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PubMed1995

[Silent myocardial ischemia in outpatients being treated for hyperlipoproteinemia].

BACKGROUND: Hyperlipoproteinaemias, in particular those associated with hypercholesterolaemia, are in a causal relationship with the development and acceleration of atherogenesis. One of the serious forms of coronary heart disease is silent myocardial ischaemia--an asymptomatic objectively confirmed ischaemic episode. The objective of the present study was to 1. assess the prevalence of this disease in subjects with hyperlipoproteinaemia and 2. to assess the optimal diagnostic procedure to detect it. METHODS AND RESULTS: The group comprises 57 subjects selected at random (23 men and 34 women) from the out-patient department for genetics and treatment of hyperlipoproteinaemias. In all subjects an ergometric loading test was made and 24-hour ambulatory ECG monitoring. Suspected silent myocardial ischaemia (i.e. positive results of the two examinations) was confirmed by load scintigraphy of the heart muscle. Silent myocardial ischaemia was proved in 3 of 23 examined men (13%) and in 4 of 34 women (11.8%). CONCLUSIONS: Prevalence of silent myocardial ischaemia is significantly higher in high risk subjects--with hyperlipoproteinaemia than in the general asymptomatic population. The best screening test for its detection is a loading test and ambulatory ECG monitoring, supplemented by loading scintigraphy of the heart muscle.

Adult↗
PubMed1998

Is there a link between African iron overload and the described mutations of the hereditary haemochromatosis gene?

Over 80%, of Caucasian patients with hereditary haemochromatosis are homozygotes for a C282Y mutation in the HFE gene on chromosome 6. Recent evidence suggests that a genetic factor may also be involved in the pathogenesis of African iron overload, although the locus has not been described. PCR analysis of DNA from 25 southern Africans, identified by segregation analysis as having a high probability of carrying the putative African iron-loading gene, failed to identify any subjects with the C282Y mutation. The possible genetic defect in African iron overload appears to be different from that described in most cases of hereditary haemochromatosis in Caucasians.

Adult↗
PubMed2002

Protective effect of interleukin-4 -589T polymorphism on human immunodeficiency virus type 1 disease progression: relationship with virus load.

The interleukin (IL)-4 -589T allele bears a single nucleotide polymorphism at position -589 upstream from the open-reading frame of the IL-4 gene. To determine the influence of this allele on human immunodeficiency virus (HIV) type 1 disease, disease progression and serum virus load were assessed by IL-4 genotype in 427 white patients with known seroconversion dates who were followed in the French SEROCO cohort between 1988 and 1996. Serum virus load was 0.20 log lower during the 6-24-month plateau phase after seroconversion in patients with IL-4 -589T than in those without this allele (P=.02). Kaplan-Meier analysis survival curves showed a slower progression to clinical AIDS in carriers of IL-4 -589T (P=.04). Adjustment for early serum virus load greatly diminished the strength of this association. These results suggest that IL-4 -589T protects against HIV-1 disease progression by reducing virus load.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Prevalence of the C282Y mutation in Brittany: penetrance of genetic hemochromatosis?

Hemochromatosis (GH) is an inborn error of iron metabolism, characterized by progressive iron loading that, if untreated, causes high morbidity and death. The gene responsible for the disease (HFE), located 4.5 megabases telomeric to the HLA-A locus, encodes a protein homologous to class I MHC molecules. A main mutation, C282Y, has been identified within the gene. Although hemochromatosis is considered as the most frequent inherited disease in the populations of Northern European origin, its prevalence in Brittany had not been evaluated yet. In this issue we report the C282Y mutation frequency in a cohort of 1000 newborns from maternity hospitals of the four breton départements. The homozygote frequency was 5/1000 and heterozygote frequency was 12%; such high frequencies raise the question of the penetrance of the disease and the relevance of systematic genotypic screening for hemochromatosis.

Alleles↗
PubMed2004

Genetic markers applied in regression tree prediction models.

Classification and regression tree (CART) modelling was used to determine infectious hypodermal and haematopoietic necrosis virus (IHHNV) resistance and susceptibility in Penaeus stylirostris. In a previous study, eight random amplified polymorphic DNA (RAPD) markers and viral load values using real-time quantitative PCR were obtained and used as the training data set in order to create numerous regression tree models. Specifically, the genetic markers were used as categorical predictor variables and viral load values as the dependent response variable. To determine which model has the highest predictive accuracy for future samples, RAPD fingerprint data was generated from new Penaues stylirostris IHHNV resistant and susceptible individuals and used to test the regression models. The best performing tree was a four terminal node tree with three genetic markers as significant variables. Marker-assisted breeding practices may benefit from the creation of regression tree models that apply genetic markers as predictive factors. To our knowledge this is the first study to use RAPD markers as predictors within a CART prediction model to determine viral susceptibility.

Animals↗
PubMed1991

Signals for cardiac muscle hypertrophy in hypertension.

Hypertension is associated with a rise in arterial pressure and a compensatory increase in cardiac mass, which if not treated effectively, progresses to decompensated congestive heart failure. This decompensation of an initially compensatory hypertrophy has intensified interest in the factors that initiate and maintain the development of cardiac hypertrophy. The potential signals that induce the development of cardiac hypertrophy are grouped as hemodynamic, growth-promoting hormonal, vasoconstriction-promoting hormonal, and genetic factors. Growth-promoting hormones such as insulin and thyroxine appear to play a permissive, but essential, role in the development and maintenance of cardiac hypertrophy. However, changes in cardiac load, both above and below normal, result in parallel changes in cardiac mass, which will return to normal when a normal load is restored. This adaptive response of the myocardium in direct response to elevated and depressed loads demonstrates that cardiac structure, composition, and function are not fixed postneonatal cardiac properties, but instead are regulated dynamically by the cardiocyte loading environment. This adaptive response is subject to modulation by vasoconstriction-promoting hormones and genetic factors. The current thrust in this research area is to elucidate the cellular signals that transduce the physical stimulus for hypertrophy into biochemical events underlying hypertrophic cardiac growth. To remove complex systemic interactions in vivo from the experimental paradigm, several in vitro models have been used to examine three general, but distinct, cellular pathways involving protein kinase C activation, cyclic AMP formation, and increased ion fluxes. Each pathway demonstrated a stimulatory effect on general protein synthesis, which is necessary for growth in all cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Erroneously low or undetectable plasma human immunodeficiency virus type 1 (HIV-1) ribonucleic acid load, determined by polymerase chain reaction, in West African and American patients with non-B subtype HIV-1 infection.

The polymerase chain reaction (PCR) assay for plasma human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) inadequately quantitates virus load for some non-B HIV-1 subtypes because of genetic diversity in the gag region targeted by the PCR primers. Unexpectedly low or undetectable plasma HIV-1 RNA findings by PCR were a clue to non-B HIV-1 infections in patients in whom plasma HIV-1 RNA was found to be substantially higher when determined by a branched-chain deoxyribonucleic acid assay.

Adult↗
PubMed1987

Reduced responsiveness to acute salt-loading of vasopressin-neurons and oxytocin-neurons in the heterozygous Brattleboro rat.

Heterozygous Brattleboro (HZ) rats exhibit a partial genetic deficiency in hypothalamic vasopressin (VP) production. The effects of this abnormality of HZ rats on the capacities of VP-neurons and oxytocin (OT)-neurons to respond to an acute salt-load were examined. Acute salt-loading was induced by intravenous infusion of 18% saline in conscious, chronically catheterized animals and the activities of VP-neurons and OT-neurons were interpreted from plasma concentrations of VP-associated neurophysin, [VP-RNP] and OT-associated neurophysin, [OT-RNP] at different time periods throughout the infusion. Plasma sodium concentration ([Na+]), plasma osmolality (Posm) and mean arterial pressure (MAP) were also monitored. Salt-loading produced significant rises in [VP-RNP] and [OT-RNP]. These rises were accompanied by increases in plasma [Na+], Posm and MAP. Releases of OT-RNP were approximately four times greater than those of VP-RNP. The responsiveness of VP-neurons to increases in Posm in the HZ rat was approximately one-half of that observed for the Long-Evans (LE) rat. Furthermore, the responsiveness of OT-neurons in these animals was approximately one-half of that for LE rats and one-third of that for homozygous Brattleboro (DI) rats. The changes in MAP during salt-loading do not appear to be different for HZ and LE rats. Hence, while VP may be involved in the rise in blood pressure during infusion of hypertonic saline, there is not a direct correlation between plasma levels of VP-RNP (and presumably VP) and rises in blood pressure.

Animals↗
PubMed2002

Genetic complexity and serum reactivity of HVR1 quasispecies of hepatitis C virus in patients with cirrhosis.

OBJECTIVE: The RNA genome of hepatitis C virus varies considerably, especially within the hypervariable region 1 (HVR1), a domain located on the 5' end of the E2/NS1 envelope region. Our previous study has suggested there were greater numbers of quasispecies in the liver than in matched serum, independent of the viral load. However, the significance of this finding has not been examined extensively at genetic and serological levels. METHODS: By large scale cloning and sequencing, we studied the genetic complexity of HVR1 quasispecies in two selected patients with cirrhosis. The serum reactivity of peptides representing different HVR1 quasispecies isolated from these cases was also estimated by standard ELISA format. RESULTS: We found the same major (dominant and/or subdominant) viral quasispecies variants in serum and in the cirrhotic liver. Genetic analysis suggested that the evolutionary pressure on HVR1 was higher than on its flanking region in quasispecies derived from the liver, whereas this trend is attenuated in quasispecies from serum. The immunoreactivity to peptides representing different HVR1 quasispecies variants showed considerable cross-reactivity with heterologous sera, whereas the reactivity was strongest against the dominant HVR1 peptide over time in homologous sera. CONCLUSIONS: These findings indicate that the formation and selection of HVR1 quasispecies may not be driven solely by humoral immune pressure, at least in these two cases.

Amino Acid Sequence↗
PubMed1999

[Molecular genetics of hemochromatosis].

Hemochromatosis is a recessive disorder of iron metabolism characterized by progressive iron loading of parenchymal organs, which accounts for clinical complications such as cirrhosis, diabetes mellitus, cardiopathy, endocrine dysfunctions and arthropathy. Clinical complications, which usually develop after the third or fourth decade of life, can be fatal but may be prevented by phlebotomy if iron excess is detected at a very early stage. The hemochromatosis gene (HFE), located 4.5 megabases telomeric to the HLA-A locus, encodes an HLA class I like protein and two missense mutations, C282Y and H63D in complete disequilibrium have been identified within this gene. Due to its high frequency in the general population, the involvement of H63D in the pathogenesis of the disease remains controversial, and it might correspond to a minor mutation. Conversely, the C282Y mutation is tightly linked to the disease, as it accounts for 80 to 100% of the hemochromatosis cases in Northern Europe. The lower frequency observed, in the patients, in Italy and South of France led to imagine either the implication of other mutations or of other genes. The C282Y mutation is absent in Asia and Africa and is present in the general population with a decreasing gradient of frequency from Northern to Southern Europe. The prevalence of the disease was usually estimated to be 3% but the observed frequency of the C282Y homozygotes is 5% in our breton population raising the question of the penetrance of the disease, and consequently the use of the genotypic test for its systematic screening. As HFE encodes a membrane protein similar to HLA class I protein, its contribution to iron overload is not obvious. The normal protein is predicted to to be expressed at the cell surface in association with beta 2-microglobulin, a localization for which C282Y is critical as it disrupts this association. This protein has also been shown to form a stable complex with the transferrin receptor leading to a decreased affinity for transferrin. A better knowledge of its function will help to decipher iron and different metal-ions metabolism. Although the exact role of the HFE protein is unknown, the genotypic test allows the clinicians to ascertain their diagnosis and genetic counselling.

Genes, MHC Class I↗
PubMed1997

Quantitative genetic analysis of susceptibility to hookworm infection in a population from rural Zimbabwe.

Overdispersion is a common feature of population distribution patterns for hookworm infection in humans. Genetic factors may be partially responsible for this observed increased susceptibility in a fraction of the exposed population. However, the hypothesis that there are genetic components to susceptibility to this infectious disease has not been tested explicitly. The purpose of this study is to quantify the influence of genetic factors on patterns of hookworm infection in a rural population in Zimbabwe. A quantitative measure of hookworm load, number of hookworm eggs per gram of feces, as determined by the Kato thick smear technique, was available for 289 individuals. Of these, 279 individuals were members of 62 nuclear families and 10 were independent individuals. We analyzed the hookworm data in combination with the pedigree structure of the sampled individuals using quantitative genetic analysis techniques. Using this variance decomposition approach, we estimated the heritability of hook worm load to be 0.37 +/- 0.09 (p < 0.0001). This significant heritability indicates that 37% of the variation (after correcting for the effects of covariates) in hookworm eggs per gram observed in this population is attributable to genetic factors. The results suggest that further investigation and characterization of the genetic components influencing susceptibility to hookworm infection are warranted.

Adolescent↗
PubMed1984

Genetic, familial and racial influences on blood pressure control systems in man.

This paper reviews investigations by the Indiana University Medical Centre Hypertension Research Centre into genetic influences on blood pressure control systems in man. Our studies have used the families of adult identical twins to partition the relationships of age, sex and body size to the genetic contribution to blood pressure variability. These studies provide little evidence for environmental influence on the familial aggregation of blood pressure and suggest that at least 63% of the variability is due to genetic factors. Studies on the renin-angiotensin-aldosterone system and on the kidney's ability to excrete sodium were also undertaken in identical and fraternal twins, as well as in black and white subjects, and provided unequivocal evidence of genetic control. Studies in first degree relatives of patients with essential hypertension have demonstrated higher plasma renin levels and a decreased ability to excrete a sodium load when compared to first degree relatives of normotensive subjects. Blacks in the U.S.A. have a decreased ability to excrete a sodium load and a greater rise in blood pressure with sodium loading than do whites. We suggest that the heritability of blood pressure is directly related to a genetic influence on the level of renin and that this increase in renin level results in subtle increases in angiotensin II. These chronic elevations of angiotensin II directly increase blood pressure and decrease the kidney's ability to excrete sodium by either a direct renal effect or indirectly by stimulating aldosterone-dependent sodium retention.

Adult↗
PubMed1992

Religion and education as mediators of attitudes: a multivariate analysis.

The transmission of social attitudes has been investigated as a possible model of cultural inheritance in a sample of 3810 twin pairs from the Australian National Health and Medical Research Twin Registry. Six social attitude factors were identified and univariate genetic models fitted to scores on each factor. A joint multivariate genetic analysis of the six attitude factors, church attendance, and education indicated that the attitudes were correlated--the same genes and shared environments influenced more than one attitude factor. A current controversy regarding social attitudes is whether the significant loadings on this shared environmental component represent true cultural influences or are actually the genetic consequences of phenotypic assortative mating for church attendance and educational attainment (Martin et al., 1986). In our data, church attendance is almost entirely due to the impact of the shared environment. The large shared environmental component on church attendance also accounts for a substantial part of the family resemblance in social attitudes, suggesting that not all of the apparent cultural effects found in earlier studies can be ascribed to the genetic effects of assortative mating. However, church attendance and education do not completely account for the cultural component. Therefore, effects in addition to church attendance, education, and assortative mating for church attendance and education must be involved in the cultural component of the inheritance of attitudes.

Adolescent↗
PubMed2003

Genetic polymorphisms of the interleukin-1 gene and early marginal bone loss around endosseous dental implants.

Dental implant surgery commonly proceeds in two stages. It is generally accepted that bone loss around implants does not occur at stage-II surgery because implants do not receive mechanical loading. However, early marginal bone loss around implants occasionally does occur during the healing period. Genetic polymorphisms in the interleukin-1 (IL-1) gene have been reported to be important for bone homeostasis and susceptibility to bone disease. We therefore investigated whether the idiopathic early marginal bone loss around implants is related to polymorphisms in the IL-1 gene. We performed a case-control study. Patients demonstrating marginal bone loss around implants at stage-II surgery were designated as the 'marginal bone loss (+)' group and those without bone loss as the 'marginal bone loss (-)' group. Polymorphisms of the IL-1alpha and IL-1beta genes (IL-1A-889, IL-1B-511 and IL-1B+3954) were detected by restriction fragment length polymorphism using NcoI, AvaI and TaqI after polymerase chain reactions. A total of 251 implants were placed in 39 patients. Marginal bone loss was observed in 36 implants. The patients with IL-1B-511 2/2 genotype exhibited a significantly higher occurrence of marginal bone loss than those with IL-1B-511 1/1 or 1/2 genotypes (OR=5.63; 95% CI=1.20-26.42; P=0.033). Multiple logistic regression analyses showed a markedly increased odds ratio (OR=10.86; 95% CI=1.64-71.90) in IL-1B-511 2/2 genotype carriers, while ORs of the other risk factors for bone loss, such as age, smoking status, post-menopausal women and bone quality, remained between 0.44 and 6.20. There was no significant difference in the distributions of the IL-1B+3954 and IL-1 A-889 genotypes between cases and controls. These data suggest that the IL-1B-511 2/2 genotype has a significant association with the incidence of early marginal bone loss around endosseous implants.

Adult↗
PubMed2006

Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses.

Natural and genetically modified oncolytic viruses have been systematically tested as anticancer therapeutics. Among this group, conditionally replicative adenoviruses have been developed for a broad range of tumors with a rapid transition to clinical settings. Unfortunately, clinical trials have shown limited antitumor efficacy partly due to insufficient viral delivery to tumor sites. We investigated the possibility of using mesenchymal progenitor cells (MPC) as virus carriers based on the documented tumor-homing abilities of this cell population. We confirmed preferential tumor homing of MPCs in an animal model of ovarian carcinoma and evaluated the capacity of MPCs to be loaded with oncolytic adenoviruses. We showed that MPCs were efficiently infected with an adenovirus genetically modified for coxsackie and adenovirus receptor-independent infection (Ad5/3), which replicated in the cell carriers. MPCs loaded with Ad5/3 caused total cell killing when cocultured with a cancer cell line. In an animal model of ovarian cancer, MPC-based delivery of the Ad5/3 increased the survival of tumor-bearing mice compared with direct viral injection. Further, tumor imaging confirmed a decrease in tumor burden in animals treated with oncolytic virus delivered by MPC carriers compared with the direct injection of the adenovirus. These data show that MPCs can serve as intermediate carriers for replicative adenoviruses and suggest that the natural homing properties of specific cell types can be used for targeted delivery of these virions.

Adenoviridae↗
PubMed1984

[Medico-genetic study of the population of Turkmenia. V. A population and demographic description of the Nokhur isolate].

The paper deals with demographic, genealogical and genetic characterization of one Turkmenian isolate--"Nochur". The data on its load of hereditary diseases were published previously. The Turkmenian "Nochurly" tribe consists of 19 large and small clanes. 600 nuclear families live in a small mountain valley of the same name. The share of prereproductive age class is 60%, of reproductive class--29%, this value for postreproductive class being 11%. The average number of children per family, when the families have completed their reproductive period, is 6.84. The average duration of generation (the mean parental age to the birth time of a mean newborn) is 37.7 and 31 years for a man and woman, respectively. Immigration into Nochur is practically absent, there is a flow of emigrants to the capital of the Republic, Ashkhabad. A very high level of assortative mating has been noted, the minimal estimation of inbreeding coefficient being 0.033 (the pedigree) and the maximal--0.0529 (isonimy). Diminishing of the number of lethal equivalents between 1940-1965 and 1966-1980 was discovered. This can be explained by a decrease in natural selection pressure. The data on distribution of genetic markers of the ABO, MN, Rh, Hp and Pp systems within this isolated population are presented.

Adolescent↗
PubMedDate not supplied

[Adaptation and ecological resistance].

The notion fitness, widely used in genetics usually serves to measure a relative rate of organism reproduction. Another important character of an organism is its ecological resistance which is basically the product of macroevolution. It can be determined as a probability of an organism survival and participation in reproduction of the species. Ecological resistance determines the level of the accidental death of organisms that are genetically valuable. For the comparison of ecological resistance in different organisms and species the negative meanings of the Malthusian parameter can be used. Ecological resistance depends on the presence in genomes of essential genes and fairly complete sets of nonessential, or adaptive, genes which can reside in genomes both as "plus" and "minus" alleles. The recovery of complete sets of adaptive genes lost as a result of mutations and, thus, of a high level of ecological resistance in organisms is provided by genetic exchange between them. With respect to mutations leading to the increase in fitness the effect of genetic exchange is negative since it leads to the formation of recombination load, i.e. a decrease in fitness of the offspring. In microevolutionary processes, the elevation in ecological resistance level does not take place since it requires a long time for the formation of new genes and new elements of organization in the process of positive selection. At the same time, a constant recovery of a high level of ecological resistance of the species decreased as a result of mutations takes place in some individuals due to genetic exchange. Mutations affecting ecological resistance of an organism, as a rule, cause a decrease in its viability and they are usually excluded from populations as a result of negative (stabilizing) selection.

Adaptation, Physiological↗
PubMed1982

The question of early insulin response to glucose in patients with ischemic heart disease: a retrospective study in twins. Preliminary communication.

The genetic determination of the early insulin response (EIR) to a standard intravenous glucose load and the relation between EIR and manifestations of ischemic heart disease (IHD) by means of ECG abnormalities was studied in 18 monozygotic (MZ) and 13 dizygotic (DZ) twin pairs aged 53-76 years. Intrapair variances for EIR and basal glucose was significantly smaller in MZ than DZ twins, indicating that genetic factors are of importance for the regulation of these two parameters. No genetic influence on glucose tolerance was found. In DZ twins discordant with respect to pathologic Q waves (Minnesota Code 1.1), significantly lower EIR was found in twin partners with Q wave abnormality. These findings also point to an association between low EIR and IHD.

Aged↗