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Biomedical subjects

J A Hansen

Publications and source records attributed to J A Hansen.

At least 19 recordsLinked to original sources
PubMed2006

Correlation of interleukin-10 gene haplotype with hepatocellular carcinoma in Taiwan.

Polymorphisms in cytokine genes can influence immune responses, inflammation and tissue injury, and may affect the outcome of hepatitis B virus (HBV) infection. We analyzed single nucleotide polymorphisms (SNP) in the interleukin (IL)-10 gene among 344 HBV carriers and 208 patients with hepatocellular carcinoma (HCC). Genotypes and haplotypes were tested for association with HCC. IL-10/-592 C/C genotype was associated with a higher risk for HCC compared with IL-10/-592 A/C and A/A genotypes [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.2-3.6]. IL-10/1927 A/A genotype was also associated with a higher risk for HCC compared with IL-10/1927 A/C and C/C genotypes (OR: 1.5, 95% CI: 1.0-2.2). Haplotype analysis revealed that the homozygosity of the C-A haplotype (defined by SNPs at positions -592 and 1927) of IL-10 gene conveys the highest risk for HCC among HBV carriers compared with the homozygosity for the A-C haplotype (OR: 2.6, 95% CI: 1.3-4.9). The results demonstrate that IL-10 gene polymorphism can affect the outcome of chronic HBV infection. Further studies are necessary to clarify how variation in the IL-10 gene affects IL-10 function and risk of HCC.

Adult↗
PubMed2005

D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus.

AIMS/HYPOTHESIS: The HLA class II DQB1*0602 allele confers strong dominant protection against type 1 diabetes but protection is not absolute. The aim of this study was to identify markers within the HLA region that differentiate DQB1*0602 haplotypes and show different associations with disease risk. METHODS: We defined alleles at eight microsatellite markers spanning the HLA region in a case-control cohort from Sweden. RESULTS: We found that allele 15 at marker D6S265 (109 kb centromeric of HLA-A) was over-represented among patients carrying DRB1*15, DQB1*0602. A detailed haplotype analysis showed that DRB1*15, DQB1*0602 haplotypes carrying D6S265*15 have a ten-fold higher odds ratio (OR) than those carrying other alleles and thus confer reduced protection [OR D6S265*15=0.186 (95% CI 0.074, 0.472) vs OR D6S265*15-=0.017 (95% CI 0.005, 0.062), p<0.001]. CONCLUSIONS/INTERPRETATION: Our data support the existence of a locus that modifies the protective effect associated with DQB1*0602. Typing for allele D6S265*15 can identify a less protective DQB1*0602 haplotype, thereby allowing a more accurate prediction of type 1 diabetes risk.

Adult↗
PubMed2005

Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling.

Upon leptin binding, the leptin receptor is activated, leading to stimulation of the JAK/STAT signal transduction cascade. The transient character of the tyrosine phosphorylation of JAK2 and STAT3 suggests the involvement of protein tyrosine phosphatases (PTPs) as negative regulators of this signalling pathway. Specifically, recent evidence has suggested that PTP1B might be a key regulator of leptin signalling, based on the resistance to diet-induced obesity and increased leptin signalling observed in PTP1B-deficient mice. The present study was undertaken to investigate the mechanism by which PTP1B mediates the cessation of the leptin signal transduction. Leptin-induced activation of a STAT3 responsive reporter was dose-dependently inhibited by co-transfection with PTP1B. No inhibition was observed when a catalytically inactive mutant of PTP1B was used or when other PTPs were co-transfected. PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.

Animals↗
PubMed2005

Regulation of pancreatic beta-cell mass and proliferation by SOCS-3.

Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Suppressors of cytokine signaling (SOCS) proteins are specific inhibitors of the JAK/STAT pathway acting through a negative-feedback loop. To investigate in vivo effects of SOCS-3 in growth hormone (GH)/prolactin signaling in beta-cells we generated transgenic mice with beta-cell-specific overexpression of SOCS-3. The relative beta-cell proliferation and volume in the mice were measured by morphometry. Beta-cell volume of transgenic female mice was reduced by over 30% compared with beta-cell volume in wild-type female mice. Stimulation of transgenic islets in vitro with GH showed a reduced tyrosine phosphorylation of STAT-5 when compared with wild-type islets. Transduction of primary islet cultures with adenoviruses expressing various SOCS proteins followed by stimulation with GH or glucagon-like peptide-1 (GLP-1) revealed that SOCS-3 inhibited GH- but not GLP-1-mediated islet cell proliferation, indicating that the decreased beta-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced beta-cell proliferation by SOCS-3. In spite of the reduced beta-cell volume the transgenic female mice exhibited enhanced glucose tolerance compared with wild-type littermates following an oral glucose-tolerance test. Together these data suggest that SOCS-3 modulates cytokine signaling in pancreatic beta-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.

Animals↗
PubMed2004

HLA-Cw*0409N is associated with HLA-A*2301 and HLA-B*4403-carrying haplotypes.

The associations of HLA-B*4402 and HLA-B*4403 with alleles of HLA-A and HLA-Cw were investigated in panels of HLA-B*4403 and HLA-B*4402 homozygous individuals and in selected individuals carrying HLA-Cw*04 and HLA-B*4403. Some of these individuals were genotyped and also carried (HLA-DRB1*0701, DQB1*02). Among the latter, we studied individuals carrying the conserved extended haplotype (CEH) [HLA-Cw*04, B*4403, FC31, DRB1*0701, DQB1*02]. Four different common (HLA-Cw*, B*44) haplotypes were identified that extended to the HLA-A locus: HLA-A*0201, Cw*0501, B*4402; HLA-A*2902, Cw*1601, B*4403; HLA-A*2301, Cw*0401, B*4403; and HLA-A*2301, Cw*0409N, B*4403. We identified eight unrelated examples of the allele HLA-Cw*0409N. HLA-A*2301 was associated with both HLA-Cw*0401 and HLA-Cw*0409N, suggesting that HLA-Cw*0409N may have arisen from a mutation in a CEH. We estimate that approximately 2 to 5 in 1000 Caucasian individuals carry the allele HLA-Cw*0409N, making it one of the most frequent null HLA alleles known to date. Our findings demonstrate the first example of three different HLA-Cw-determined subtypes of a common or CEH carrying a shared HLA-B allele, in this case HLA-B*4403.

Alleles↗
PubMed2003

Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks.

The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small (< 0.2 Mb) blocks of relatively conserved DNA sequence: HLA-Cw/B; TNF; complotype; and HLA-DR/DQ. Each of these small blocks is composed of two or more alleles of closely linked loci inherited as one genetic unit. We updated the concept of the conserved extended haplotype (CEH) using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units (>/= 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA-A and -DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.

Alleles↗
PubMed2003

Polymorphisms within the tumor necrosis factor and lymphotoxin-alpha genes and endemic pemphigus foliaceus--are there any associations?

The purpose of this study was to analyze the possible influence of the TNF and LTA loci polymorphisms on the susceptibility/resistance to endemic pemphigus foliaceus, also named fogo selvagem (FS), an autoimmune disease characterized by blisters due to acantholysis of the superficial-most epidermal cells. Autoantibodies, mainly of the IgG4 subclass, are directed against a desmosomal glycoprotein known as desmoglein 1. FS shares clinical, histological and immunological features with nonendemic pemphigus foliaceus. Most residents of the endemic regions do not develop the disease, and familial clustering has been documented, suggesting that host factors play a role in susceptibility. In fact, strong positive and negative associations with HLA class II genes have been reported. The TNF and LTA genes are located in the class III region of the Human Major Histocompatibility Complex. Their location, the function of their products, which are cytokines and pluripotent immunomodulators, as well as their genetic variability make them candidate genes for complex diseases with an altered immune response. A total of 162 patients and 191 controls were enrolled in this study. No significant associations were found with any one of the three LTA single nucleotide polymorphisms (SNP) analyzed (at nucleotides 249, 365, 720), nor with the TNF SNP located at positions -863 and -308. The frequency of allele TNF*238A was slightly decreased in patients (OR = 0.45). In conclusion, the results of this study indicate that genetic variability of the TNF and LTA genes does not play a major role in susceptibility/resistance to pemphigus foliaceus.

Alleles↗
PubMed2003

Tissue typing in support of unrelated hematopoietic cell transplantation.

The success of unrelated hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies has closely paralleled development of robust typing methods for comprehensive and precise donor-recipient matching. The application of molecular methods in clinical research has led to a more complete understanding of the immunogenetic barriers involving host-vs-graft (HVG) and graft-vs-host (GVH) reactions. Along with the development of less toxic transplant regimens, advances in the prevention and treatment of graft-vs-host disease (GVHD) and in the supportive care of the transplant recipient, improved HLA matching of potential unrelated donors has led to clinical results that begin to compare favorably with that of HLA-identical sibling transplants.

Alleles↗
PubMed2003

Hydrogenated dietary fat improves pork quality of pigs from two lean genotypes.

Pork quality is influenced by nutrition, genetics, management, and pork-processing procedures. Pigs of lean genotype fed diets high in unsaturated fat may have thinner, lower-quality bellies with a soft fat composition. Therefore, we investigated the effects of supplementing 5% choice white grease that had been chemically hydrogenated to iodine values of 80, 60, 40, or 20 on pork quality. Diets were fed to barrows and gilts of two genotypes (NPD [Ham-line x Manor hybrid] and PIC [406, 419, or 420 x C22]; n = 240) in a 4 x 2 x 2 factorial design. Pigs (76.8 kg of mean initial weight) were placed on test at a common age and were fed dietary treatments for 52 d. Pigs of PIC genotype were heavier at trial initiation, had higher feed intake and feed conversion ratio (F/G; P < 0.05), and greater backfat (26.3 vs. 24.0 mm; P < 0.001) and loin depth (59.0 vs. 55.3 mm; P < 0.001) compared with the NPD genotype pigs. As the iodine value of dietary fat was reduced, belly thickness increased (P < 0.05) and length decreased linearly (P < 0.05). Congruently, belly fat iodine value decreased from 73.9 to 67.4 (linear effect; P < 0.001) and belly fat C18:2 concentration declined from 20.6 to 16.3% (linear and quadratic effect; P < 0.001). The belly mono- and polyunsaturated fat ratio increased 29% as diet iodine value declined from 80 to 20 (linear and quadratic effect; P < 0.001). Further, there was a linear increase (P < 0.001) in saturated fatty acid concentration of belly fat (C14:0, C16:0, and C18:0) as dietary fat iodine value declined. Quadratic (P < 0.005) effects were detected in the level of C18:1trans as iodine value decreased from 80 to 20, paralleling dietary content. Dietary fat iodine value did not affect fat digestibility, ADFI, or F/G. Pork belly quality was improved as defined by reduced iodine value, C18:2 content, increased saturated fatty acid content, increased thickness, and decreased length as dietary iodine value decreased. Results indicate that reduction of dietary fat iodine value by chemical hydrogenation has the desirable effect of improving pork quality and does not alter growth performance.

Abdomen↗
PubMed2002

The effects of long-term cadmium exposure on the growth and survival of juvenile bull trout (Salvelinus confluentus).

Bull trout (Salvelinus confluentus) have been listed recently as threatened in the United States under the federal Endangered Species Act. This species currently resides, or historically resided, in several waterways that either are impacted or are under threat of impact from metals mining activities. We conducted a 55-day sub-chronic (i.e. sublethal) cadmium (Cd) exposure in water at 30 mg l(-1) (as CaCO(3)) hardness, pH 7.5, and 8 degrees C. Exposures were conducted using six replicate exposure tanks for each of the six treatments (five Cd concentrations and one control). Measured Cd concentrations were <0.013 (control), 0.052, 0.089, 0.197, 0.383, and 0.786 microg Cd l(-1). Exposure to 0.786 microg Cd l(-1) caused increased mortality (37%) and reduced growth (28% reduction in weight change) in fish exposed for 55 days. All Cd exposure concentrations caused significant whole body accumulation of Cd compared with controls. Our results indicate that even though fish are significantly accumulating Cd in each non-control treatment, growth reductions in bull trout occurred only at Cd concentrations that also caused significant mortality. The Cd concentration that reduced growth and survival in this long-term exposure (0.786 microg Cd l(-1)) is greater than the recently-revised US federal aquatic life criteria (ALC) value for the corresponding hardness concentration (ALC=0.62 microg Cd l(-1) for acute effects and 0.11 microg Cd l(-1) for chronic effects).

Animals↗
PubMed2002

Relationship between exposure duration, tissue residues, growth, and mortality in rainbow trout (Oncorhynchus mykiss) juveniles sub-chronically exposed to copper.

We conducted a 56-day sub-chronic test on the effects of Cu on rainbow trout (Oncorhynchus mykiss) fry at a nominal water hardness of 100 mg l(-1) (as CaCO(3)). Response measures were growth, whole body Cu concentrations, and mortality. Significant mortality was observed in fish exposed to 54.1 microg Cu l(-1) (47.8%) and 35.7 microg Cu l(-1) (11.7%). Growth was dose-dependent over the range of Cu treatments (0-54 microg Cu l(-1)), and was modeled as a function of Cu exposure concentration and exposure duration. Calculated inhibition concentrations (based on change in wet weight through a 56-day Cu exposure) were IC(50)=54.0 microg Cu l(-1), IC(20)=21.6 microg Cu l(-1), IC(10)=10.8 microg Cu l(-1), and IC(01)=1.1 microg Cu l(-1). Measured whole body Cu was also dose-dependent, and growth of trout fry was readily modeled as a function of tissue Cu and exposure duration. This model was virtually identical to a model previously developed for rainbow trout exposed to Cu at a hardness of 25 mg l(-1). Following the 56-day exposure period, we performed a 96-h acute challenge to Cu and Cd to evaluate the effects of Cu acclimation on acute Cu and Cd toxicity. Sensitivity to Cu was dependent on the 'acclimation dose'; trout previously held in control aquaria (i.e. not acclimated to Cu) suffered over 80% mortality, whereas trout previously exposed to 35.7 microg Cu l(-1) for 56 day suffered 20% mortality. These fish also showed somewhat reduced sensitivity to Cd, suggesting acclimation to Cu can enhance tolerance to other metals. Finally, the relationship between growth response and hardness (derived from several studies) appeared to have a different slope than the hardness relationship previously observed for lethality responses.

Adaptation, Physiological↗
PubMed2002

Simultaneous genotyping of single nucleotide polymorphisms in the IL-6, IL-10, TNFalpha and TNFbeta genes.

Single nucleotide polymorphisms (SNP) in the human IL-6, IL-10, TNFalpha and TNFbeta genes have been associated with gene function and susceptibility to disease. In this study, primers containing mismatches at 1-3 nucleotide positions were designed to incorporate a new restriction site recognized by endonucleases AlwNI, BcgI, BglI, BsaBI, BslI, BstXI, EcoNI or XcmI for genotyping SNPs in the IL-6 gene (position - 174), IL-10 gene (positions -592 and -1082), TNFalpha gene (positions -238, - 308 and -863) and TNFbeta gene (position + 249) by mismatched polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP). Our results show that appropriately designed BslI-based mismatched PCR/RFLP assays can be successfully used to determine the genotypes for approximately 40% of SNPs. The mismatched PCR strategy can be coupled with multiplex-amplification to enable simple and rapid determination of several SNP genotypes in a single reaction.

Cytokines↗
PubMed2002

Efficient cloning and expression of HLA class I cDNA in human B-lymphoblastoid cell lines.

Analysis of HLA restriction specificity is one of the important steps in characterizing T cell clones. This usually requires either a panel of HLA-typed cells or HLA cDNA transfectants. Although preparation of HLA cDNA transfectants is laborious, utilization of transfectants is advantageous when a suitable panel is not available due to linkage disequilibrium or rarity of the HLA allele of interest. In this report, we describe an efficient and rapid HLA cloning and expression system. Three sets of PCR primers specific for HLA-A, B and C loci were designed by extensively sequencing 5'- and 3'- untranslated regions of HLA class I genes. The PCR-amplified products were introduced into modified Phoenix retrovirus vectors containing a puromycin resistant gene under the control of a LTR promotor. Gibbon ape leukemia virus (GALV)-pseudotyped retrovirus was produced and infected into B-lymphoid cell lines. Following expansion in selection media, more than 80% of cells expressed transduced HLA at a comparable level to that normally expressed. These results indicate that locus-specific PCR cloning and utilization of GALV-pseudotyped retroviral vector can be an effective and relatively efficient tool for constructing a panel of different HLA transfectants.

Antibodies, Monoclonal↗
PubMed2002

The effects of dietary fat sources, levels, and feeding intervals on pork fatty acid composition.

Two experiments investigated the quantitative relationship between dietary fat and fatty acid composition of pork. Experiment 1 was designed to establish the rate of decline for linoleic acid and iodine value of pork fat during the late fattening phase following a dietary reduction. Gilts (n = 288) were fed diets varying in linoleic acid content from 4.11 to 1.56% for 4, 6, or 8 wk prior to slaughter. The maximum rate of decline was 2% 18:2 per week and 2.5 iodine value units per week. Experiment 2 evaluated the effects of dietary fat source and level on carcass fatty acid composition and on pork quality characteristics. Barrows (n = 147) and gilts (n = 147) were allocated to seven dietary treatments for the last 6 wk of the finishing phase. Diets contained 0, 2.5, or 5% dietary fat comprised of 100, 50, or 0% beef tallow. The balance was provided by animal-vegetable blended fat. As the level of tallow increased there was a linear decrease (P < 0.05) in 18:2 content and iodine value of carcass fat. Conversely, 16:1 and 18:1 increased linearly (P < 0.05) as tallow increased. However, 16:1 decreased linearly (P < 0.05) as level of fat increased. As the level of tallow was increased a greater reduction in 18:2 and iodine value was observed in diets with 5% dietary fat compared to diets with 2.5% fat (P < 0.05). These results indicate that reduction of dietary PUFA content had the desired effect of lowering 18:2 content and iodine value of pork fat and that significant alterations could be elicited in as little as 6 to 8 wk of feeding.

Adipose Tissue↗
PubMed2001

Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.

BACKGROUND: Successful engraftment of hematopoietic stem cells from unrelated donors is influenced by disparities between the donor and recipient for HLA-A, B, and C alleles. Disparities between HLA sequence polymorphisms that are serologically detectable are termed antigen mismatches, whereas those that can be identified only by DNA-based typing methods are termed allele mismatches. Whether both kinds of polymorphisms are important in transplantation is not known. We tested the hypothesis that allele mismatches that are detectable only at the DNA level are less immunogenic than those that are serologically detectable and thereby are associated with a lower risk of graft failure after hematopoietic-cell transplantation METHODS: We used DNA sequencing to define the HLA-A, B, and C alleles in 471 patients who received bone marrow from unrelated donors for the treatment of chronic myeloid leukemia after myeloablative conditioning therapy. The odds ratios for graft failure were determined for recipients of transplants from donors with a single class I allele mismatch, a single class I antigen mismatch, or two or more class I mismatches, as compared with those with no mismatch RESULTS: A single HLA allele mismatch did not increase the risk of graft failure, whereas a single antigen mismatch significantly increased the risk. The risk was also increased if the recipient was HLA homozygous at the mismatched class I locus or if the donor had two or more class I mismatches CONCLUSIONS: HLA class I antigen mismatches that are serologically detectable confer an enhanced risk of graft failure after hematopoietic-cell transplantation. Transplants from donors with a single class I allele mismatch that is not serologically detectable may be used without an increased risk of graft failure.

Genes, MHC Class I↗