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At least 613 records · Page 34Linked to original sources
PubMed1998

JTT-501, a novel oral antidiabetic agent, improves insulin resistance in genetic and non-genetic insulin-resistant models.

1. We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxa zolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. 2. JTT-501 (10-100 mg kg(-1) day(-1)) was administered orally to Zucker fatty rats for 7-21 days. In the high-fat fed rat model, JTT-501 (100 mg kg(-1) day(-1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. 3. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. 4. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.

Animals↗
PubMedDate not supplied

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Dutch Migraine Genetics Research Group.

Clinical and genetic heterogeneity as well as influence of environmental factors have hampered identification of the genetic factors which are involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subtypes, may help to unravel the pathogenesis of the more common forms. Recently, different types of mutation in the brain-specific P/Q type calcium channel alpha 1A subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebellar ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and without aura. In the tottering and leaner mouse, which are characterised by epilepsy and ataxia, similar mutations were identified in the mouse homologue of the calcium channel alpha 1A subunit gene. These findings add to the growing list of episodic (and now also chronic) neurological disorders, which are caused by inherited abnormalities of voltage-dependent ion channels. The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.

Animals↗
PubMed2006

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia.

Alternative genetic pathways were previously outlined in the pathogenesis of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) based on cytogenetic characteristics. Some of the chromosome aberrations, the recurrent balanced translocations or inversions, directly result in chimeric rearrangement of genes for hematopoietic transcription factors (class II mutations) which disturb cellular differentiation. Other genetic abnormalities in t-MDS and t-AML comprise activating point mutations or internal tandem duplications of genes involved in signal transduction as tyrosine kinase receptors or genes more downstream in the RAS-BRAF pathway (class I mutations). The alternative genetic pathways of t-MDS and t-AML can now be further characterized by a different clustering of six individual class I mutations and mutations of AML1 and p53 in the various pathways. In addition, there is a significant association between class I and class II mutations possibly indicating cooperation in leukemogenesis, and between mutations of AML1 and RAS related to subsequent progression from t-MDS to t-AML. Therapy-related and de novo myelodysplasia and acute myeloid leukemia seem to share genetic pathways, and surprisingly gene mutations were in general not more frequent in patients with t-MDS or t-AML as compared to similar cases of de novo MDS and AML studied previously.

Acute Disease↗
PubMed2001

When genetic distance matters: measuring genetic differentiation at microsatellite loci in whole-genome scans of recent and incipient mosquito species.

Genetic distance measurements are an important tool to differentiate field populations of disease vectors such as the mosquito vectors of malaria. Here, we have measured the genetic differentiation between Anopheles arabiensis and Anopheles gambiae, as well as between proposed emerging species of the latter taxon, in whole genome scans by using 23-25 microsatellite loci. In doing so, we have reviewed and evaluated the advantages and disadvantages of standard parameters of genetic distance, F(ST), R(ST), (delta mu)(2), and D. Further, we have introduced new parameters, D' and D(K), which have well defined statistical significance tests and complement the standard parameters to advantage. D' is a modification of D, whereas D(K) is a measure of covariance based on Pearson's correlation coefficient. We find that A. gambiae and A. arabiensis are closely related at most autosomal loci but appear to be distantly related on the basis of X-linked chromosomal loci within the chromosomal Xag inversion. The M and S molecular forms of A. gambiae are practically indistinguishable but differ significantly at two microsatellite loci from the proximal region of the X, outside the Xag inversion. At one of these loci, both M and S molecular forms differ significantly from A. arabiensis, but remarkably, at the other locus, A. arabiensis is indistinguishable from the M molecular form of A. gambiae. These data support the recent proposal of genetically differentiated M and S molecular forms of A. gambiae.

Animals↗
PubMed2000

Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium.

VNP20009 is a genetically modified strain of Salmonella typhimurium possessing an excellent safety profile, including genetically stable attenuated virulence (a deletion in the purI gene), reduction of septic shock potential (a deletion in the msbB gene), and antibiotic susceptibility. VNP20009 is genetically stable after multiple generations in vitro and in vivo. In mice, VNP20009 is rapidly cleared from the blood from a peak level of 1x104 cfu/mL to undetectable levels in 24 h. In tumor-bearing mice, VNP20009 accumulates preferentially in tumors over livers at a ratio of 1000&rcolon;1. In nonhuman primates, VNP20009 was also rapidly cleared from the blood, from a peak level of 1.0x106 cfu/mL to undetectable levels in 24 h. VNP20009 was detected in the liver, spleen, and bone marrow of monkeys; the amount decreased over time, and VNP20009 was cleared from all organs by day 41; no VNP20009 could be detected in the urine or feces of the monkeys. VNP20009 is genetically stable after many generations of growth (>140) both in vitro and in vivo.

Animals↗
PubMed2004

Familial clustering and genetic risk for dementia in a genetically isolated Dutch population.

Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14% of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45%) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55% of its origin is still unknown.

Age of Onset↗
PubMed2000

Genetic analysis of wild-type Dobrava hantavirus in Slovenia: co-existence of two distinct genetic lineages within the same natural focus.

Genetic analysis was performed of wild-type (wt) Dobrava hantavirus (DOB) strains from Slovenia, the country where the virus was first discovered and where it was found to cause haemorrhagic fever with renal syndrome (HFRS), with a fatality rate of 12%. Two hundred and sixty mice of the genus APODEMUS:, trapped in five natural foci of DOB-associated HFRS during 1990-1996, were screened for the presence of anti-hantavirus antibodies and 49 APODEMUS: flavicollis and four APODEMUS: agrarius were found to be positive. RT-PCR was used to recover partial sequences of the wt-DOB medium (M) and small (S) genome segments from nine A. flavicollis and one A. agrarius. Sequence comparison and phylogenetic analysis of the Slovenian wt-DOB strains revealed close relatedness of all A. flavicollis-derived virus sequences (nucleotide diversity up to 6% for the M segment and 5% for the S segment) and the geographical clustering of genetic variants. In contrast, the strain harboured by A. agrarius showed a high level of genetic diversity from other Slovenian DOB strains (14%) and clustered together on phylogenetic trees with other DOB strains harboured by A. agrarius from Russia, Estonia and Slovakia. These findings suggest that the DOB variants carried by the two species of APODEMUS: in Europerepresent two distinct genetic lineages.

Animals↗
PubMed2001

Genetic probes of three theories of maternal adjustment: II. Genetic and environmental influences.

This is the first report of the Twin Mom Study, an investigation of three hypotheses concerning influences on maternal adjustment. These hypotheses concern the role of the marital and parent-child relationships in mediating genetic influences on maternal adjustment and on the importance of the mothers' marital partners as a specifiable source of influences on their adjustment not shared with their sisters. The study's sample of 150 monozygotic (MZ) twins and 176 dizygotic (DZ) twins was drawn randomly from the Swedish Twin Registry and is, with some small exceptions, likely to be representative of women in the Swedish population. The sample included the marital partners of these twins and their adolescent children. Self-report and coded videotapes were a source of information about family process. Results reported in this first report focus on comparability of American and Swedish samples on scales measuring psychiatric symptoms, and on an analysis of genetic and environmental influences on nine measures of mothers' adjustment. Results suggest comparability between the US and Sweden. Genetic influences were found for all measures of adjustment, particularly in the psychological manifestations of anxiety and for smoking. The pattern of findings also underscored the importance of influences unique to each sibling within the twin pair, thus focusing attention on the potential role of marital partners in maternal adjustment. Results also suggested that experiences shared by the twin sisters, experiences unrelated to their genetic similarity, may influence their fearfulness and alcohol consumption. Our model did not include these influences and thus must be amended.

Adaptation, Psychological↗
PubMed1976

Genetics of affective disorders. II. Morbidity risk and genetic transmission.

Morbidity risk and genetic transmission data on a small population of bipolar, unipolar and schizo-affective outpatients suggest a possible genetic overlap between bipolar and schizo-affective patients. There is a conspicuous absence of a homologous illness in the relatives of schizo-affective probands, although the incidence of schizophrenia was higher in these relatives as compared to the relatives of either bipolar or unipolar probands. The data, although tentative because of the relatively small numbers involved, suggest a multifactorial mode of transmission in some affective illnesses. These disease entities appear familial rather than 'genetically transmitted'. There are select families who show the heritable genetic penetrance previously recorded for these mental disorders.

Adult↗
PubMed2004

Multiplexed genetic analysis using an expanded genetic alphabet.

BACKGROUND: All states require some kind of testing for newborns, but the policies are far from standardized. In some states, newborn screening may include genetic tests for a wide range of targets, but the costs and complexities of the newer genetic tests inhibit expansion of newborn screening. We describe the development and technical evaluation of a multiplex platform that may foster increased newborn genetic screening. METHODS: MultiCode PLx involves three major steps: PCR, target-specific extension, and liquid chip decoding. Each step is performed in the same reaction vessel, and the test is completed in approximately 3 h. For site-specific labeling and room-temperature decoding, we use an additional base pair constructed from isoguanosine and isocytidine. We used the method to test for mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The developed test was performed manually and by automated liquid handling. Initially, 225 samples with a range of genotypes were tested retrospectively with the method. A prospective study used samples from >400 newborns. RESULTS: In the retrospective study, 99.1% of samples were correctly genotyped with no incorrect calls made. In the perspective study, 95% of the samples were correctly genotyped for all targets, and there were no incorrect calls. CONCLUSIONS: The unique genetic multiplexing platform was successfully able to test for 31 targets within the CFTR gene and provides accurate genotype assignments in a clinical setting.

Autoanalysis↗
PubMed2005

[Genetic epidemiology: epidemiology, genetics or none of them?].

In an attempt to contribute to a better understanding of the identity of Genetic Epidemiology, we review its conception, its field of influence, its appropriate methods and techniques and, at last, some of its applications. Genetic Epidemiology involves the study of genetic factors acting on diseases and on their environmental interactions. These includes two major areas: a descriptive one, related to the distribution of such conditions in families and populations, to the epidemiologic surveillance and to the study of determinants; and another characterized by intervention, which is related to preventive measures. Because of the difficulty in considering all possible situations, especial attention is given to review some converging epidemiological and genetical methods and techniques. Among them, we stress the case studies on lab methodologies, as dermatoglyphics, and on quantitative procedures, as path analysis. Some studies are taken as examples for application, since they have been object of research in our country: leprosy, hydrargyrism and schizophrenia.

English Abstract↗
PubMed1976

[Genetic-statistical analysis of multiple births in humans. I. Genetic analysis of predisposition to multiple birth].

Genetico-statistical analysis was made to check various hypotheses of the tendency to multiple birth inheritance. The material involved was comprised of 115 MZ and 228 DZ twin families burdened by recurrent cases of multiple births in their genealogy. Test data included 516 single birth probands, 5 from which had twins among sibs; this results in p = 0,97% for the evaluation of population frequency of the "affected" couples having twins). Vienberg proband method was applied to check monogenous-autosomal model and Edward & Smith approximating formulae to check additive-polygenous model with liminal results (manifestation). It is shown: 1) that the degree of genetical determination of MZ and DZ twinning is approximately the same for both multiple birth types; H-61 and 53% respectively; 2) in MZ twinning both mother's and father's genotypes perform as multiple birth factors; H-76% for the group of mother's sisters and 64% for that of father's brothers; 3) in case of DZ twinning mother's genotype is much more valid as a multiple birth factor as compared to the father's one; H-68% for the group of mother's sisters and H-25% for father's brothers; 4) at least some genetical factors, involved in multiple birth determination, are common for MZ and DZ twins; the rate of DZ twinning (of different sexes) among sibs of parents of MZ twins is reliable and more than 5-fold increases that in common population. It is suggested that the contradiction of literary data on multiple birth genetics is due to unadequate methods in many early investigations: calculations have been carried out on the basis of twin birth rate, and not on the rate of "affected" (couples having twins); differential Veinberg's method has been used, which is adequate in populational analysis and is unsuitable for genealogical studies for the estimation of MZ and DZ twinning frequency; cases of "sporadic" multiple birth have not been excluded from summary family material. On the basis of the authors' and literary data it is suggested also that the number of main genetic factors determining the tendency to multiple births is more than 2 (probably 3) and does not exceed 5, and their interaction approximated by oligenic-complementary model, which does not exclude the presence of genocopying loci in a total system.

Adolescent↗
PubMed2000

Low levels of genetic variation within and high levels of genetic differentiation among populations of species of Abies from southern Mexico and Guatemala.

Populations of Abies in southern Mexico and Guatemala (A. flinckii, A. guatemalensis, A. hickeli, and A. religiosa) have a patchy distribution. This pattern is particularly clear in A. guatemalensis. Genetic diversity within populations, measured by average heterozygosity at 16 isozyme loci, is lower than the range reported for most conifers (mean H(o) ranging from 0.069 in A. guatemalensis to 0.113 in A. flinckii), while differentiation among populations is higher than that observed in most conifer species studied (θ = F(st) ranging from 0.073 in A. hickeli to 0.271 in A. flinckii). Estimated levels of gene flow are low (ranging from 0.672 in A. flinckii to 3.17 in A. hickeli). Populations in most cases had an excess of homozygosity over that expected under Hardy-Weinberg equilibrium, suggesting some inbreeding (F(is) ranging from 0.074 in A. flinckii to 0.235 in A. guatemalensis). A significant relationship between gene flow and geographic distance was observed in A. religiosa, but not in the other three taxa studied. The patterns of genetic variation appear to have been influenced by the distributions and histories of these species. Paleoclimatic evidence suggests that the ranges of these species retreated upwards during the Pleistocene glaciation and became fragmented during the warming period that followed. The populations could have passed through genetic bottlenecks that reduced genetic variation and led to interpopulation differentiation.

Journal Article↗
PubMed2002

Behavioral phenotypes in genetic syndromes: genetic clues to human behavior.

A behavioral phenotype is the characteristic cognitive, personality, behavioral, and psychiatric pattern that typifies a disorder. A number of genetic syndromes have been identified as having this type of distinctive and consistent behavior pattern. It may act as an important diagnostic sign, like a malformation or characteristic facial appearance. Such patterns are also useful for the physician's anticipatory guidance from an educational, rehabilitative, and parenting perspective. In addition, because they are the consequences of known genetic alterations, behavioral phenotypes can be potentially highly valuable clues to the identification of genes in the population that are important to determination of cognitive skills or deficits, personality determinants, behavioral abnormalities, or psychiatric disorders. The nature of a behavioral phenotype and its potential for genetic insight can be appreciated through the examples of Williams syndrome, Prader-Willi syndrome, and Angelman syndrome. The cognitive and behavioral characteristics of these disorders are distinctive. Williams syndrome is known for its association with remarkable conversational verbal abilities and excessive empathy, whereas Prader-Willi syndrome is known for temper tantrums and obsessive-compulsive features, and Angelman syndrome is associated with a constantly happy affect and hyperactivity. The genetic basis for each of these disorders is known, and the pathophysiology and genotype-phenotype correlations are beginning to provide insight into genes responsible for personality characteristics and behavioral abnormalities.

Angelman Syndrome↗
PubMed2005

African Jordanian population genetic database on fifteen short tandem repeat genetic loci.

AIM: To establish a genetic database of the African-Jordanian population for forensic and paternity testing purposes. METHOD: Allelic distribution at fifteen short tandem repeat (STR) loci was determined for 95 healthy unrelated African-Jordanians. The 15 autosomal STR loci, included within the GenePrint PowerPlex 16 system, were amplified from the subset of the 95 DNA extracts isolated from the population sample. Electrophoresis for each polymerase chain reaction (PCR) product was carried out using the ABI Prism 310 Genetic Analyzer and the length of the amplified DNA fragments was determined using the Genotype 2.0 and PowerTyper 16 Macro softwares. Calculations of allelic frequencies, forensic efficiency parameters, Hardy-Weinberg departure, and quantitative analysis of the allele frequencies in various populations were determined. RESULTS: DNA extracts were successfully amplified and the genetic database was compiled. All tested loci showed no significant statistical deviation from Hardy-Weinberg expectations. Furthermore, no significant difference was observed between the sample population under investigation and other population genetic databases. CONCLUSION: The loci investigated here proved to be sufficiently polymorphic for forensic purposes, since the forensic efficiency values suggest that they are very discriminating in the African-Jordanian subpopulation.

Africa↗
PubMedDate not supplied

[Genetic-statistical analysis of environmental and genetic influences on the outcome of the juvenile and breeding performance tests for behaviour traits in Hovawart dogs].

The objective of the present study was to evaluate the importance of genetic and environmental sources of variation for results of behaviour tests recorded at juvenile and breeding performance tests in the Hovawart dog. For these analyses behaviour test results of 1882 (juvenile evaluation), respectively 929 dogs (breeding performance test) born in 1995 to 2000 had been used. Variance component estimation was performed for the traits appearance, play instinct, hunting affinity, group of people, shoot, acoustical and optical influences and temperament using multivariate linear animal models and Residual Maximum Likelihood (REML). The models included test-year-season, sex, litter size, age and inbreeding coefficient of the animal as fixed effects. Additive genetic effects of the animal, permanent environmental effect of the litter and the effect of the kennel were considered as random factors. The sex of the dog was significant for appearance, play instinct, hunting affinity, acoustical and optical influences of juvenile evaluation and for the traits temperament, play instinct, hunting affinity, acoustical and one of the optical influences of breeding performance test. The age of the dog at test significantly influenced the traits play instinct, hunting affinity and acoustical influences of juvenile evaluation and optical influences and hunting affinity of breeding performance test. All traits with exception of hunting affinity and group of people were significantly affected by the test-year-season. The inbreeding coefficient was significant for appearance of juvenile evaluation and play affinity of breeding performance test. The effect litter size did not influence any of the traits significantly. The estimated heritabilities for the behaviour traits of juvenile and breeding performance test ranged from h2 = 0.01 to h2 = 0.13, respectively h2 = 0.01 to h2 = 0.14, with standard errors of up to 0.03. The additive genetic correlations between most of the traits were moderately to highly positive (r(g) = 0.20 to r(g) = 1.0, respectively r(g) = 0.29 to r(g) = 1.0). Negative additive genetic correlations were only found for a few traits of juvenile (r(g) = -0.02 to r(g) = -0.58) and breeding performance test (r(g) = -0.28 to r(g) = -0.83). Progress in breeding for the behaviour traits investigated here may only be meaningful when information from all relatives is used in an animal model instead of selection based on the phenotype of the single animal.

Age Factors↗
PubMed1983

Estimation of genetic risks and increased incidence of genetic disease due to environmental mutagens.

In the estimation of the genetic hazards of environmental mutagens there are major problems in extrapolating from experimental data to human situations. Methods of overcoming these problems have been proposed, and may be achieved in the future. At present extrapolation can rarely be justified except where there are data on mutagenicity in germ cells of mammals. Where such data are available it is possible to estimate numbers of induced cases of genetic disease by making use of the principles and knowledge used in estimating genetic hazards of radiation, but the methods require modification. From experimental data the relative mutagenic effect (RME) of a compound may be obtained where the RME is defined as the ratio of induced mutation rate per unit dose to the spontaneous rate. From the RME and information on doses received environmentally a mutation index (MI) may be calculated where this is the product of the RME multiplied by dose and any relevant sensitivity factors. Tables may be prepared giving expected cases of genetic disease for known MI, and hence the effects of environmental exposures may be obtained. Some examples are shown for cytotoxic drugs.

Abnormalities, Drug-Induced↗
PubMed1995

[Genetic structure of soil population of the fungus Fusarium oxysporum Schlechtend.: Fr.: molecular reidentification of the species and genetic differentiation of isolates using polymerase chain reaction with universal primers (UP-PCR)].

The genetic structure of three soil populations of fungus Fusarium oxysporum was analyzed using polymerase chain reaction with universal primers (UP-PCR). Distinct UP-PCR variants revealed by means of cross-dot hybridization of amplified DNA and restriction analysis of nuclear ribosomal DNA represent subspecies or sibling species of F. oxysporum. The remaining isolates of F. oxysporum showed moderate UP-PCR polymorphism characterized by numerous types, whose relatedness was analyzed by computer treatment of the UP-PCR patterns. The genetic distance trees based on the UP-PCR patterns, which were obtained with different universal primers, demonstrated similar topology. This suggests that evolutionarily important genome rearrangements correlatively occur within the entire genome. Isolates representing different UP-PCR polymorphisms were encountered in all populations, being distributed asymmetrically in two of these. In general, soil populations of F. oxysporum were represented by numerous genetically isolated groups with a similar genome structure. The genetic heterogeneity of the isolates within these groups is likely to be caused by the parasexual process. The usefulness of the UP-PCR technique for population studies of F. oxysporum was demonstrated.

Base Sequence↗