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T Herrmann

Publications and source records attributed to T Herrmann.

At least 37 records · Page 2Linked to original sources
PubMed2000

Analysis of single-nucleotide polymorphisms in the interleukin-4 receptor gene for association with inflammatory bowel disease.

Genetic linkage analysis in families with multiple cases of inflammatory bowel disease (IBD) has mapped a gene which confers susceptibility to IBD to the pericentromeric region of chromosome 16 (IBD1). The linked region includes the interleukin(IL)-4 receptor gene (IL4R). Since IL-4 regulation and expression are abnormal in IBD, the IL4R gene is thus both a positional and functional candidate for IBD1. We screened the gene for single-nucleotide polymorphisms (SNPs) by fluorescent chemical cleavage analysis, and tested a subset of known and novel SNPs for allelic association with IBD in 355 families, which included 435 cases of Crohn's disease and 329 cases of ulcerative colitis. No association was observed between a haplotype of four SNPs (val50ile, gln576arg, A3044G, G3289A) and either the Crohn's disease or ulcerative colitis phenotypes using the transmission disequilibrium test. There was also no evidence for association when the four markers were analyzed individually. The results indicate that these variants are not significant genetic determinants of IBD, and that the IL4R gene is unlikely to be IBD1. Linkage disequilibrium analyses showed that the val50ile and gln576arg variants are in complete equilibrium with each other, although they are separated by only about 21 kilobases of genomic DNA. This suggests that a very dense SNP map may be required to exclude or detect disease associations with some candidate genes.

Alleles↗
PubMed2000

A polymorphism of the rat T-cell receptor beta-chain variable gene 13 (BV13S1) correlates with the frequency of BV13S1-positive CD4 cells.

Three rat BV13S1 alleles (T-cell receptor beta-chain variable gene 13) were characterized by new BV13S1-allele specific monoclonal antibodies (18B1 and 17D5) and sequence analysis of expressed and genomic BV13S1. Two alleles were functional and designated BV13S1A1 present in strains LEW, BUF, PVG, and BV13S1A2 present in BN and WF. Their products differed by six amino acids, two of them in complementarity-determing region (CDR)1 and one in CDR2. A third nonfunctional allele, BV13S1A3P, was found in strains F344 and DA. Apart from a single nucleotide insertion, it was identical to BV13S1A2. All 12 rat strains tested showed association of TCRBC1 with BV8S2/4 alleles but not with the BV13S1 alleles, which may reflect a different gene order of the rat BV compared to mouse. BV13S1A1-encoded T-cell receptors (TCRs) which bind both monoclonal antibody (mAb) 18B1 and mAb 17D5 are over-represented in the CD4 lymphocyte subset. BV13S1A2-encoded TCRs which are stained by mAb 18B1 but not by mAb 17D5 show a slight CD8-biased expression. Preferential usage of BV13S1A1-positive TCRs by CD4 but not by CD8 cells in (LEW x WF)F1 hybrids and cosegregation of BV13SA1 and increased frequency of BV13S1 TCR-positive CD4 cells in a (LEW x BN)x BN backcross suggest structural differences of the two allelic products as the reason for their contrasting CD4/CD8 subset bias.

Alleles↗
PubMed2000

Lack of effect of small high-dose volumes on the dose-response relationship for the development of fibrosis in distant parts of the ipsilateral lung in mini-pigs.

PURPOSE: Multi-field radiation therapy for intrathoracic tumours results in a heterogeneous dose distribution in lung tissue. This study investigated whether irradiation of small lung volumes with high fibrogenic doses affects the dose-response relationship for development of fibrosis in distant parts of the ipsilateral lung of mini-pigs. MATERIALS AND METHODS: The whole right lung of 26 'Mini-Lewe' pigs was irradiated with homogeneous doses of between 25 Gy and 40 Gy given in five equal fractions using opposing anterior-posterior portals and a linear accelerator. Another 32 animals were irradiated with a constant dose of 35 Gy to a small house-shaped high-dose field (base 3.0 cm, height 4 cm) located 3 cm caudolateral to the right hilus, while the surrounding right lung received either no irradiation or homogeneous doses of between 20 Gy and 30 Gy. The radiation fields were simulated and port films were obtained for each of the 10 fields in all pigs. Fibrosis was quantified 9 months after irradiation by determination of the hydroxyproline (HP) content of the 32 high-dose volumes and in the lung apex and the basolateral lung of all 58 pigs. Based on the reference value for the HP-ratio, i.e. the HP-concentration of the right lung over the left lung, obtained in 12 unirradiated control animals, the experimental results were converted into quantal data for probit analysis, a responder being an animal with an HP-ratio > 1.33. RESULTS: A dose-response relationship for the HP-ratio was obtained in the different lung sites and irradiation groups. For a given dose level the mean HP-ratios and response rates did not differ systematically between the lung apex and the basolateral lung. Probit analysis of the pooled data produced ED50 values of 21.8 Gy (95% CI 12-37) for irradiation without a high-dose volume and 25.9 Gy (24-28) for irradiation with a high-dose volume. These values are not significantly different. The results from both irradiation groups could be well fitted by a common dose-response curve with an ED50 value of 26.1 Gy. Unexpectedly, the response rates in the high-dose volume increased with increasing dose to the surrounding right lung. Analysis of the port films provided an explanation for this finding: inaccuracies in daily field positioning. When this error was corrected for by use of the mean dose to the high-dose volume, a dose-response curve with an ED50 of 25.2 Gy (22-29) was determined for the high-dose volume. CONCLUSIONS: The results of the study indicate that the irradiation of a small lung volume with high fibrogenic doses does not affect the dose-response relationship for development of fibrosis in distant parts of the ipsilateral lung.

Animals↗
PubMed2000

[Effects of knowledge acquisition on verbal linearization about spatial orientation].

This paper deals with determinants of linearization in spatial communication. The well-known linearization principles, such as the principle of natural order, primarily emphasize features of the given information. We assume that verbal linearization is in addition influenced by the speakers' knowledge acquisition. Six experiments with a total of 272 participants are reported here. A particular spatial constellation was presented to the participants, who were asked to talk about it afterwards. The linearizations then produced were defined as dependent variables. The results show that the linearizations were influenced by the speaker's experience with the configuration (according-to-experience effect) and also demonstrate the importance of the first encounter (anchor effect). Further characteristics of the effects mentioned above are described and discussed regarding memory research and psycho-linguistics.

Adult↗
PubMed1999

HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells.

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular "labile iron pool." The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

Down-Regulation↗
PubMed1999

Usage of Vbeta3.3 T-cell receptor by myelin basic protein-specific encephalitogenic T-cell lines in the Lewis rat.

T-cell receptor (TCR) beta-chain usage in experimental autoimmune encephalomyelitis (EAE) seems to be much more heterogeneous than previously assumed even for a single autoantigen in an inbred animal strain. Owing to the lack of suitable antibodies, this has been demonstrated only at the RNA level so far. To characterize further the TCR elements used in the Lewis rat for the recognition of the main encephalitogenic region of myelin basic protein (MBP), BALB/c mice were immunized with T-cell hybridomas expressing non-Vbeta8.2 TCR specific for guinea pig MBP peptide aa 68-88. Two B-cell hybridomas (clones C-A11 and F-D6) producing TCR Vbeta3.3-specific monoclonal antibodies were selected. Specificity was demonstrated by RT-PCR and cloning of PCR products obtained from sorted T-cell lines and naive T cells. MBP-specific Vbeta3.3 T cells used the L-S motif in the VDJ region, were associated with Valpha2 or Valpha8 chains, and specifically recognized MBP peptide aa 68-88. Vbeta3.3 TCR-positive T cells were detected in all of a panel of six MBP-specific T-cell lines, although to a lesser degree than Vbeta8.2 TCR-positive T cells. After intravenous injection of sorted Vbeta3.3 T cells, animals developed EAE, and Vbeta3.3-positive cells were found by immunocytochemical analyses in the spinal cord. Furthermore, treatment of EAE induced by immunization with MBP was more effective when a combination of anti-Vbeta3.3 and anti-Vbeta8.2 mAbs was used. These results confirm the functional role of TCR Vbeta3.3 and thus underscore the heterogeneity of TCR usage in MBP-associated autoimmunity.

Animals↗
PubMed1999

NMR structure and metal interactions of the CopZ copper chaperone.

A recently discovered family of proteins that function as copper chaperones route copper to proteins that either require it for their function or are involved in its transport. In Enterococcus hirae the copper chaperone function is performed by the 8-kDa protein CopZ. This paper describes the NMR structure of apo-CopZ, obtained using uniformly (15)N-labeled CopZ overexpressed in Escherichia coli and NMR studies of the impact of Cu(I) binding on the CopZ structure. The protein has a betaalphabetabetaalphabeta fold, where the four beta-strands form an antiparallel twisted beta-sheet, and the two helices are located on the same side of the beta-sheet. A sequence motif GMXCXXC in the loop between the first beta-strand and the first alpha-helix contains the primary ligands, which bind copper(I). Binding of copper(I) caused major structural changes in this molecular region, as manifested by the fact that most NMR signals of the loop and the N-terminal part of the first helix were broadened beyond detection. This effect was strictly localized, because the remainder of the apo-CopZ structure was maintained after addition of Cu(I). NMR relaxation data showed a decreased correlation time of overall molecular tumbling for Cu(I)-CopZ when compared with apo-CopZ, indicating aggregation of Cu(I)-CopZ. The structure of CopZ is the first three-dimensional structure of a cupro-protein for which the metal ion is an exchangeable substrate rather than an integral part of the structure. Implications of the present structural work for the in vivo function of CopZ are discussed, whereby it is of special interest that the distribution of charged residues on the CopZ surface is highly uneven and suggests preferred recognition sites for other proteins that might be involved in copper transfer.

Amino Acid Sequence↗
PubMed1999

[Results of irradiation of inoperable stage III non-small cell lung cancer with 25Gy in five fractions].

BACKGROUND: Patients with advanced Stage III inoperable non-small cell lung cancer who were not suitable for irradiation with curative doses, were treated at the Department of Radiotherapy of the University Hospital of Dresden with 25 Gy in 5 fractions over 1 to 2 weeks. Survival of these patients was compared in this retrospective study to the survival of patients treated during the same period with 60 Gy in 30 fractions. PATIENTS AND METHOD: Between 1985 and 1994 298 patients were treated for a histologically or cytologically proven non-small cell lung carcinoma with 60 Gy in 30 fractions (n = 80), with 40 Gy in 20 fractions (n = 26) or with 25 Gy in 5 fractions (n = 192). Overall survival was determined using actuarial methods. Prognostic parameters were analyzed using uni- and multivariate tests. RESULTS: Median overall survival for all patients was 6 months (95% confidence interval 5; 7). In univariate analysis, survival of the patients treated with 60 Gy was significantly better than survival in the other groups. Median survival was 11 months (9; 13) after 60 Gy, 6 months (4; 8) after 40 Gy and 5 months (4; 6) after 25 Gy. In multivariate analysis the treatment schedule lost its significant influence on outcome of the therapy. The most important prognostic parameter was the performance status of the patients. CONCLUSIONS: When stratified for performance status as the most important prognostic parameter the survival time after hypofractionated irradiation to 25 Gy given in 5 fractions in 1 to 2 weeks was not significantly different from the results after conventional fractionation to 60 Gy. Hypofractionated radiation schedules are often more convenient for the patient, economical, and have been shown to be effective in symptom control. Thus, in clear palliative situations hypofractionated treatment with 25 Gy in 5 fractions or a comparable schedule appears to be a reasonable therapeutic option.

Actuarial Analysis↗
PubMed1999

[Delayed toxicity of brief preoperative irradiation and risk-adjusted postoperative radiotherapy of operative rectal carcinoma. Results of a randomized prospective study].

AIM: Analysis of a randomized study of preoperative radiation therapy for operable carcinoma of the rectum with regard to late sequelae. Results of tumor control and survival, which have already been published in detail are summarized for comparison and for confirmation of the conclusions. PATIENTS AND METHODS: Between January 1988 and October 1993 94 patients with operable carcinoma of the rectum were included in a randomized trial. Fourty-seven patients were treated with 5 x 3.3 Gy (field size 16 x 16 cm, 9 MeV photons) 24 to 48 hours prior to surgery; 46 patients did not receive preoperative irradiation. If risk factors (T4-stage, R1/R2 resection, intraoperative tumor perforation) were present, postoperative irradiation was performed after CT-planning. Total postoperative doses of 41.4 Gy (preoperative irradiation) or 59.8 Gy (surgery only) were applied with doses per fraction of 1.8 to 2.0 Gy. Local control, survival, and pattern of side effects were analyzed at 5 years after conclusion of the trial. RESULTS: The frequency of local recurrence was markedly reduced by preoperative irradiation of R0-resected patients (24% vs 13%, p = 0.08). The time to recurrence was delayed (1.9 vs 3 years). The 5-year actuarial survival rate was significantly higher in the preoperatively irradiated group compared to the not pre-irradiated group (40% vs 28%, p = 0.027). Multivariate analysis revealed UICC-grading as the only independent parameter for local control (p = 0.0003), while preoperative irradiation (p = 0.07) and T-stage (p = 0.08) only displayed a trend. For patient survival, age (p = 0.0003). R-status (p = 0.01) and UICC-score (p = 0.001) were significant prognostic factors. Preoperative irradiation had a non-significant effect only (p = 0.078). Radiation-induced side effects with a LENT-SOMA score > 2 were observed neither during frequent follow-up nor at an additional examination of those patients still alive in 1998 (n = 25). Of 4 pre- and postoperatively irradiated patients with risk factors, 3 had side effects grade 1 or 2, predominantly rectal changes, at 5 to 11 years after treatment. CONCLUSIONS: A positive effect on tumor control and survival is achieved with preoperative irradiation with the doses used in this study, with moderate side effects.

Actuarial Analysis↗
PubMed1999

Response of pig lung to irradiation with accelerated 12C-ions.

The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.

Animals↗
PubMed1999

Different manifestations of Toxoplasma gondii infection in F344 and LEW rats.

There is evidence that not only the immune status, but also the genetic predisposition of certain hosts influence the clinical outcome of Toxoplasma gondii infection. By far the majority of our knowledge on genetic and immunological mechanisms involved in control of T. gondii infection has been obtained by studying mouse models, which in terms of clinical outcome of infection differ considerably from humans. Rats which show a rather similar course of infection in comparison to humans have not so far been investigated for effects of genetic differences on course of the infection. In this study we show that, like mice, different strains of rats exhibit a remarkable variation in the number of brain cysts arising from chronic infection. LEW rats seem to be highly resistant to cyst formation, in contrast to F344 rats that are susceptible. In addition, F344 rats express high numbers of gammadelta T cells during the acute phase of infection, whereas LEW rats express elevated but comparably low numbers of gammadelta T cells. The RT1 (rat MHC) haplotypes of both strains are identical in the RT1A and RT1B/D regions, which encode the restriction elements for conventional peptide antigens. Consequently, rat strain-specific differences may be useful to define MHC-independent mechanisms of resistance against T. gondii, which may also act in humans.

Animals↗
PubMed1999

Late complications after a combined pre and postoperative (sandwich) radiotherapy for rectal cancer.

BACKGROUND AND PURPOSE: The purpose of this study was to analyse the treatment related side effects, the outcome and the prognostic significance of clinical parameters in two groups of patients with rectal cancer receiving either preoperative or pre and postoperative radiotherapy after radical resection. The authors of this study were not involved in the radiation treatments. PATIENTS AND METHODS: From 1986 to 1990, 63 patients received a combined pre and postoperative (sandwich) radiotherapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days. Postoperative irradiation consisted mostly of 15 x 2 Gy (31 patients) but the range was 20-40 Gy. The results were compared with those on 73 patients who only received preoperative radiotherapy in the same time period. The distribution of prognostic factors was not very different between treatment groups. Out of 63 patients in the sandwich group, 22 received concurrent chemotherapy and 18 also received radiotherapy to the liver. Radical surgery usually followed on the day after the last preoperative radiotherapy session. Median follow-up of survivors was 6 years. RESULTS: Local tumour control was 88% after 5 years and 84% after 8 years in the sandwich group, and 90 and 85%, respectively, in the preoperative radiotherapy group. Thus, tumour control was similar for the two radiotherapy regimens applied. However, the percentage of patients suffering from one or more complications after 5 years was 84% in the sandwich and 17% in the preoperative radiotherapy group. The incidence of severe late complications (grade > or = 3) was recorded as a function of time after start of treatment. In the sandwich group the actuarial rates of late complications at 5 years (and the median time to diagnosis) were 53% (27 months) for anorectum, 43% (37 months) for bladder, 28% (51 months) for bone, 19% (36 months) for dermis, 47% (48 months) for ileum, 41% (32 months) for lymphatic and soft tissue, and 44% (53 months) for ureters. CONCLUSIONS: Severe late reactions did not occur within a certain period of time, but continued to appear for at least 10 years after radiotherapy. Sandwich therapy, as given in this series, did not appear to give a greater tumour control than preoperative radiotherapy alone, whereas the rate of complications was drastically enhanced. Thus, the rationale of a sandwich therapy with a long time interval between surgery and postoperative irradiation appears questionable.

Actuarial Analysis↗
PubMed1999

Heterogeneity of T-cell receptor usage in experimental autoimmune neuritis in the Lewis rat.

In experimental autoimmune neuritis (EAN), T-cell receptor (TCR) variable (V)-region gene usage by neuritogenic T cells has been reported to be clonally restricted at the RNA level. This study was designed to verify TCR usage by neuritogenic T cells at the protein level. We generated two monoclonal antibodies (mAbs) 7H4 and 8G8 specific for a Vbeta4/Valpha11 associated idiotype expressed by the majority of neuritogenic cells of P2-specific T-cell lines. The remaining neuritogenic P2-specific T cells either exhibited a dominant usage of the TCR Vbeta13 chain recognized by the recently generated mAbs 17D5 and 18B1 or showed diverse Vbeta usage. Treatment of adoptive-transfer (AT)-EAN or of EAN actively induced with the neuritogenic P2 peptide by mAbs 7H4 and 8G8 led to a partial, but significant, reduction of clinical disease. Treatment with Vbeta13-specific mAb 17D5 had no clear effect on active EAN. Our data show that at least three different TCR are used by P2-specific pathogenic T cells in EAN, an animal model for human inflammatory neuropathies.

Adoptive Transfer↗