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K H Usadel

Publications and source records attributed to K H Usadel.

At least 19 recordsLinked to original sources
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

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↗
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↗
PubMed1995

[Systemic infection due to group A Streptococcus pyogenes].

A 47-year-old woman developed oedematous swelling of the skin over the left hip and leg, with joint pains and reddening over joints of the hands and left ankle. 2 months before her son had had scarlet fever, following which the patient had two episodes of fever. Shortly before hospitalization she was treated with a glucocorticoid because a rheumatic disease had been suspected. On admission the blood sedimentation rate was 58/90, the white cell count was 15.100/microliters with left shift in the differential count. The swellings in arms and legs became abscesses which were incised. An abscess over the left buttock, diagnosed by 67-gallium whole-body scintigraphy, was also treated surgically. On the day of admission penicillin (10 mill. IU three times daily intravenously) and, from the 4th day onwards, gentamicin (80 mg three times daily intravenously) were administered. Histological examination of fascia and muscle biopsies revealed nonspecific inflammation without signs of malignancy, white blood culture grew group A Streptococcus pyogenes. 20 days after the surgical intervention the patient was discharged in full health. Necrotizing fasciitis caused by Streptococcus pyogenes has become more frequent in the last few years and has often been accompanied by severe systemic complications.

Fasciitis↗
PubMed1995

Verapamil and flunarizine protect the isolated perfused rat liver against warm ischemia and reperfusion injury.

Using the model of the isolated perfused rat liver, we investigated the influence of the two pharmacologically different calcium channel blockers, verapamil and flunarizine, on changes of ion homeostasis, liver weights, pH deviations and enzyme activities during warm ischemia (37 degrees C) and reperfusion. The LDH and GLDH activities were determined and the calcium, potassium, and sodium concentrations were measured in the effluent. Warm ischemia (180 min) caused an increased enzyme release, a high influx of calcium and sodium into the liver and a massive potassium efflux current. Normoxic reperfusion led to a further increase in hepatic enzyme release and although the loss of potassium ceased, the calcium influx into the liver continued. By the end of reperfusion the liver weight had increased significantly (P < 0.01) in the control group. The two calcium entry blockers were added to the perfusate in various concentrations. Both substances protected the liver against warm ischemia and normoxic reperfusion damage, but they did not inhibit calcium inflow. However, the potassium efflux was significantly reduced by all concentration tasted (P < 0.001). After reperfusion the liver weights were significantly lower in the treated groups (P < 0.001) than in control animals. Thus, the calcium entry blockers verapamil and flunarizine protect liver cells against damage caused by warm ischemia and reperfusion. Furthermore, they prevent the disruption of intracellular potassium homeostasis, which seems to be related to improved volume regulation of liver cells.

Animals↗
PubMed1995

Stimulation of proliferation and inhibition of function of xenotransplanted human thyroid tissue by epidermal growth factor.

A stimulation of thyroid epithelial cell proliferation by epidermal growth factor (EGF) has been repeatedly reported in different in vitro systems. Furthermore, a suppression of thyroid epithelial cell function by EGF has been described in vitro. In order to investigate the effects of EGF on the thyroid in vivo, human Graves' disease tissue was transplanted to 59 nu/nu mice. EGF was given once, and over a period of 7 days 7 times intermittently or continuously by osmotic mini pumps to mice. 3-H-thymidine histoautoradiography of transplants showed an increased 3-H-thymidine incorporation of thyroid epithelial cells and mesenchymal cells, following each form of EGF application. Thyroid epithelial cell nuclear volume, which has previously been shown to be a parameter for thyroid epithelial cell function showed a decrease following EGF application. There was a tendency to a more intensive proliferation and differentiation following intermittent EGF application compared to continuous stimulation. These results demonstrate that EGF does stimulate proliferation of thyroid epithelial as well as mesenchymal cells in vivo. The growth stimulating effect of EGF is linked with a concomitant decrease of thyroid function in vivo. The latter is most likely due to the dedifferentiating action of EGF previously shown in in vitro systems.

Animals↗
PubMed1995

Modification of the responses of endothelin-1 to exhaustive physical exercise under simulated high-altitude conditions with acute hypoxia.

To assess whether acute alveolar hypoxia leads to the release of endothelin-1 (ET) in vivo, ET, cortisol (CORT), and lactate (LA) levels were determined in 15 healthy subjects at rest and during exhaustive incremental cycle ergometry on two separate test days. The subjects were to breathe a gas mixture with reduced O2 content ([H] fraction of inspired O2, 0.14) on one day and normal air on the other (N). Modified responses of LA and CORT to exhaustive incremental cycle ergometry on the H day indicated elevated anaerobic tissue metabolism and increased physical stress. With acute alveolar hypoxia, the response of ET to exhaustive physical labor was found to be augmented.

Acute Disease↗
PubMed1995

Alterations of Na+,K(+)-ATPase activity after hypoxia and reoxygenation in the perfused rat liver: an electron microscopic cytochemical study.

BACKGROUND/AIMS: Using the cerium technique for ultrastructural cytochemical studies, Na+,K(+)-ATPase activity was investigated in hypoxic and reoxygenated rat liver. METHODS: In the control group, the livers were perfused with oxygenated hemoglobin-free Krebs-Henseleit buffer for 1 h. For hypoxia (60 min), the flow rate of the perfusate was decreased and oxygen was replaced by nitrogen. For reoxygenation, the liver was reperfused under oxygenated conditions for 5 min after 60 min of hypoxia. RESULTS: In control livers, a strong Na+,K(+)-ATPase activity was detected at the basolateral membrane of hepatocytes while the apical membrane forming the bile canaliculi did not display any staining. In hypoxic livers, Na+,K(+)-ATPase activity had ceased in the plasma membrane of hepatocytes. In reoxygenated livers, Na+,K(+)-ATPase was rapidly reactivated in the basolateral hepatic membrane. The membrane of blebs generated during the hypoxic phase also showed enzyme activity. In addition, a striking accumulation of reaction product could be observed in about 10% of the apical membranes lining the bile canaliculi. CONCLUSION: The results indicate a plasticity of the Na+,K(+)-ATPase in hypoxic and reoxygenated rat liver.

Animals↗
PubMed1995

Increase of serum insulin and stable c-peptide concentrations with exhaustive incremental graded exercise during acute hypoxia in sedentary subjects.

Hypoxia was shown to reduce insulin concentrations at rest and during exercise. However, some studies have also demonstrated increases in the hormone associated with arterial desaturation. This study was conducted in order to decide [1] whether acute alveolar hypoxia increased or decreased the circulating insulin levels, and [2] to elucidate whether interactions of insulin with other hormones were of relevance in this respect. Glucose (GLU), insulin (INS), c-peptide (CP), adrenaline and noradrenaline (CATs), atrial natriuretic peptide (ANP) and cortisol (CORT) as well as the capillary blood gases were determined in 15 healthy fasting male volunteers (age: 26.2 +/- 2.8 years, body mass index: 22.4 +/- 2.7 kg.m-2). On two separate test days the subjects breathed, in random order, either normal air (N) or a gas mixture with reduced oxygen content (H; FIO2: 0.14). Measurements were made at rest as well as during an incremental cycle exercise in a supine position (increments of 6 min and 50 W) at 100 W and 150 W, at volitional exhaustion (N: 227 +/- 36 W; H: 200 +/- 32 W) as well as in the 5th min of recovery. Arterial desaturation was seen throughout on H-day. At rest all hormones and GLU were normal and showed no influence of H. During exercise INS remained constant on N-day, increased on H-day and was significantly higher with H than with N, most pronounced at 150 W and at volitional exhaustion with 20%, respectively. For CP and GLU no significant exercise-induced changes were seen on either test day and no influence of H was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

Long-term adherence to intensified conventional insulin therapy.

All diabetic patients of the outpatient clinic of the University of Frankfurt/Main, who started intensified conventional insulin therapy (ICT) between 1980 and 1991, and who could be followed for at least one year (n = 141) were evaluated retrospectively. Fourteen patients changed from ICT to continuous subcutaneous insulin infusion (CSII). No patient changed back permanently to conventional insulin therapy. Mean glycosylated hemoglobin-levels (HbA1) decreased significantly in the first year from 9.3% to 8.5% and remained at a near normal level in the following years. HbA1-levels were found not to be associated with age, age at diagnosis, weight gain, frequency of visits to the outpatient clinic, number of consultations with the dietician as well as the frequency of attendance at special seminars for ICT. These results demonstrate that ICT lowered blood glucose levels permanently, that patients were highly compliant, and that ICT was practicable and safe for long-term treatment under routine conditions without initial hospitalization and with an acceptable expenditure of time for patients and medical staff.

Adult↗
PubMed1995

Intravital measurement of donor lymphocyte adhesion to islet endothelium of recipient animals in diabetes transfer experiments.

An in vivo microscopic technique is described that was developed to measure the interaction between transferred donor lymphocytes and islet endothelium in diabetes transfer experiments. With double fluorescent tracer staining by acridine red and FITC-dextran the simultaneous assessment of lymphocyte adhesion and shear forces acting upon adherent cells was possible. Staining the isolated donor lymphocytes with acridine red did not significantly affect their viability. Proliferation capability was maintained after the staining procedure. By using exocrine pancreatic tissue as a reference vascular bed, the specificity of the observed changes in lymphocyte adherence in pancreatic islets could be demonstrated. This new approach in microcirculatory research will help to clarify the mechanisms underlying the initial steps of lymphocyte infiltration into islet tissue in autoimmune diabetes mellitus.

Animals↗
PubMed1995

PVU II polymorphism of LST-1 (leucocyte specific transcript-1) in type I diabetes mellitus, Graves' disease and healthy controls.

The polymorphism of the LST-1 gene (the human homologue of the mouse B144 gene) can be identified by Pvu II restriction enzyme digestion. We investigated the contribution of this RFLP to disease susceptibility in 117 patients with type I diabetes mellitus (IDDM), 110 with Graves' disease (GD) and 93 healthy controls. The distribution of the different LST-1 alleles (LST-1*1:1323 bp, LST-1*2:610 bp/713) was similar among IDDM and GD patients as well as in controls. The combination of DQA1*0501, DQB1*0201 and DQB1*0301, all predisposing to endocrine autoimmune disease, with LST-1*1 or LST-1*2 was not increased in patients. Analysis of two informative families with IDDM demonstrated cosegregation of DQA1 and DQB1 alleles with LST-1 alleles. No association of LST-1 polymorphisms with IDDM nor GD could be demonstrated.

Alleles↗