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Biomedical subjects

K H Usadel

Publications and source records attributed to K H Usadel.

At least 91 records · Page 5Linked to original sources
PubMed1997

Clinical evidence for a neuromodulator action of endothelin in the hypothalamic-pituitary-adrenal axis in man.

In order to investigate whether the ubiquitous signalling peptide endothelin might also act as a neuromodulator in the stimulation of the hypothalamic-pituitary-adrenal axis, 15 patients (4 female, 11 male, aged 35-67 years) with hypopituitarism were investigated and the results were compared to those of 8 healthy male volunteers (aged 24-31 years). Patients and controls received double-blind in random order either 0.1 IE per kg body weight regular insulin (insulin induced hypoglycemia) or 1 ml 0.9% sodium chloride (placebo) on 2 separate days. Control subjects only received on an additional day 0.1 IE per kg body weight regular insulin plus glucose 10% (euglycemic hyperinsulinemic glucose clamp). In control subjects hypoglycemia resulted in a significant increase in adrenocorticotropin (ACTH) and cortisol which was preceded by an increase in circulating endothelin levels (p < 0.01 vs placebo and euglycemic clamp) while endothelin, ACTH and cortisol remained unchanged both after placebo and in the euglycemic hyperinsulinemic clamp. In contrast, patients with hypopituitarism showed neither changes in circulating endothelin levels nor a stimulation of the hypothalamic-pituitary-adrenal axis during insulin-induced hypoglycemia. These data demonstrate that 1) endothelin levels are enhanced by metabolic stress 2) the responsiveness of endothelin levels to metabolic stress is linked to the presence of an intact pituitary gland and 3) endothelin might be involved in the stimulation of the hypothalamic-pituitary-adrenal axis.

Adrenocorticotropic Hormone↗
PubMed1997

Polymorphisms of TAP1 and TAP2 genes in German patients with type 1 diabetes mellitus.

Type 1 diabetes mellitus (IDDM) is an autoimmune disorder in which the alleles HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 confer strong susceptibility. The genes for transporters associated with antigen processing (TAP1 and TAP2) are located near HLA DQ and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to IDDM possibly by selection of different antigen peptides, we investigated sequence variants of TAP1 and TAP2 genes in 120 German patients with IDDM and 218 random healthy German controls by polymerase chain reaction (PCR) followed by sequence-specific oligonucleotide analysis (SSO), single-strand conformation polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*02011 (16% vs. 4% in controls, P = 0.001, RR = 5.0) and TAP2*0101 (96% vs. 69% in controls, P < 0.0001, RR = 10.6) showed a positive association with IDDM. However, these associations disappeared when patients and controls were matched for predisposing HLA DQA1 or DQB1 alleles as well as for DRB1*0401. In conclusion, our findings indicate that the observed association of TAP variants with IDDM in German patients is due to linkage disequilibrium with HLA DQ alleles/DRB1*04 subtypes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Polymorphisms of TAP1 and TAP2 genes in Graves' disease.

Graves' disease is an autoimmune disorder in which HLA DQA1*0501 and DQB1*0201 confer predisposition. The genes for transporters associated with antigen processing (TAP1 and TAP2) locate near to HLA DQ coding regions and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to Graves' disease by a possibly different selection of antigenic peptides, we investigated sequence variants of TAP1 and TAP2 genes in 235 patients with Graves' disease and 218 random healthy controls by polymerase chain reaction (PCR) followed by sequence specific oligonucleotide analysis (SSO), single strand conformational polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*0301 (Val-333/Asp-637: 71% vs. 55% in controls, p < 0.008, RR = 2.05) and TAP2*0101 (Val-379/Ala-565/Thr-665/stop-687: 83% vs. 69% in controls, p < 0.03, RR = 2.20) showed a positive association with Graves' disease whereas TAP1*0401 a negative (Ile-333/Gly-637: 4% vs. 13% in controls, p < 0.01, RR = 0.25). After selection of patients and controls for HLA DQA1*0501 a similar association was found for TAP1*0301 (72% vs. 50% in controls, p < 0.02, RR = 2.63) and TAP1*0401 (4% vs. 16% in controls, p < 0.04, RR = 0.22), when matching for HLA DQB1*0201 as well as for TAP1*0401 (3% vs. 16% in controls, p < 0.05, RR = 0.18). Our findings indicate that the positive association of TAP1*0301 and the negative of TAP1*0401 with Graves' disease cannot only be explained by linkage disequilibrium between TAP alleles and HLA DQ. Therefore, these TAP alleles contribute to genetic susceptibility in Graves' disease as additional permissive and protective factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Polymorphisms of tumor necrosis factor receptor 2 are not associated with insulin-dependent diabetes mellitus or Graves' disease.

Insulin-dependent diabetes mellitus (IDDM) and Graves' disease (GD) are autoimmune endocrinopathies and associated with distinct HLA-DR and -DQ alleles as well as several tumor necrosis factor alpha (TNF-alpha) and beta (TNF-beta) alleles. TNF-alpha and TNF-beta interact with TNF receptor (TNF-R), of which two subtypes have been described: TNF-R1 and TNF-R2. We investigated TNF-R2 alleles in 90 patients with IDDM, 101 with GD and 70 healthy controls. Genomic DNA was amplified with specific flanking primers for the untranslated 3' region of TNF-R2. SSCP analysis revealed two alleles by different fragment patterns: TNF-R2*1 and TNF-R2*2. Patients with IDDM or Graves' disease and controls did not differ significantly: TNF-R2*1/*1:IDDM(8%)/GD(2%)/KO(4%); TNF-R2*2/*2:IDDM(34%)/GD(48%)/KO(42%), heterozygosity TNF-R2*1/*2:IDDM(58%)/GD(50%)/KO(54%) (IDDM vs KO: P=0.46, chi2=1.57; GD vs KO: P=0.59, chi2=1.05). In conclusion, the studied polymorphism of TNF-R2 was associated with neither IDDM nor GD in a German population.

Alleles↗
PubMed1997

Highly polymorphic promoter regions of HLA DQA1 and DQB1 genes do not help to further define disease susceptibility in insulin-dependent diabetes mellitus.

HLA DQA1, HLA DQB1 genes confer susceptibility to insulin-dependent (type 1) diabetes mellitus (IDDM). Since variants of their upstream regulatory regions are linked to the exons, we investigated their promoter polymorphisms (QAP and QBP) by a combination of PCR-based typing protocols in 136 IDDM patients, 167 controls and 6 families with an IDDM proband to identify possible additional susceptibility markers. Of major interest for IDDM susceptibility are the promoter "splits" of HLA DQA1*0301 (QAP3.1 and QAP3.2) and HLA DQB1*0302 (QBP3.2 and QBP3.3). QAP 3.1 (96% in patients vs 98% in controls) and QBP3.2 (100% vs 99%) were found to be the most frequent promoter variants for HLA DQA1*0301 and DQB1*0302, respectively, whereas QAP3.2 and QBP3.3 were very rare. Furthermore the promoter "splits" were equally distributed on the respective exon alleles in all groups and cosegregated in families as expected. In conclusion, HLA DQ-mediated susceptibility and protection in IDDM is not restricted to the exon but extends to the promoter region without further defining the genetic risk.

Diabetes Mellitus, Type 1↗
PubMed1997

Reduction of non-steroidal anti-inflammatory drug induced gastric injury and leucocyte endothelial adhesion by octreotide.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) induce gastric ulcers. AIMS: To assess whether the somatostatin analogue octreotide prevents NSAID induced mucosal gastrointestinal damage in both animals and humans. The effect of octreotide on neutrophil adhesion to the endothelium was also evaluated. METHODS: Male Sprague-Dawley rats were pretreated either with saline (0.3 ml subcutaneously) or octreotide (0.001-1 ng/kg subcutaneously). After 30 minutes gastric ulcers were induced by the intragastric application of NSAIDs (20 mg/kg indomethacin, 200 mg/kg aspirin, 200 mg/kg ibuprofen, or 50 mg/kg diclofenac). Four hours later the rats were killed and gastric mucosal lesions were assessed by computed planimetry. To determine whether octreotide could prevent indomethacin induced injury in humans, 20 healthy volunteers were evaluated in a double blind, placebo controlled study. RESULTS: Octreotide prevented NSAID induced gastric mucosal lesions (p < 0.05). The dose response curve was U shaped and the most effective dose was 0.1 ng/kg. Leucocyte adherence in submucosal venules of the stomach was evaluated by in vivo microscopy. Octreotide (0.1 ng/kg subcutaneously) prevented indomethacin (20 mg/kg intragastric) induced leucocyte adherence in gastric submucosal venules (p < 0.05). Healthy human volunteers received 50 mg indomethacin orally thrice a day concomitantly with either an identical placebo or 0.01 microgram, 0.1 microgram, or 1 microgram octreotide subcutaneously thrice a day for three days. Injury was assessed by endoscopy. There was a negative correlation between the octreotide dose and injury score (p < 0.03 for gastric injury, p < 0.001 for duodenal injury). CONCLUSIONS: Octreotide protects the stomach from NSAID induced gastric injury, probably via its ability to reduce NSAID induced neutrophilic adhesion to the microvasculature. Octreotide also ameliorated indomethacin induced gastric and duodenal injury in humans.

Animals↗
PubMed1997

Superoxide dismutase reduces islet microvascular injury induced by streptozotocin in the rat.

Intravenous administration of streptozotocin (STZ) leads to permanent diabetes mellitus in rats. We investigated the possible role of islet microcirculatory changes and free radical formation in this animal model. In vivo fluorescence microscopy was performed for 4 h after administration of STZ. Vascular permeability, capillary blood flow, and endothelial leukocyte adhesion were measured in endocrine and exocrine pancreatic tissue. The earliest microcirculatory event was an increase in vascular permeability in pancreatic islets, with a peak 1 h after STZ administration. The difference between islet and exocrine tissue light intensity was +15.8 +/- 5.6% at t = 60 min. Islet blood flow velocity significantly decreased after 3 h, whereas blood flow in the exocrine pancreas was not affected. Complete stasis of islet blood flow was observed only in rats receiving STZ. Neither increased leukocyte adhesion to islet vascular endothelium nor ischemia-reperfusion phenomena were observed. Prophylactic administration of the radical scavenger superoxide dismutase prevented STZ-induced damage to the islet microcirculation in the initial phase of this model. We conclude that STZ leads to severe microcirculatory disturbances within pancreatic islets in rats. Apparently, these changes are mediated at least in part by free oxygen radicals.

Animals↗
PubMed1997

CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus.

The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.

Abatacept↗
PubMed1997

Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.

Endocrine autoimmune disorders share susceptibility and resistance factors of the human leukocyte antigen system on the short arm of chromosome 6, but other gene loci also contribute to predisposition and protection. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility to Graves' disease, as well as to type 1 (insulin-dependent) diabetes mellitus, we investigated this dimorphism in the other endocrine autoimmune disorders: Hashimoto's thyroiditis and Addison's disease. We analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto's thyroiditis, 76 with Addison's disease, and 466 healthy controls. This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restriction fragment length polymorphism analysis using BbvI. Patients with Hashimoto's thyroiditis had significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in patients (75%), compared with controls (61%), P < 0.03. Patients with Addison's disease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more CTLA4 Ala17 positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to Hashimoto's thyroiditis, whereas this applies only to the subgroup of DQA1*0501+ patients with Addison's disease.

Abatacept↗
PubMed1997

[Pre- and intraoperative localization of neuroendocrine tumors].

Previous studies of the intraoperative use of a hand-held gamma probe to localize metastases and primary tumors of colorectal cancer have shown improved assessment of tumor spread and changes in surgical management based on added information gained by radioimmunoguided surgery. Following the injection of 180 MBq [111In-DTPA-D-Phe1]-pentetreotide and/or 500 MBq 99mTc-dimercaptosuccinic acid (both for dual-radionuclide scintigraphy) preoperative somatostatin receptor imaging [11 patients with GEP tumors] and dual-radionuclide scintigraphy. (8 patients with relapsing medullary thyroid carcinomas) was performed. One patient with a metastasizing pheochromocytoma underwent 123]-MIBg scintigraphy. Results were combined with the information obtained from conventional imaging modalities. Intraoperative radiodetection was performed 24 hours after administration of [111In-DTPA-D-Phe1]-pentetreotide or 4 hours following the injection of 99mTc(V)DMSA using a hand-held gamma probe (Tec Probe 2000. Stratec, FRG). Intraoperative gamma counting localized 39 somatostatin receptor positive lesions of GEP tumors whereas preoperative receptor imaging visualized 81%, surgical palpation 41% and radiological imaging modalities localized only 31%. In 8 patients with recurrent medullary thyroid carcinoma the surgeon was successful in localizing and removing 18 tumor lesions by the help of the gamma probe. Dual-radionuclide scintigraphy revealed 77% (Octreoscan 5/18; 99mTc-V-DMSA 9/18), surgical palpation 55% and conventional imaging methods (CT, sonography) only 38% of all lesions detected intraoperatively by the hand-held gamma probe. In summary, this preliminary data show that intraoperative hand-held gamma probe detection of microscopic and occult endocrine tumors is feasible and more sensitive than external scintigraphy and conventional imaging.

Adrenal Gland Neoplasms↗
PubMed1996

Endogenous retroviral long terminal repeats of the HLA-DQ region are associated with susceptibility to insulin-dependent diabetes mellitus.

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HER V-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 *0301 and DQB1 *0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 x 10(-5)), even after matching for the high-risk alleles DQA1 *0501, DQB1 *0201-DQA1 *0301, and DQB1 *0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 *04 alleles in all DQB1 *0302+ individuals showed 56% DRB1 *0401, DQB1 *0302 [LTR' patients vs. 29% controls with the same haplotype (p < 0.002)]. In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 *0401-, DQA1 *0301-, and DQB1 *0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM.

Diabetes Mellitus, Type 1↗
PubMed1996

Effect of Graves' intrathyroidal lymphocytes. Effect of Graves' disease intrathyroidal lymphocytes (ITL) on xenotransplants of human thyroid tissue in athymic nude mice.

It has been suggested that ITL are of importance in the pathogenesis of human autoimmune thyroid disease. Aim of our study was to investigate function and morphology of xenotransplanted human thyroid tissue in nude mice following systemic application of lymphocyte preparations from patients with Graves' disease (GD) and non-toxic nodular goiter (NTG). ITL obtained from 13 patients with GD and peripheral blood lymphocytes (PBL) from 12 patients with NTG were injected into nude mice bearing 8 weeks old xenografts of normal human thyroid tissue. ITL- and PBL-subsets were analyzed by flow cytometer (FACScan) before engraftment. Two days after injection the thyroid transplants were examined histologically (HE) as well as immunohistologically by staining with: CD3, CD31, CD45R, HLA class II, ICAM-1, VCAM-1, IgG, IgM and Ki67. Flow cytometry showed a significant higher number of the lymphocyte-subsets CD3, DR+ and CD4 in GD-ITL as compared to the subsets in NTG-ITL. After injection of GD-ITL to the nude mice also a significant higher number of CD3+ human lymphocytes was found in the transplants. GD-lymphocytes stimulated thyroid tissue function significantly more pronounced than NTG-lymphocytes (histomorphological evaluation). In addition, a significant increase of HLA-class II, ICAM-1-, VCAM-1-, CD45-expression and number of Ig presenting plasma cells were observed only after injection of GD-ITL. Our data demonstrate, for the first time in vivo (nude mouse model), that GD-lymphocytes of both peripheral and intrathyroidal origin selectively migrate into human thyroid transplants ("homing"). They survive there for at least two days and induce significant functional as well as histological changes, like expression of gene products and IgG synthesis. These results suggest an important role of ITL in the pathogenetic mechanisms and clinical course of GD.

Animals↗
PubMed1996

Genetic markers in diagnosis and prediction of relapse in Graves' disease.

Hyperthyroidism of Graves' disease takes an unpredictable clinical course in the long-term follow-up. Whereas roughly 30-60% of patients relapse after their first antithyroid drug treatment, the likelihood of remission in the remaining group can not be foreseen. We have analysed-retrospectively-patients with Graves' disease that had been on antithyroid drug treatment for one year and were followed up thereafter. Patients were investigated for a variety of clinical parameters like ophthalmopathy status and relapse or remission as well as gene polymorphisms of the HLA and other regions. Of the 259 patients analysed so far, patients with ophthalmopathy did not differ from those without for HLA DQA1 and CTLA4 alleles tested. Also, the subgroup of patients with relapses after antithyroid drug treatment showed no different distribution of those alleles from the group with long-term remission. This study also confirms that the allele HLA DQA1* 0501 confers susceptibility to Graves' disease, furthermore, that the CTLA4-alanine 17 allele is an additional predisposing factor.

Abatacept↗
PubMed1996

[Electronic data processing in a surgical and medical intensive care unit].

A prospective documentation of patients data on an internal and a surgical intensive care unit (ICU) has been transacted. The physician and nursing staff used an online electronic documentation program, which has been developed in Frankfurt. Main emphasis has been placed on the epidemiological data, clinical diagnoses as well as diagnostically and therapy costs. The medical ICU of university hospital of Frankfurt has been analysed since 1992 and the surgical ICU of Städtisches Krankenhaus of Lüneburg since 1994. Up to now data from 2001 patients from Frankfurt are available. Period spent on the ICU was 4.7 +/- 0.16 days (average +/- SEM), mortality was 15%. 47% of the whole group suffered from cardiac disease, of which 211 had an acute myocardial infarction (10.6%), 156 patients a serious ventricular arrhythmia (7.8%) as well as 88 patients an unstable angina (4.4%). Long-term observation revealed a rise of the duration spent on the ICU (from 4.1 +/- 0.17 to 5.5 +/- 0.38 days, P < 0.0002), an increasing number of technical examinations (for example: chest x-ray from 2.25 +/- 0.13 to 4.52 +/- 0.4/patient, P < 0.0001) and a steady mortality between 1992 and 1994. Detailed analysis of patients with acute myocardial infarction showed an impressive reduction of total mortality within the 3 years observed. In Lüneburg data of 1004 patients have been recorded so far. The average time spent on the ICU was 6.4 +/- 0.33 days. 4.1% patients passed away. Neoplasia of gastric intestinal tract (143; 14.2%), femoral neck fracture (64; 6.4%) and ilei (54; 5.4%) have been the most frequent diagnoses. Patients underwent 2.2 +/- 0.12 chest x-rays and 1.4 +/- 0.1 ultrasound investigations. The study shows that an online data processing is practicable and can be integrated in the daily work flow. Furthermore, it can be seen that the collected data play an important role to secure the increasing administrative requisition to the modern medicine in view of costs and quality management.

Adult↗