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At least 523 records · Page 29Linked to original sources
PubMed2006

The influence of genetic background on the induction of oxidative stress and impaired insulin secretion in mouse islets.

AIMS/HYPOTHESIS: We determined whether high-glucose-induced beta cell dysfunction is associated with oxidative stress in the DBA/2 mouse, a mouse strain susceptible to islet failure. MATERIALS AND METHODS: Glucose- and non-glucose-mediated insulin secretion from the islets of DBA/2 and control C57BL/6 mice was determined following a 48-h exposure to high glucose. Flux via the hexosamine biosynthesis pathway was assessed by determining O-glycosylated protein levels. Oxidative stress was determined by measuring hydrogen peroxide levels and the expression of anti-oxidant enzymes. RESULTS: Exposure to high glucose levels impaired glucose-stimulated insulin secretion in DBA/2 islets but not C57BL/6 islets, and this was associated with reduced islet insulin content and lower ATP levels than in C57BL/6 islets. Exposure of islets to glucosamine for 48 h mimicked the effects of high glucose on insulin secretion in the DBA/2 islets. High glucose exposure elevated O-glycosylated proteins; however, this occurred in islets from both strains, excluding a role for O-glycosylation in the impairment of DBA/2 insulin secretion. Additionally, both glucosamine and high glucose caused an increase in hydrogen peroxide in DBA/2 islets but not in C57BL/6 islets, an effect prevented by the antioxidant N-acetyl-L: -cysteine. Interestingly, while glutathione peroxidase and catalase expression was comparable between the two strains, the antioxidant enzyme manganese superoxide dismutase, which converts superoxide to hydrogen peroxide, was increased in DBA/2 islets, possibly explaining the increase in hydrogen peroxide levels. CONCLUSIONS/INTERPRETATION: Chronic high glucose culture caused an impairment in glucose-stimulated insulin secretion in DBA/2 islets, which have a genetic predisposition to failure, and this may be the result of oxidative stress.

Adenosine Triphosphate↗
PubMed1992

A study of autologous anti-idiotypic antibody-forming cells in mice of different ages and genetic backgrounds.

Antibody response to phosphorylcholine, an immunodominant epitope of Streptococcus pneumoniae R36a (Pn), is characterized by a public idiotype, T15, that is expressed on a large proportion of antibody molecules produced by all mouse inbred strains. The ability of the immune system to produce an autologous antibody to T15 upon immunization with Pn vaccine was investigated using a modified ELISA plaque assay for detection of single antibody-forming cells (AFC). The limit of ELISA assay for detection of specific anti-T15 AFC is approximately 300 cells/spleen. However, our studies failed to detect any autologous anti-T15 AFC in the course of the primary antibody response to Pn vaccine in young/adult (2-4 months) BALB/c and C57BL/6 mice. Aged mice (20-22 months) also failed to develop any specific auto-anti-T15 AFC upon the primary Pn immunization, despite the fact that the anti-Pn response in these animals changes both quantitatively and qualitatively. In order to generate specific anti-T15 AFC, BALB/c mice had to be immunized repeatedly with Pn vaccine (four weekly injections) or immunized directly with T15 protein in CFA. Different results were obtained with D1.LP mice that are low responders to Pn and express lower levels of T15 Id as compared to BALB/c. Young D1.LP mice produced high numbers of auto-anti-T15 AFC of both IgM and IgG isotypes following a single immunization with Pn vaccine. The kinetics of auto-anti-T15 response in D1.LP mice was similar to that of the antigen-specific response. These results demonstrate that the ability of the immune network to produce autologous antibody to a shared Id depends on the genetic makeup of the host, and that this response may be regulated by the level of Id expression.

Age Factors↗
PubMed1998

The expression and regulation of inducible nitric oxide synthase gene differ in macrophages from chickens of different genetic background.

It has been previously reported that lipopolysaccharide (LPS)-stimulated macrophages from Cornell K-Strain chickens (B15B15) and a transformed cell line, MQ-NCSU, (broiler origin) produced significantly higher levels of inducible nitric oxide synthase (iNOS) mRNA than macrophages isolated from GBI (B13B13) and GB2 (B6B6) chickens. The purpose of this study was to determine the basis of such differential iNOS gene expression and to study the relationship of high or low expression of iNOS mRNA with iNOS enzyme activity in macrophages from GB2 (low iNOS mRNA expresser), K-strain and MQ-NCSU (high iNOS mRNA expressers). The enzyme activity in lysates from LPS-stimulated macrophages was lower in GB2 (range: 23 to 41 microM, P < 0.05) as compared with the K-strain and MQ-NCSU macrophages that exhibited intermediate (range: 27 to 59 microM) and the highest (range: 144 to 217 microM) activity, respectively. Total RNA collected from LPS-treated macrophages at various time-points post-actinomycin D treatment revealed comparable iNOS mRNA levels in MQ-NCSU, GB2, and K-strain macrophages, suggesting that post-transcriptional regulation mechanism(s) do not account for the difference in iNOS mRNA expression. To determine if differences in the transcription rate are the basis of the differential iNOS gene expression, macrophages were stimulated with or without LPS and nuclei-isolated. Inducible NOS mRNA probes were generated and hybridized with immobilized iNOS cDNA (reverse Northern blot). The resulting lumigraph yielded enhanced transcriptional activity from K-strain and MQ-NCSU macrophages whereas this activity was lower in GB2 macrophages. Therefore, these studies suggest that the previously reported genetically-based difference in iNOS mRNA expression further translates into differences in iNOS enzyme activity, and that the iNOS gene in chickens is transcriptionally regulated.

Animals↗
PubMed1999

Scintigraphic evidence for a specific long-chain fatty acid transporting system deficit and the genetic background in a patient with hypertrophic cardiomyopathy.

The mechanism of cardiac uptake of long-chain free fatty acids has not been fully determined. We encountered a hypertrophic cardiomyopathy patient who showed a lack of cardiac uptake of 2 different types of long-chain fatty acid analogues on the scintigraphic images. Flow cytometric analysis revealed no platelet or monocyte CD36 molecule expression (type I CD36 deficiency) and his CD36 gene showed homozygous mutation for 478C to T substitution, leading to an abnormal CD36 amino acid sequence. These findings strongly suggest that a specific transporting system rather than a simple diffusion is commonly involved in the cardiac uptake of long-chain free fatty acids in humans, and that the CD36 protein is the most likely candidate for the specific transporter and to explain scintigraphic defects on fatty acid imaging.

Adult↗
PubMed2002

Multiple effects of genetic background on variegated transgene expression in mice.

BLG/7 transgenic mice express an ovine beta-lactoglobulin transgene during lactation. Unusually, transgene expression levels in milk differ between siblings. This variable expression is due to variegated transgene expression in the mammary gland and is reminiscent of position-effect variegation. The BLG/7 line was created and maintained on a mixed CBA x C57BL/6 background. We have investigated the effect on transgene expression of backcrossing for 13 generations into these backgrounds. Variable transgene expression was observed in all populations examined, confirming that it is an inherent property of the transgene array at its site of integration. There were also strain-specific effects on transgene expression that appear to be independent of the inherent variegation. The transgene, compared to endogenous milk protein genes, is specifically susceptible to inbreeding depression. Outcrossing restored transgene expression levels to that of the parental population; thus suppression was not inherited. Finally, no generation-dependent decrease in mean expression levels was observed in the parental population. Thus, although the BLG/7 transgene is expressed in a variegated manner, there was no generation-associated accumulated silencing of transgene expression.

Animals↗
PubMed1996

Interethnic variability in birth weight and genetic background: a study of placental alkaline phosphatase.

The relationship between human placental alkaline phosphatase (PLAP) genotype and birth weight is investigated in a sample of white, black and Puerto-Rican new-born infants from New Haven, Connecticut (total 710 subjects). Black and Puerto-Rican infants show a higher incidence of growth retardation and a higher frequency of ALPp*1/*1 genotype as compared to whites. The proportion of newborns with a low birth weight (below the 10th percentile) is lower in infants with ALPp*1/*1 genotype than in those with other PLAP genotypes, especially among non-whites. It is argued that the higher frequency of ALPp*1 allele among non-whites might be, at least in part, a consequence of their adaptation in the past to environmental conditions adverse to optimal intrauterine development.

Black or African American↗
PubMed1989

Neonatal growth delay in alpha-1-antitrypsin disease. Influence of genetic background.

We have developed a transgenic mouse strain, Z#2, which represents a model for alpha 1-protease inhibitor (alpha 1-antitrypsin: alpha 1-Pi)-associated liver disease (Dycaico et al., 1988). Fifteen percent of human infants with alpha 1-Pi disease develop non-viral hepatitis which is sometimes associated with growth retardation. Such hepatitis and growth retardation tend to occur in a subset of families with other alpha 1-Pi affected members who have had non-viral hepatitis. The Z#2 mouse strain exhibits non-viral hepatitis and growth retardation. This phenotype is more pronounced in transgenic offspring of crosses between Z#2 mice and DBA/2J inbred mice, and less pronounced in transgenic offspring of crosses between Z#2 and CBA/J inbred mice. Such phenotypic differences resemble the phenotypic differences seen in human families with alpha 1-Pi-associated liver disease.

Animals↗
PubMed1996

Generalized pustular psoriasis in Japan: two distinct groups formed by differences in symptoms and genetic background.

A multi-center study for investigating generalized pustular psoriasis was carried out in Japan in order to clarify the prevalence, the etiology, and the standard therapy. Through questionnaires, 541 cases of patients with generalized pustular psoriasis and related disorders were collected, and the history, the precipitating factors, the symptoms and the laboratory findings were analyzed from medical records. The statistic analysis revealed that 902 (+/- 102.2) patients with generalized pustular psoriasis were expected at the time, and that the prevalence of generalized pustular psoriasis in Japan was 7.46/million. Of 541 patients with generalized pustular psoriasis, 208 cases had the recurrent episodes of symptoms with generalized pustules which had been referred to von Zumbusch type pustular psoriasis or to the acute form of generalized pustular psoriasis. Two hundred and eight patients were further subdivided into two groups: one with a preceding history of ordinary psoriasis (pso+ generalized pustular psoriasis; 65 cases) and another without a psoriasis history (pso- generalized pustular psoriasis; 143 cases). Subdivision into the two groups defined that the onset of pustular outbreak was earlier in the pso- generalized pustular psoriasis group. It was also pointed out that the precipitating factors were different, as the pso- generalized pustular psoriasis group was more frequently affected after infections, and that the pso+ generalized pustular psoriasis group was more frequently affected by preceding corticosterold therapy. HLA analysis of 92 cases with von Zumbusch type generalized pustular psoriasis confirmed that A2, B14, B35 phenotypes were weakly correlated, and when 92 cases were subdivided into the two groups, the pso+ generalized pustular psoriasis group revealed a statistically significant correlation with A1 (p < 0.01), B37 (p < 0.02) and DRw10 (p < 0.05), which was closely related with psoriasis vulgaris patients in Japan. Both clinical surveillance and genetic analysis have disclosed the heterogeneity of von Zumbusch type generalized pustular psoriasis, as there exist two types; one is closely related to psoriasis and the other not.

Adolescent↗
PubMed2000

Early detection of lung disease and its association with the nutritional status, genetic background and life events in patients with cystic fibrosis.

Progression of lung disease is the most prominent cause of morbidity and death in patients with cystic fibrosis (CF), but the severity of lung disease and the rate of lung function decline are highly variable. An attempt was made to define accurate estimates of disease progression in these patients early diagnosed and prospectively evaluated until 10 years of age. The primary question to ask was whether functional abnormalities detected already in infancy are associated with functional derangements later on in life, and may be useful as parameters of prognostic value. Early diagnosis of CF can best be achieved by screening of mutation by new techniques (buccal cell brushing) in infants, even when the sweat test or accurate blood sampling is not available. Moreover, in infants lung function can be assessed by infant whole-body plethysmography enabling the study of the interrelationship with delayed weight gain and growth retardation, as well as the associations with the most common disease-causing mutations. Out of a cohort of 80 infants (39 males, 41 females) with CF a follow-up study was started with 50 CF infants diagnosed during infancy (mean age 4.6 +/- 4.0 months; range 0.1-12.7 months) and prospectively evaluated at 6-month intervals during the first 2 years of life. Moreover, in 32 CF children out of this cohort, follow-up was continued until 10 years of age. Differences were encountered with respect to the different events occurring during the first years of life, especially the onset of chronic colonization with Pseudomonas aeruginosa. The association between infant lung function and specific mutations (DeltaF508 homozygotes, frameshift DeltaF508/3905insT compound heterozygotes and nonsense DeltaF508/R553X compound heterozygotes) furthermore revealed that differences in lung function within the genetic groups are mainly related to the degree of pulmonary hyperinflation. Pulmonary hyperinflation was also associated with the degree of impaired nutritional status. An association between impaired gas exchange characteristics at 10 years of age and the degree of pulmonary hyperinflation during infancy finally demonstrates that by early mutation screening, lung function testing and assessment of the nutritional status predictors of disease progression later on in life can be defined. Therefore, preventive therapeutic measures should primarily be based on such prognostic factors.

Age Factors↗
PubMed2002

Genetic background as a possible determinant of clinical and biological features of Epstein-Barr virus infection--a hypothetical view.

Epstein-Barr virus (EBV) is involved in various clinical disorders and many of the disease entities are lymphoid and epithelial malignancies. The exact mechanisms that determine the exact form of EBV-related disorder are not clear at present. Many of the clinical manifestations of these diseases are based on the biological characteristics of the target cells for EBV infection and the expression and function of EBV gene, which also perturb host immune functions. In this monograph, I propose a hypothesis regarding the mechanism involved in shaping the manifestation of EBV infection that genomic instability of EBV-infected cells and how a defective immune surveillance system against such cells plays a critical role in determining the clinical manifestation of EBV infection. Using EBV-infected B-cells from patients and carriers with ataxia telangiectasia as an example of EBV infection, I present and discuss evidence in support of the proposed hypothesis.

Ataxia Telangiectasia↗
PubMed2001

Genetic background for immune-mediated diseases.

Gene variants (alleles) involved in the immune response are most likely selected during evolution. The allelic polymorphisms that may be advantageous in fighting harmful agents may be susceptibility genes in immune-mediated diseases. Identification of susceptibility genes is important because these genes encode proteins, which are most probably involved in the disease process. Hence, the identification of susceptibility genes may lead to an improved understanding of the pathogenesis and may therefore help the development of preventive and therapeutic measures. Susceptibility genes may be identified by analyzing genes known to be involved in immune responses (candidate gene search) or by analyzing gene markers evenly distributed over the genome (genome-wide scan). However, since several genes jointly contribute to disease susceptibility, the frequencies of single susceptibility genes may be quite high in the normal population. Moreover, different set of genes may predispose to the same clinical disease. It may therefore be very difficult to identify susceptibility genes, apart from the major histocompatibility complex (MHC) genes, which have now been shown to predispose to several immune-mediated diseases.

Genetic Markers↗
PubMed1999

Influence of the genetic background on the pattern of lesions developed by resistant and susceptible mice infected with Paracoccidioides brasiliensis.

To compare the sequential evolution of lesions developed by resistant (A/Sn) and susceptible (B10.A) mice to Paracoccidioides brasiliensis infection we inoculated a virulent isolate of the fungus and collected the pancreas/peripancreatic omentum monthly (from 1 to 6 months) post infection. After fixation, tissue sections were stained by conventional methods for light microscopy to investigate the cellular composition, the extracellular matrix (ECM) patterns and the morphology of the yeasts in the lesions. In both strains, the fungal lesions were localized mostly in the omentum; a few lesions in the pancreatic parenchyma were observed, mostly in B10.A mice. In both strains, macrophages and plasmocytes were the predominant cells in all lesions, followed by neutrophils (PMN) and macrophages transformed into giant and epithelioid cells. Remarkable differences were observed between resistant and susceptible mice, specially related to the ECM structure of the granulomatous lesions. In A/Sn mice, from the 1st month on, the coexistence of two types of lesions was observed: one type showed a well-defined encapsulated nodule, constituted mainly of type I collagen. Neutrophils were abundant in areas of massive fungal destruction and few viable yeasts were observed. The other type showed residual characteristics, with sparse collagen deposits and presence of xantomatous-like macrophages, containing degenerated fungi. Such residual lesions predominated after the 2nd month and were the only type observed from the 4th month on, indicating the control of the infection. In B10.A mice, on the contrary, only one type of lesion was observed, showing less tendency to encapsulation and the formation of multiple small granulomatous foci, individualized by reticular type III collagen fibers. There were many plasmocytes in the periphery and large numbers of budding yeasts, with no evidence of fungal destruction. In the course of the infection the lesions progressively increased in number and size. Altogether, the comparative histopathological analysis demonstrates the influence of the genetic pattern of the host on the lesions developed by resistant and susceptible mice to P. brasiliensis infection.

Animals↗
PubMed1993

Difference in HLA-linked genetic background between mixed connective tissue disease and systemic lupus erythematosus.

We have typed 64 Japanese patients with mixed connective tissue disease (MCTD) and 53 Japanese patients with systemic lupus erythematosus (SLE) for HLA-DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, and DPB1 genes by the HLA-DNA typing method using the PCR-SSOP technique. Frequencies of HLA-DRB1*0401, DRB1*0901, DRB4*0101, and DQA1*03 were increased and those of HLA-DRB1*0405 and DQB1*0401 were decreased in the patients with MCTD, while the frequencies of HLA-DRB1*1501, DRB5*0101, and DQB1*0602 were increased in the patients with SLE. The typing results suggest that susceptibility to MCTD is strongly associated with the HLA-DRB1*0401-DRB4*0101-DQA1*03-DQB1*0301 haplotype, and that to SLE is associated with the HLA-DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 haplotype. The observation that the MCTD-associated HLA alleles are distinct from the SLE-associated ones may support the clinical entity of MCTD different from SLE.

Alleles↗
PubMed1993

Genetic background of clinical homogeneity of phenylketonuria in Poland.

In order to elucidate the clinical homogeneity and severity of the hyperphenylalaninaemias in Poland, a total of 71 children with typical phenylketonuria (PKU) originating from western and northern Poland were screened for 13 mutations in the phenylalanine hydroxylase (PAH) gene. Eighty percent of all PKU alleles tested were found to carry an identified mutation. One mutation, namely the R408W mutation, accounted for more than 63% of mutant PAH alleles in Poland, the other 27% being accounted for by six mutations: IVS12nt1 (5%), IVSnt546 (5%), Y414C (4%), R252W (1.5%), R261Q (< 1%), and G272ter (< 1%). The predominance of the R408W mutation resulted in a high rate of homozygotes (35.2%) and compound heterozygotes for this mutation in children from western and northern Poland. The frequency and deleterious nature of this mutation probably accounts for the clinical homogeneity and severity of the hyperphenylalaninaemias in Poland. In addition, the high rate of the R408W mutation and its association with mutant haplotype 2 at the PAH locus in Poland give additional support to the Balto-Slavic origin of this mutant gene.

Base Sequence↗
PubMed2005

Advanced glycoxidation end products in chronic diseases-clinical chemistry and genetic background.

Several diseases (atherosclerosis, diabetes mellitus, chronic renal failure) are associated with oxidative and carbonyl stress, microinflammation and eventually autoimmune reaction. Both oxidative and carbonyl stress cause damage to important biological structures-proteins, carbohydrates, lipids and nucleic acids and may enhance inflammatory response. New compounds and modified structures are formed, among them advanced oxidation protein products (AOPP), advanced glycation end products (AGEs-e.g. pentosidine, carboxymethyllysine) and advanced lipoperoxidation end products (ALEs). Accumulation of glycoxidation products, upregulation of protective mechanisms like glyoxalase I as well as enhanced transcription of genes coding for cytokines, growth factors and adhesive molecules via AGE-RAGE (receptor for AGEs) interaction and subsequent increase of classical acute phase reactants (e.g. CRP-C-reactive protein or orosomucoid) can be observed in a variety of chronic diseases. Additionally, several RAGE gene polymorphisms have shown association with some pathological states-diabetic complications, vascular damage, inflammatory response or antioxidant status. Recent advances in understanding the pathogenesis of chronic diseases provide new possibilities for diagnostics and monitoring of severely ill patients, however, further studies are still required to establish efficient therapeutical strategies.

Chemistry, Clinical↗
PubMed2004

The positive regulatory effect of TGF-beta2 on primitive murine hemopoietic stem and progenitor cells is dependent on age, genetic background, and serum factors.

TGF-beta is considered a negative regulator of hemopoietic stem and progenitor cells. We have previously shown that one TGF-beta isoform, TGF-beta2, is, in fact, a positive regulator of murine hemopoietic stem cell function in vivo. In vitro, TGF-beta2, but not TGF-beta1 and TGF-beta3, had a biphasic dose response on the proliferation of purified lin-Sca1(++)kit(+) (LSK) cells, with a stimulatory effect at low concentrations, which was subject to mouse strain-dependent variation. In this study we report that the stimulatory effect of TGF-beta2 on the proliferation of LSK cells increases with age and after replicative stress in C57BL/6, but not in DBA/2, mice. The age-related changes in the TGF-beta2 effect correlated with life span in BXD recombinant strains. The stimulatory effect of TGF-beta2 on the proliferation of LSK cells requires one or more nonprotein, low m.w. factors present in fetal calf and mouse sera. The activity of this factor(s) in mouse serum increases with age. Taken together, our data suggest a role for TGF-beta2 and as yet unknown serum factors in the aging of the hemopoietic stem cell compartment and possibly in organismal aging.

Aging↗
PubMed2002

A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse.

Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.

Animals↗
PubMed2004

Maize centromeres: organization and functional adaptation in the genetic background of oat.

Centromeric DNA sequences in multicellular eukaryotes are often highly repetitive and are not unique to a specific centromere or to centromeres at all. Thus, it is a major challenge to study the fine structure of individual plant centromeres. We used a DNA fiber-fluorescence in situ hybridization approach to study individual maize (Zea mays) centromeres using oat (Avena sativa)-maize chromosome addition lines. The maize centromere-specific satellite repeat CentC in the addition lines allowed us to delineate the size and organization of centromeric DNA of individual maize chromosomes. We demonstrate that the cores of maize centromeres contain mainly CentC arrays and clusters of a centromere-specific retrotransposon, CRM. CentC and CRM sequences are highly intermingled. The amount of CentC/CRM sequence varies from approximately 300 to >2800 kb among different centromeres. The association of CentC and CRM with centromeric histone H3 (CENH3) was visualized by a sequential detection procedure on stretched centromeres. The analysis revealed that CENH3 is always associated with CentC and CRM but that not all CentC or CRM sequences are associated with CENH3. We further demonstrate that in the chromosomal addition lines in which two CenH3 genes were present, one from oat and one from maize, the oat CENH3 was consistently incorporated by the maize centromeres.

Adaptation, Physiological↗