5 week old SHRSP, reduced BP in 25 week old SHRSP, but had no effect on BP in normotensive SD rats. Similarly, fenofibrate prevented the increase in BP in Dahl S rats on a high salt diet, but had no effect in Dahl S rats on a low salt diet. Fenofibrate increased UVol (and reduced weight gain) in young SHRSP and tended to increase it in other groups. It also increased PRA 2 to 5-fold in all groups except older SHRSP. Young SHRSP receiving fenofibrate excreted significantly less urine protein than control rats. The drug reduced proteinuria in Dahl S rats on high salt diet, but had no significant effect on proteinuria in other groups. In summary, fenofibrate reduced blood pressure and weight gain, increased UVol and PRA, and reduced urine protein excretion in young SHRSP. Other groups of animals showed these changes to a variable, but directionally similar extent. These findings are consistent with a natriuretic effect of fenofibrate.     

Dietary sodium and arterial blood pressure: evidence against genetic susceptibility.

Thirty five subjects with both parents in the top third of their age specific blood pressure distributions and 31 subjects with both parents in the bottom third of their blood pressure distributions restricted their intake of sodium for eight weeks while taking part in a double blind, randomised crossover trial of supplements of sodium and placebo. A comparison of two periods of four weeks at different intakes of sodium showed no differences in blood pressure in either the groups as a whole or the subgroups who complied best with the diet and tablets. In the compliant subgroups mean urinary sodium excretions were above 120 mmol(mEq) and below 50 mmol/day. The study provides evidence against the hypothesis that people with a family history of high blood pressure are more susceptible in their blood pressure response to dietary sodium.