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T Höhler

Publications and source records attributed to T Höhler.

At least 19 recordsLinked to original sources
PubMed2006

Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels--a study in twins.

Elevated baseline levels of acute-phase proteins such as C-reactive protein (CRP) or cytokines like interleukin-6 (IL-6) are known risk factors for atherosclerosis and cardiovascular disease (CVD) events. However, until today, there is only controversial information about the contribution of genetic and environmental factors. Therefore, we performed an open prospective study in 108 monozygotic (MZ) and 60 same-sex dizygotic (DZ) twin pairs to analyse the genetic and environmental contributions to plasma CRP and IL-6 levels. Heritability of IL-6 was 0.61, indicating that plasma IL-6 levels are to a major part influenced by genetic determinants; however, for CRP, heritability was only 0.22, pointing to a moderate genetic influence. Plasma CRP levels were strongly influenced by female gender, older age and especially the body mass index. Our data underline the central role of IL-6 in low-grade inflammation contributing to atherosclerosis and CVD.

Adult↗
PubMed2005

Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer.

An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m(-2), LV 500 mg m(-2), 24-h 5-FU 2000 mg m(-2), and ELF comprised three once-daily doses of etoposide 120 mg m(-2), LV 300 mg m(-2), 5-FU 500 mg m(-2). In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29-1.13, P = 0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33-0.97; P = 0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P = 0.4542), and overall survival was 10.8 vs 8.3 months (P = 0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.

Adenocarcinoma↗
PubMed2005

[TACE: therapy of the HCC before liver transplantation--experiences].

PURPOSE: Analysis of the course of disease in patients with histologically proven HCC before and after orthotopic liver transplantation (LTx) who received transarterial chemoembolization (TACE). MATERIAL AND METHODS: Thirty-five of a total collective of 363 patients with histologically proven HCC underwent LTx. Before LTx, all patients were treated with sequential TACE. According to treatment pattern, TACE should be performed every 6 weeks, using a suspension consisting of max. 10 mg Mitomycin C as well as 10 - 30 ml iodized oil (Lipiodol). Patients were classified according to the Milano criteria. Criteria were called exceeded if the tumor size was > 5 cm and/or > 3 tumors larger than 3 cm were found. Therapy success and liver function were examined by means of spiral CT and laboratory controls. Investigation parameters included the number of tumor knots as well as the maximum tumor size. Additionally, the Lipiodol accumulation, the patency of the portal vein and the occurrence of complications were checked. RESULTS: Altogether, 184 TACE procedures were accomplished (5.3 +/- 3.3, range 1 - 14). The waiting period up to the transplantation amounted to 366 +/- 255 days (range 44 - 1137). The average number of tumor knots for each patient was 3.1 +/- 2.2 before and 2.9 +/- 2.2 after TACE (p = 0.887). The average tumor size was 4.2 +/- 2.5 before and 2.8 +/- 1.4 after TACE. The Milano criteria to LTx crossed 17/35 patients. Patients with exceeded Milan criteria showed a highly significant size reduction of the tumor after TACE (p = 0.001); in 9/17 cases the transplantation criteria were secondarily fulfilled through downstaging. A successful LTx was accomplished in 35/35 cases. Follow up after LTx was 769 +/- 509 days. The tumor recurrence in patients with exceeded vs. fulfilled transplantation criteria was 11.1 % vs. 11.8 % (p = 0.99). The recurrence free survival was 93.3 %, 82.5 % and 82.5 % at 1, 3 and 5 years, respectively. There were no relevant differences between patients with exceeded vs. fulfilled transplantation criteria (p = 0.99). CONCLUSION: The sequential TACE is an effective method for the therapy of the HCC before LTx in selected patients. A relevant downsizing could be achieved by TACE in patients with advanced HCC. Patients with larger tumors showed a significantly stronger size reduction after TACE. The recurrence rate and the survival rate for patients with advanced or small tumors do not differ.

Adult↗
PubMed2005

[ASCO-Update 2005--Highlights of the 41st Meeting of the American Society of Clinical Oncology/ASCO 2005].

Currently, the treatment of gastrointestinal cancers is rapidly changing due to the implementation of novel chemotherapeutic agents as well as the introduction of targeted therapies into treatment protocols. The following review provides an overview of the most important clinical trials in esophageal, gastric, colorectal, pancreatic and hepatobiliary cancer that were presented at the annual meeting of the American Society of Clinical Oncology.

Clinical Trials as Topic↗
PubMed2003

[New chemotherapeutic options in advanced gastric cancer].

Over the last years the therapeutic possibilities for advanced gastric cancer have significantly increased. Here we discuss the new chemotherapeutic options and the existing results in palliative therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Differential regulation of interleukin-10 production by genetic and environmental factors--a twin study.

Interleukin-10 (IL-10) has a critical role in the regulation of immune responses. The relative contribution of genetic and environmental factors to IL-10 production is under debate. We performed a twin study in 246 monozygotic and dizygotic twins to assess the heritability of IL-10 production after LPS stimulation in whole blood. In addition, the influence of promoter single nucleotide polymorphisms (-1082, -819 and -592) on transcriptional activity and their binding to nuclear factors was studied in luciferase reporter gene and electrophoretic mobility shift assays. IL-10 production showed a genetic determination with a heritability of 0.5. Decreasing body mass index (BMI), smoking and female gender lead to decreased IL-10 production. In monocytes, the -1082A allele showed higher binding affinity to the transcription factor PU.1 resulting in decreased transcriptional activity of -1082A promoter haplotypes. Genetic determination of IL-10 secretion is probably lower than that previously reported. Fifty percent of the observed variability explained by genetic factors. Female individuals produce less IL-10 than male subjects. Environmental factors like smoking and decreasing BMI exert suppressing effects on IL-10 production. Although the -1082A allele shows higher binding affinity to the PU.1 transcription factor and lower transcriptional activity, this polymorphism probably explains only a small fraction of the observed heritability.

Binding Sites↗
PubMed2002

Differential association of polymorphisms in the TNFalpha region with psoriatic arthritis but not psoriasis.

OBJECTIVE: To investigate the potential association of tumour necrosis factor alpha (TNFalpha) microsatellite and promoter alleles with psoriatic arthritis (PsA). METHODS: DNA from 89 white patients with PsA, 65 patients with psoriasis, and 99 healthy white controls was investigated for two TNFalpha promoter (-238 and -308) and three microsatellite polymorphisms (TNFa, c, and d). Patients had previously been studied by serology for HLA class I antigens and by sequence-specific polymerase chain reaction for DRB1* alleles. In addition, TNFalpha production of Ficoll separated peripheral blood mononuclear cells (PBMC) into culture supernatants after stimulation with lipopolysaccharide, alphaCD3 antibodies, phytohaemagglutinin, and streptococcal superantigen C was determined. RESULTS: A significant, HLA class I independent increase of the TNFa6c1d3 haplotype was found in the group with PsA but not among patients with psoriasis (32% v. 8%, pc<0.008; relative risk (RR)=5.3). In addition, patients with PsA showed a marked decrease of the TNF308A promoter allele (6% v. 18%; pc<0.008; RR=3.5) compared with healthy controls, which was independent of the increased frequency of the -238A polymorphism in this group. PBMC from patients with PsA secreted significantly less TNFalpha than cells from patients without arthritis. In particular, the TNFa6 microsatellite was associated with decreased TNFalpha production. CONCLUSION: These data indicate that allelic variations at the TNFalpha locus influence susceptibility to PsA. Decreased production of TNFalpha is at least in part genetically determined and might be related to the development of arthritis. However, the association of the TNF308G allele with the disease also points to other disease related haplotypes with still unknown susceptibility genes.

Adult↗
PubMed2001

IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients.

OBJECTIVE: To investigate the association of microsatellites and single-nucleotide promoter polymorphisms (SNPs) in the gene for the cytokine interleukin-10 (IL-10) with susceptibility to and outcome of reactive arthritis (ReA). METHODS: From genomic DNA, IL-10 microsatellites G and R and IL-10 promoter polymorphisms at positions -1087 and -524 were typed by polymerase chain reaction, automated fragment length analysis, and restriction fragment digestion in 85 Finnish patients with ReA and 62 HLA-B27-positive Finnish controls. ReA patients had been followed up for 20 years. Genotypes and haplotypes of IL-10 were correlated with distinct features of the disease course, such as triggering agent, chronic arthritis, development of ankylosing spondylitis, and other chronic features. RESULTS: There was a significant decrease in the promoter alleles G12 (allele frequency 0.206 versus 0.033; corrected P < 0.001, odds ratio 0.14) and G10 (0.183 versus 0.092; P < 0.05, odds ratio 0.44) in the ReA group compared with the HLA-B27-positive controls. Chronic arthritis developed significantly more frequently in the B27-positive subjects than in the B27-negative subjects (P < 0.05) as well as in patients with [corrected] the IL10.G8 allele. No associations were observed for either SNP or for the IL10.R microsatellite polymorphism. CONCLUSION: IL10.G12 and G10 microsatellite alleles show a strong protective effect against the development of ReA in Finnish subjects. Since these polymorphic markers themselves do not have direct functional implications, they most likely mark promoter haplotypes with distinct functional properties, suggesting that differential production of IL-10 is an important susceptibility factor for the development of ReA.

Adult↗
PubMed2001

Sequence analysis of the DRB1 promoter reveals limited polymorphism with no influence on gene expression.

HLA-class II promoters contain a set of conserved regulatory regions necessary for constitutive and induced gene expression. For the HLA-DQB as well as for the DRB1 promoter sequence, polymorphisms with influence on gene expression have been reported. In contrast to these data we could show that there is very limited allele-specific polymorphism among the HLA-DRB1 promoter alleles. In a long range PCR we amplified a DNA sequence containing the promoter and the second exon of the DRB1 gene in one fragment. Nested PCR products of this PCR fragment for the promoter and for the second exon were analysed by DNA sequencing to allow the linkage of a promoter to its DR allele. Most investigated DRB1 alleles exhibited the same promoter consensus sequence except for two point mutations. An A to T transversion (position -70 bp) was closely associated with DRB1*08, whereas a C-deletion (position -30 bp) was most commonly observed together with DRB1*10. Both polymorphisms did not influence promoter activity in luciferase reporter gene assays.

Base Sequence↗
PubMed2001

CD4+ and CD8+ clonal T cell expansions indicate a role of antigens in ankylosing spondylitis; a study in HLA-B27+ monozygotic twins.

Ankylosing spondylitis (AS) is a complex genetic disease in which both MHC and non-MHC genes determine disease susceptibility. To determine whether the T cell repertoires of individuals with AS show signs of increased stimulation by exogenous antigens, CD4+ and CD8+ T cell subsets of five monozygotic HLA-B27+ twins (two concordant and three discordant for AS) and CD8+ T cell repertoires of three healthy HLA-B27+ individuals were characterized by TCR beta-chain (TCRB) CDR3 size spectratyping. Selected TCRB-CDR3 spectra were further analysed by BJ-segment analysis and TCRB-CDR3 from expanded T cell clones were sequenced. In an analysis of all data (519/598 possible TCRB-CDR3 spectra), AS was associated with increased T cell oligoclonality in both CD8+ (P = 0.0001) and CD4+ (P = 0.033) T cell subsets. This was also evident when data were compared between individual twins. Nucleotide sequence analysis of expanded CD8+ or CD4+ T cell clones did not show selection for particular TCRB-CDR3 amino acid sequence motifs but displayed sequence homologies with published sequences from intra-epithelial lymphocytes or synovial T cells from rheumatoid arthritis patients. Together, these results provide support for the hypothesis that responses to T cell-stimulating exogenous or endogenous antigens are involved in the induction and/or maintenance of AS.

Adult↗
PubMed2001

Cytokine gene polymorphisms relevant for the spondyloarthropathies.

Results of sibling and twin studies suggest that a substantial proportion of susceptibility to spondyloarthropathies arises from genes outside the human leukocyte antigen (HLA) region. There is increasing evidence that the pattern of cytokine secretion influences the course of spondyloarthropathies. A Th2 cytokine pattern (low tumor necrosis factor [TNF]-TNF-alpha low interferon [IFN]-gamma, and high interleukin [IL]-10) dominates in the joints of reactive arthritis patients. For IL-10 and TNF-alpha a substantial proportion of cytokine production is under genetic control and influenced by genetic polymorphisms. Here we review the evidences for association of TNF-alpha and IL-10 polymorphisms with spondyloarthropathies and their functional implications.

Arthritis, Psoriatic↗
PubMed2001

Psoriatic arthritis: clinical aspects, genetics, and the role of T cells.

In the last 2 years there has been considerable progress in investigating the genetic and immunologic background of psoriasis and psoriatic arthritis. This review focuses on genetics and the role of T-cells in the immunopathogenesis of the disease, with particular reference to psoriatic arthritis.

Arthritis, Psoriatic↗
PubMed2001

Cobalt-specific T lymphocytes in synovial tissue after an allergic reaction to a cobalt alloy joint prosthesis.

Metals such as cobalt and nickel are common contact allergens. We studied the mechanisms underlying an allergic reaction with marked synovial inflammation in a patient with a cobalt alloy arthroplasty. After removing the joint prosthesis the adjacent synovial tissue was examined for cobalt-specific T lymphocytes. Synovial membrane mononuclear cells were expanded in interleukin 2 and cloned using a representative cloning protocol. T cell clones were tested for their proliferative response to cobalt and further characterized with regard to cytokine secretion, phenotype, and HLA restriction. Additionally, synovial fibroblasts were tested for their function as antigen presenting cells (APC). Almost 30% of the T cell clones reacted to cobalt, but not to the control nickel. All these T cell clones were CD4 positive. The cobalt induced proliferative response could be blocked by anticlass II antibodies. Also, synovial fibroblasts expressing class II molecules induced by interferon-gamma were able to serve as APC. However, when testing a panel of APC of HLA class II mismatched donors, no requirement for a certain HLA class II molecule could be defined. Further studies are necessary to determine mechanisms of presentation and recognition of cobalt by T lymphocytes, a prerequisite for improved prevention and treatment of metal induced allergic reactions.

Antigen Presentation↗
PubMed2000

Heterozygosity for the hemochromatosis gene in liver diseases--prevalence and effects on liver histology.

BACKGROUND/AIMS: The effect of heterozygosity for the C282Y mutation in the HFE hemochromatosis gene on iron accumulation and disease progression in liver disease patients is unclear. METHODS: We investigated the prevalence of this mutation in 531 patients and 205 healthy controls. In addition, we assessed the influence of the mutation on liver histology in 34 C282Y heterozygous and 124 age-, sex- and disease-matched controls without the mutation using the modified HAI and Chevallier score. RESULTS: The highest prevalence of the C282Y mutation was observed in patients with autoimmune hepatitis (17.2%, p<0.01) compared to 6.4% in healthy controls. Heterozygotes with hepatitis C and B virus infection showed higher ferritin and hepatic iron concentrations than patients without the mutation. However, we did not detect significant differences in necroinflammatory or fibrosis scores between carriers of the mutation and controls. CONCLUSIONS: There are marked differences in the prevalence of the C282Y mutation in patients with different liver diseases, with the highest prevalence rates in autoimmune hepatitis and PBC. However, the C282Y mutation alone only leads to a mild increase in iron accumulation in the majority of the patients, with the exception of H63D/C282Y compound heterozygotes. We found no evidence for more pronounced fibrosis in C282Y heterozygotes.

Adult↗