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PubMed1989

Delayed lung maturation in the macrosomic offspring of genetically determined diabetic (db/+) mice.

We studied a genetically determined diabetes in pregnancy, the heterozygous diabetes (db/+) mouse. We found that fetal mice from these pregnancies are macrosomic with increased body, lung, and placenta wt, have altered organ protein, DNA and phospholipid content, and exhibit abnormal carbohydrate metabolism with increased liver and glycogen content. We further studied the effect of increased substrate availability and utilization on lung growth and maturation in (db/+) fetal mice, by measuring lung phospholipid synthesis as represented by the incorporation of the radiolabeled precursors, [3H]choline and [14C]glycerol, in fetal lung at 18 days' gestation (term = 19). Diabetic fetuses incorporated significantly more [3H]choline into disaturated phosphatidylcholine than controls (1.32 +/- 0.10 X 10(-2) versus 0.78 +/- 0.05 X 10(-2) nmol/g protein/min, mean +/- SE; p less than 0.001), but significantly less [14C]glycerol into phosphatidylglycerol than controls (3.18 +/- 0.38 versus 4.91 +/- 0.53 nmol/g protein/min, mean +/- SE; p less than 0.002), and their phosphatidylglycerol/phosphatidylinositol synthesis ratios were decreased (1.81 +/- 0.18 versus 3.17 +/- 0.14; mean +/- SE; p less than 0.001). Diabetic fetal lungs appeared morphologically less mature than controls at 18 days' gestation, as shown by a significantly decreased air space density (0.27 +/- 0.01 versus 0.43 +/- 0.02, mean +/- SE; p less than 0.001) and alveolar epithelial cell/total tissue ratio (0.54 +/- 0.02 versus 0.66 +/- 0.03, mean +/- SE; p less than 0.01). The increased synthesis of lung disaturated phosphatidylcholine in diabetic fetal mice may reflect the enhancement of body and lung growth in these macrosomic fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

[Cloning the genetic determinant of alpha-hemolysin and obtaining a series of insertional mutations in this determinant by the transposon Tn1000].

Functionally active genetic determinant of alpha-hemolysin was cloned. Hemolytic plasmid pHly195 was used as a donor of the determinant and pBR322 plasmid served as recipient. Cloning was done with a help of HindIII restriction endonuclease. The recombinant plasmid obtained represents pBR322 plasmid with the built-in fragment of 7.4 kb containing genes of functionally active determinant of alpha-hemolysin. Restriction map was constructed using HindIII, EcoRI, BamHI and SalI restriction endonucleases. Insertional mutagenesis was carried out with the help of the Tn1000 transposon. Plasmid DNAs were isolated from insertional mutants of Hly- phenotype and treated with EcoRI, SalI and BamHI. On the basis of the sizes of restriction fragments of the mutant plasmid DNAs localization and orientation of insertions of Tn1000 into the cloned determinant of alpha-hemolysin were determined.

Bacterial Proteins↗

PubMed1984

Cytokinetics of mononuclear phagocyte response to listeriosis in genetically-determined sensitive and resistant murine hosts.

Genetically-determined differences in resistance to infection with L. monocytogenes are controlled by a single, non-H-2 linked gene Lr, which is expressed in some facet of the response of the mononuclear phagocyte system to listeriosis. In this study, the kinetics of monocyte production and turnover have been compared in Listeria-resistant B10.A and Listeria-sensitive A strain mice, in response to either listerial infection or stimulation with a water-soluble monocytosis-producing activity extracted from L. monocytogenes. Promonocyte generation time in resistant mice fell from approximately 17 to 13 h on the first day of infection, or several hours following injection of monocytosis-producing activity, whereas there was no such shortening of promonocyte generation time in susceptible mice at these times. Similarly, the half-time of circulating monocytes fell by approximately 8-9 h following listerial infection or injection of extracts of monocytosis-producing activity in resistant, but not in susceptible, mice. The Lr gene may, therefore, be controlling the production and emigration of mononuclear phagocytes shortly following infection, this in turn determining the degree of susceptibility of the host to listeriosis.

Animals↗

PubMed1999

Genetic determinants of sports participation and daily physical activity.

OBJECTIVE: The purpose is to review the existing literature on genetic determinants of sports participation, daily physical activity (PA) resting metabolic rate (RMR) and activity as a temperamental trait. DESIGN: A synthesis will be given of the published material on this topic with special focus on twin and family data, and association and linkage studies. MEASUREMENTS: Self reported sports participation, daily PA, RMR and activity as a temperamental trait. ANALYSIS: Transmission and heritability coefficients calculated from twin and family data will be reported. RESULTS: The reported heritability coefficients for sports participation vary between 0.35-0.83, and those for daily PA between 0.29-0.62. If one of the parents or co-twins is active in sports, it is more likely that the child or co-twin is also active in sports (odds ratios (ORs) vary from 1.2-5.8). Twin and parent-child correlations for RMR also indicate a moderate genetic effect. At present, only a linkage between RMR and uncoupling protein 2 markers has been demonstrated. CONCLUSION: The genetic determination of sports participation, daily PA and RMR, varies from low to moderately high, and only between the uncoupling protein 2 genetic marker and RMR has a linkage has been demonstrated.

Basal Metabolism↗

PubMed1999

Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females.

The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL turnover were studied in 36 normolipidemic female subjects on a whole-food low-fat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein size, and apolipoprotein turnover parameters were determined, as were genetic variation at one site in the hepatic lipase promoter and six sites in the apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on HDL-C or turnover. Stepwise multiple regression analysis revealed that HDL-C was most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the variation in HDL-C. HDL size was inversely correlated with triglycerides, body mass index, and hepatic lipase activity, which together accounted for 82% of the variation in HDL size. The hepatic lipase promoter genotype had a strong effect on hepatic lipase activity and could account for 38% of the variation in hepatic lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of apoA-I levels, but AI-TR was not associated with six common genetic polymorphism in the apoAI/CIII/AIV gene cluster.A simplified model of HDL metabolism is proposed, in which A-I and apoA-II levels combined with triglycerides, and hepatic lipase activity could account for 80% of the variation in HDL-C.

Adult↗

PubMed2000

Genetic determination of human essential hypertension.

Recent advances in genetic determination of human essential hypertension (EHT) are discussed by reviewing the candidate genes. Candidate genes have been selected based on genetic information from classical linkage analysis (affected sib-pair analysis) or mendelian hypertension (autosomal dominant inheritance of hypertension). Most of these genes are, directly or indirectly, coupled to salt handling of the kidney, being included in the renin-angiotensin system (RAS), steroid-hormone metabolism, and renal sodium transporters. Angiotensinogen (AGT) gene in RAS was first described as a strong candidate associated with the onset of hypertension, since sib-pair linkage analysis has demonstrated the trait loci for hypertension which includes the coding region for AGT. M235T polymorphism of AGT has been studied extensively in many populations including Japanese, and the results suggest a weak, but significant linkage with hypertension. The presence (insertion [I]) or absence (deletion [D]) of 287bp in intron 16 of angiotensin converting enzyme gene has also been examined in RAS, and the results suggest D polymorphism as a risk factor for hypertension in men. Other components in RAS, such as renin, angiotensinogen II type I receptor, or kallikrein have also been studied, but the available information is still incomplete. Genetic investigations of mendelian hypertension has identified the genetic mechanisms for glucocorticoid remediable aldosteronism, apparent mineral corticoid excess, and Liddle's syndrome as chimeric gene duplications of CYP11B1 (aldosterone synthase gene) and CYP11B2 (11beta-hydroxylase gene), mutations in the gene of 11beta-hydroxysteroid dehydrogenase type 2 that catalyzes the conversion of cortisol to cortisone, and mutations in beta or gamma subunit of epithelial sodium channel (ENaC), respectively. Subsequently, genetic variants of CYP11B2 and beta or gamma subunit of ENaC have been found, suggesting the -344C polymorphism of CYP11B2, 594S variant of betaENaC, and two rare variants of gammaENaC as risk factors for EHT. In spite of the extensive research, haplotypes in individual populations remain to be elucidcated in most candidate genes. Even casual conclusions of possible linkage with EHT need to be further examined with better determinations of phenotypes, such as ambulatory and home blood pressure monitoring or identification of onset of hypertension in cohort studies.

Aldosterone↗

PubMed1988

[Genetic determinants of antibiotic resistance in gram negative bacteria].

Modern data on spreading, structural and functional organization and evolution of the genetic determinants of antibiotic resistance in the gram-negative bacteria are reviewed. Some mechanisms for resistance to trimethoprime, sulphonamides, tetracyclines, chloramphenicol aminoglycosides, beta-lactam antibiotics controlled by the plasmid and chromosomal genes are presented. The problem of using the molecular DNA-probes containing the genetical determinants for antibiotic resistance in the practical work of clinical laboratories is discussed.

Drug Resistance, Microbial↗

PubMed2003

Maxillary canine displacement and genetically determined predisposition to disturbed development of the dentition.

BACKGROUND: The relationship between maxillary canine displacement and the simultaneous occurrence of "genetically determined predisposition to disturbed development of the dentition" as defined by Hoffmeister was investigated in 675 patients. PATIENTS AND METHODS: Panoramic radiographs taken of each patient during the first and the second mixed dentition periods were evaluated. Canine inclination and the distance between the tip of the canine and a line connecting the cusps of the molars were computed in five different age groups according to Dausch-Neumann. RESULTS: Statistical analysis revealed 34 patients with "potential canine displacement", who exhibited further symptoms of "genetically determined predisposition to disturbed development of the dentition" significantly more frequently than the total group. The symptoms concerned were agenesia, displaced tooth buds, rotated or tilted incisors, aplasia and microdontia of lateral incisors. CONCLUSION: Careful follow-ups in patients with a predisposition to disturbed dental development enables risks to be anticipated and canine displacement to be detected at an early stage.

Child↗

PubMed1987

Molecular cloning and characterization of the genetic determinant encoding CS3 fimbriae of enterotoxigenic Escherichia coli.

The genetic determinant encoding the synthesis and surface expression of CS3 fimbriae of colonization factor antigen II-(CFA/II-) positive enterotoxigenic Escherichia coli was cloned on a 5.1 kb HindIII DNA fragment in pBR322 from the wild-type plasmid pCS001 to yield the CS3+ plasmid pCS100. Subcloning of EcoRI fragments of 1.8 kb and 2.5 kb into vector plasmid pACYC184 and the isolation of a series of pCS100::Tn5 insertion mutants revealed that more than one cistron was involved in the synthesis and expression of CS3 fimbriae. Polypeptides of 94, 26, 24, 17 and 15 kDa were detected in E. coli minicells harbouring pCS100. In Western immunoblotting the 17 kDa and 15 kDa polypeptides reacted with specific anti-CS3 fimbriae serum. The 15 kDa polypeptide comigrated with the structural subunit of CS3 fimbriae. Inhibition of protein processing in minicells by ethanol confirmed that the 17 kDa polypeptide was the precursor form of the 15 kDa structural subunit. A physical map of the cloned DNA was constructed showing the location and direction of transcription of the genes for the 17 and 94 kDa polypeptides. Using the 5.1 kb HindIII fragment of pCS100 as a genetic probe for the CS3 determinant, Southern hybridization analysis of plasmid and total cellular DNA was performed in wild-type enterotoxigenic E. coli strains.

Antigens, Bacterial↗

PubMed1981

Pre-beta 1-lipoprotein in patients with ischemic heart disease. Genetic determination and relation to early insulin response.

The genetic determination of pre-beta 1-lipoprotein and its relation to insulin response was studied in 18 male monozygotic and 13 male dizygotic twin pairs, aged 51-74. They had been selected from the Swedish Twin Registry by means of an angina pectoris questionnaire. Results revealed a heritability index for the pre-beta 1-lipoprotein, determined quantitatively, to be as high as 0.94. The subjects in whom pre-beta 1-lipoprotein was present exhibited a significantly delayed early insulin response compared to subjects without this lipoprotein fraction. Our data seem to justify the use of pre-beta 1-lipoprotein as a genetic marker. Data also indicate that important metabolic differences may exist between pre-beta 1+ and pre-beta 1- individuals, and it is possible that such differences may explain in part an increased susceptibility to ischemic heart disease for those possessing the pre-beta 1 fraction.

Aged↗

PubMed2001

Genetic determinants of bone mineral content in premature infants.

Genetic determinants of bone mineral content in prematurely born children at 3 months and 9-11 years of age were studied. The findings suggest that multiple genes are involved in the regulation of site specific bone mass accumulation during childhood.

Absorptiometry, Photon↗

PubMed1999

Genetically determined vascular diseases.

Review of literature data concerning genetically determined blood vessel diseases is presented. These disorders are a cause of a process similar to Binswanger's disease but occurring familial. Recurrent TIA, ischemic strokes and other kind of blood supply disturbances lead to numerous and various intensity vasogenic brain tissue damage, particularly in the white matter. Progressive neurological symptoms and dementia form the picture of subcortical leukoencephalopathy in several members of family. Moyamoya disease, fibromuscular dysplasia, hereditary hemorrhagic telangiectasia, hereditary cerebral hemorrhage with amyloidosis, pseudoxanthoma elasticum, two types of subcortical encephalopathy in Japan, HERNS and CADASIL are described.

Brain Diseases↗

PubMed1988

A rare genetically determined electrophoretic variant of human leucocyte type III hexokinase.

Various lines of evidence from starch gel electrophoretic experiments demonstrate the existence of a genetically determined rare variant form of the type III isozyme of hexokinase (HK) in the leucocytes of a small percentage of the general human population. This enzymatically active variant (designated IIIS) migrates slightly, but significantly, slower than the common form (designated IIIF). In addition to finding various individuals with a two-banded pattern (heterozygotes containing both IIIS and IIIF), a finding reported previously by S. Povey, G. Corney, and H. Harris ((1975) Ann. Hum. Genet. 38, 407-415), we discovered one person homozygous for the variant phenotype. In close agreement with Povey et al., screening of 59 individuals at random indicated a gene frequency of about 0.017 for the IIIS allele, corresponding to a homozygous genotype for this allele that would be expected in about one of every 3500 individuals. Experiments involving the mixing of blood samples from the individual homozygous for IIIS with those homozygous for IIIF indicate that secondary in vitro changes, a possibility suggested by Povey et al., are not responsible for the appearance of the variant. This conclusion was supported by a demonstration of the specificity of the alteration in type III's mobility in comparison with the lack of alterations in any of the LDH isozymes, glucose-6-phosphate dehydrogenase, and various amido black-stainable proteins. These studies confirm the proposal for a genetically determined polymorphism of type III HK. No differences could be found between the total HK activity (according to spectrophotometric assays) of extracts from the subject homozygous for the variant and the activity from the homozygote for the common form, in terms of either their Km values for glucose or their heat stability properties. The similarity of Km values was supported by kinetic assays performed during staining of the individual forms on electrophoretic gels. Previous findings, reported elsewhere, of type III HK in RBC extracts were shown here to be attributable to contamination, by leucocytes, of the extracts. As a consequence of these studies, slight, but significant, amounts of type II-like HK were also discovered in leucocytes. Because our studies described above were completed in 1969, advantage was taken of the opportunity to test the HK pattern 17 years later from some of the same subjects. The patterns of the homozygotes for IIIS and for IIIF and the heterozygotes were found to be identical to the original ones, indicating no age-, environmental-, or other time-related changes that could explain the variation in type III HK.

Adult↗

PubMed2005

Genetic determination and correlation of body mass index and bone mineral density at the spine and hip in Chinese Han ethnicity.

The purpose of the present study was to evaluate the magnitude of genetic determination of spine and hip bone mineral density (BMD) and body mass index (BMI), and to explore the genetic, environmental, and phenotypic correlations among the above phenotypes in Chinese Han ethnicity. The sample was composed of at least 217 complete nuclear families in Chinese Han ethnicity. BMD at the spine and hip was measured using a dual-energy X-ray absorptiometry scanner. The heritability (h2) of BMI and BMD at the spine and hip, the genetic correlation (rhoG) and environmental correlation (rhoE) among the three phenotypes were evaluated via variance analysis, with age, sex, and age-by-sex interaction as covariates. The phenotypic correlation (rhoP) and the bivariate heritability rhoG2 were also calculated. The heritability for BMD and BMI was approximately 0.70 and approximately 0.50, respectively (p<0.0001). The common environment shared by household members (household effect) is significant for BMI variation (p=0.0004). Significant genetic, environmental, and phenotypic correlation was observed. The rhoG2 values were 0.13 for BMI/spine BMD, 0.18 for BMI/hip BMD, and 0.58 for the spine BMD/hip BMD. While BMD at the spine and hip have significant genetic determination, BMI is more likely to be affected by environmental factors than BMD. In addition, BMD at the spine and hip shares more genetic effect (pleiotropy) than BMI and BMD do in Chinese Han ethnicity, though the effects are significant for both.

Adult↗

PubMed1994

Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels.

Genetic factors have been shown to play an important role in determining interindividual variation in plasma HDL-C levels, but the specific genetic determinants of HDL cholesterol (HDL-C) levels have not been elucidated. In this study, the effects of variation in the genomic regions encoding hepatic lipase, apolipoprotein AI/CIII/AIV, and the cholesteryl ester transfer protein on plasma HDL-C levels were examined in 73 normotriglyceridemic, Caucasian nuclear families. Genetic factors accounted for 56.5 +/- 13% of the interindividual variation in plasma HDL-C levels. For each candidate gene, adjusted plasma HDL-C levels of sibling pairs who shared zero, one, or two parental alleles identical-by-descent were compared using sibling-pair linkage analysis. Allelic variation in the genes encoding hepatic lipase and apolipoprotein AI/CIII/AIV accounted for 25 and 22%, respectively, of the total interindividual variation in plasma HDL-C levels. In contrast, none of the variation in plasma HDL-C levels could be accounted for by allelic variation in the cholesteryl ester transfer protein. These findings indicate that a major fraction of the genetically determined variation in plasma HDL-C levels is conferred by allelic variation at the hepatic lipase and the apolipoprotein AI/CIII/AIV gene loci.

Apolipoprotein A-I↗

PubMed1998

Setting in motion the immune mechanisms underlying genetically determined resistance and susceptibility to infection with Leishmania major.

The murine model of infection with Leishmania major has allowed the demonstration of a causal relationship between, on the one hand, genetically determined resistance to infection and the development of a Th1 CD4+ cell response, and on the other hand, genetically determined susceptibility and Th2 cell maturation. Using this murine model of infection, the role of cytokines in directing the functional differentiation pathway of CD4+ T cell precursors, has been demonstrated in vivo. Thus, IL-12 and IFN-gamma have been shown to favour Th1 cell development and IL-4 is crucial for the differentiation of Th2 responses. Maturation of a Th2 response in susceptible BALB/c mice following infection with L. major is triggered by the IL-4 produced during the first two days after parasite inoculation. This IL-4 rapidly renders parasite specific CD4+ T cells precursors unresponsive to IL-12. A restricted population of CD4+ T cells expressing the V beta 4V alpha 8 TCR heterodimer and recognizing a single epitope on the LACK (Leishmania Activated C-Kinase) antigen of L. major is responsible for this rapid production of IL-4, instructing subsequent differentiation towards the Th2 phenotype of CD4+ T cells specific for several parasite antigens.

Animals↗

PubMed2005

Epidemiology of Hoffmeister's genetically determined predisposition to disturbed development of the dentition in patients with true skeletal class III malocclusion.

AIM: The prevalence of symptoms of Hoffmeister's "genetically determined predisposition to disturbed development of the dentition" as studied in patients with true skeletal Class III malocclusion; results of the study were compared with those found in the scientific literature regarding samples from the normal population and from orthodontic patients. PATIENTS AND METHODS: The prevalence of 20 defined symptoms was evaluated in 120 patients with true skeletal Class III malocclusion. The patients were selected on the basis of a positive family history and on the presentation of typical characteristics of a skeletal Class III morphology in a lateral cephalogram. The mean age of the patients evaluated was 12.4 years. The patients' files, 1161 radiographs and plaster casts were analyzed. The prevalence of the individual symptoms was compared by means of the chi(2)-test (p < or = 0.05). RESULTS: 118 patients (98.3%) were found to have 292 symptoms of "genetically determined predisposition to disturbed development of the dentition". Increased distance between molar buds, atypical tooth bud position and atypical root shape were the symptoms recorded most frequently. With regard to the simultaneous existence of several symptoms, the combination of four such symptoms was most frequent (20.8%), followed by the combination of three symptoms (15.8%), and five symptoms (15.0%). Congenital hypodontia was found in 19.2% of the patients. CONCLUSION: It should be kept in mind for patients with true skeletal Class III malocclusion that this type of dysgnathia is most likely combined with other symptoms of disturbed development of the dentition. The higher prevalence of those symptoms found in patients with skeletal Class III malocclusion when compared with the normal population and other orthodontic patients renders orthodontic treatment of those patients more difficult and calls for comprehensive clinical and radiological examination prior to any treatment.

Adolescent↗

PubMed1986

Effects of sera from Cohen, genetically determined diabetic rats, streptozotocin diabetic rats and sucrose fed rats on in vitro development of early somite rat embryos.

The effects of sera from genetically determined Cohen diabetic rats, streptozotocin (STZ) diabetic rats and non-diabetic control rats fed a 72% sucrose diet on the in vitro development of 9 1/2 day old rat embryos from control rats have been studied. Hyperglycemic sera from diabetic rats had a high teratogenic effect: abnormalities were seen in 41.5% of embryos cultured in serum from Cohen diabetic animals and in 54% of embryos cultured in serum from STZ-diabetic rats. Malformations were seen in 25-27% of embryos cultured in serum from 2 groups of control rats fed a high sucrose diet compared with 10.7% in serum from control rats maintained on regular diet. When embryos from the experimental groups were cultured in serum from control rats on regular diet malformations were seen in 24.7% of embryos from Cohen genetically determined diabetic rats vs 10.9-12.4% in embryos from 2 non-diabetic groups. Only 14% of embryos from STZ-diabetic rats exhibited malformations when cultured in the control serum, but 42% of embryos from the same rats showed abnormalities when grown in serum from STZ-diabetic rats. Normalization of glucose level in the serum of STZ-diabetic rats by prior injection of insulin did not reduce the high incidence of malformations (51%). The high rate of embryonic malformations correlated with the ultrastructural changes of their visceral yolk sac endoderm. We suggest that serum from diabetic rats is teratogenic even at moderate hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗