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Biomedical subjects

T Kirchner

Publications and source records attributed to T Kirchner.

At least 163 records · Page 9Linked to original sources
PubMed1994

Effect of atropine, HLö 7 and HI 6 on respiratory and circulatory function in guinea-pigs poisoned by O-ethyl S-[2-(diisopropylamino) ethyl] methylphosponothioate (VX).

In a guinea-pig model with on-line respiratory and circulatory monitoring the therapeutic efficacy of atropine, HLö 7 and HI 6 in VX poisoning was compared. In female urethane-anaesthetized Pirbright-white guinea-pigs the a. carotis, v. jugularis and trachea were cannulated. After base line measurements the animals received VX (22.5, 45 or 90 micrograms/kg = 5, 10 or 20 x LD50) intravenously and 2 min. later the antidotes: HLö 7 or HI 6 (30 mumol/kg, each) or atropine 10 mg/kg or a combination of atropine and one of the oximes (all intravenously). Respiratory and circulatory parameters were recorded for 60 min. or until death of the animal. Erythrocyte, brain and diaphragm acetylcholinesterase (AChE) activity was determined after the experiment. VX poisoning caused a rapid respiratory arrest within 4-5 min. Atropine treatment was effective in improving the respiratory function after VX, 22.5 micrograms/kg, but had only a small effect after the higher VX doses. The treatment of VX (10 or 20 x LD50) poisoned animals with oxime plus atropine improved respiration to various extents, restored circulation and prolonged the survival time, HLö 7 being more effective than HI 6 after VX 90 micrograms/kg. Oximes alone were completely ineffective. Erythrocyte and diaphragm AChE was reactivated by HLö 7 and, less effectively, by HI 6, while brain AChE remained almost completely inhibited in all groups. The results of this investigation demonstrate a reasonable efficacy of atropine after lower VX doses and of HLö 7 and HI 6 (plus atropine) after high-dose VX poisoning, HLö 7 being slightly more effective than HI 6.

Acetylcholinesterase↗
PubMed1994

[Thymus-like expression and molecules accessory to division and of thymocyte-stroma interactions in thymomas: a prerequisite for the establishment of an abnormal T-cell repertoire?].

Costimulatory stromal receptors were identified in thymuses and myasthenia gravis (MG)-associated thymic epithelial tumors (TETs) by immunohistochemistry. ICAM-1 occurred in areas with medullary or cortical differentiation of TETs and thymuses. B7 and LFA-3, absent in the normal cortex, were hyperexpressed in cortical type TETs. VCAM-1, confined to endothelium and dendritic cells in cortex and medulla, was focally expressed by epithelial cells of a medullary thymoma. We suggest that aberrantly expressed costimulatory molecules may contribute to the pathogenesis of paraneoplastic MG by an intratumorous activation of mature T cells.

Antigens, CD↗
PubMed1994

Cloning of a cDNA coding for the acetylcholine receptor alpha-subunit from a thymoma associated with myasthenia [correction of myastenia] gravis.

To investigate the role of the acetylcholine receptor (AchR) in the pathogenesis of paraneoplastic Myasthenia gravis (MG), we screened a cDNA library of a MG-associated thymoma with a DNA oligonucleotide coding for aa 371-378, i.e. for part of the very immunogenic cytoplasmatic epitope (VICE-alpha, aa 373-380) of the human AChR alpha-subunit. We isolated two cDNA clones. Analysis of these clones has identified an open reading frame of 1371 bp, coding for the AChR alpha-subunit. No point mutation, insertion or deletion could be detected. Since the thymoma did not contain thymic myoid cells, which normally express AChR, the origin of the AChR transcripts must be the tumor cells itself. These findings confirm former results, where AChR alpha-subunit sequences from MG-thymomas were amplified by PCR.

Base Sequence↗
PubMed1994

Distribution of molecules mediating thymocyte-stroma-interactions in human thymus, thymitis and thymic epithelial tumors.

Two findings in thymic epithelial tumors are correlated with the occurrence of myasthenia gravis(MG): (1) the expression of an acetylcholine receptor (AChR)-like-epitope in the neoplastic epithelium, and (2) the preservation of thymus-like features in the neoplasms, indicated by the presence of immature thymocytes. On this background it has been proposed that paraneoplastic MG may start with an intratumorous abnormal T cell selection due to aberrantly expressed AChR-epitopes (self-peptides). As appropriate thymocyte-stroma-interactions are prerequisites for thymocyte development in the thymus (and probably in MG-associated thymic tumors, too), we analyzed the expression of CD28/B7(BB1), CD2/:LFA3, LFA-1/ICAM-1 and VLA-4/VCAM-1 in human thymus and thymomas by immunohistochemistry. In normal thymuses and thymitis the stromal molecules were expressed at higher levels in the medulla than in the cortex. This was particularly true for B7(BB1) that was undetectable by immunoperoxidase techniques in the cortex. In contrast, cortical-type thymic epithelial tumors (cortical thymoma and well differentiated thymic carcinoma), known to exhibit the highest association with myasthenia, expressed the stromal molecules at almost medullary levels. The findings may be a clue to a functional difference between neoplastic and normal cortical epithelial cells: while we find the former to have the capacity to present soluble antigen to antigen-specific CD4+ T cells in vitro, normal cortical epithelium failed to do so. This altered microenvironment in thymomas might contribute to the autoimmunization by stimulating mature recirculating AChR-specific T cells.

CD2 Antigens↗
PubMed1994

Myogenesis in thymic transplants in the severe combined immunodeficient mouse model of myasthenia gravis. Differentiation of thymic myoid cells into striated muscle cells.

Thymic myoid cells (TMCs) bearing acetylcholine receptors (AchR) on their surface have a central role in the concept of intrathymic autosensitization in the pathogenesis of myasthenia gravis. In a SCID mouse model of myasthenia gravis, solid pieces of thymuses with lymphofollicular hyperplasia were transplanted into SCID mice. The chimeric mice displayed long-term secretion of anti-AchR antibodies. Here, we traced the fate of TMCs contained in transplanted myasthenia gravis thymuses. Unexpectedly, the number of thymic TMCs in transplanted tissue was slightly higher than in untransplanted thymus. More strikingly, the transplanted TMCs were more highly differentiated than their nontransplanted counterparts. This was demonstrated by a more than 10-fold increase of AchR-main immunogenic region epitopes recognized by monoclonal antibody 198. Some TMCs had even differentiated into striated muscle cells. The abundance of AchRs in human thymic transplants in the SCID mouse model of myasthenia gravis may help to study the mechanisms of autosensitization against the AchR in vivo.

Animals↗
PubMed1994

Tepoxalin: a dual cyclooxygenase/5-lipoxygenase inhibitor of arachidonic acid metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profile.

Tepoxalin [5-(4-chlorophenyl)-N-hydroxy-(4-methoxyphenyl)-N-methyl-1H- pyrazole-3-propanamide] is a potent inhibitor of sheep seminal vesicle cyclooxygenase (CO) (IC50 = 4.6 microM), rat basophilic leukemia cell (RBL-1) lysate CO (IC50 = 2.85 microM) and CO from intact RBL-1 cells (IC50 = 4.2 microM). The compound inhibits the production of thromboxane B2 (TxB2) in Ca++ ionophore A-23187-stimulated human peripheral blood leukocytes (HPBL; IC50 = 0.01 microM) and human whole blood (IC50 = 0.08 microM) and is a potent inhibitor of epinephrine-induced human platelet aggregation (IC50 = 0.045 microM). Tepoxalin inhibits lipoxygenase (LO) in RBL-1 lysates (IC50 = 0.15 microM) and intact RBL-1 cells (IC50 = 1.7 microM) and inhibits the generation of leukotriene B4 (LTB4) in calcium ionophore A-23187-stimulated HPBL (IC50 = 0.07 microM) and human whole blood (IC50 = 1.57 microM). Human platelet 12-LO (IC50 = 3.0 microM) is inhibited, but 15-LO is only weakly so (IC50 = 157 microM). In vivo, tepoxalin, administered orally, demonstrated potent anti-inflammatory activity in the established adjuvant arthritic rat (ED50 = 3.5 mg/kg) and potent analgesic activity in the acetic acid abdominal construction assay in mice (ED50 = 0.45 mg/kg). In an ex vivo whole blood eicosanoid production assay, tepoxalin produces a dose-related inhibition of prostaglandin (PG) and LT production in dogs (PGF2 alpha - ED50 = 0.015 mg/kg; LTB4 - ED50 = 2.37 mg/kg) and adjuvant arthritic rats following oral administration. In adjuvant arthritic rats, tepoxalin is devoid of ulcerogenic activity within its anti-inflammatory therapeutic range (1-33 mg/kg p.o.) and does not exhibit ulcerogenic activity in normal rats at doses lower than 100 mg/kg (UD50 = 173 mg/kg p.o.). Tepoxalin represents a new class of anti-inflammatory drugs which may exhibit less gastrointestinal toxicity and may be efficacious in immunoinflammatory disease states where excessive PG and LT production has been implicated and may offer a significant alternative to nonsteroidal and corticosteroidal anti-inflammatory therapy.

Animals↗
PubMed1993

[Acute pancreatitis and stomach wall necrosis caused by cholesterol embolisms].

A 60-year-old man was hospitalized because of a sudden onset of severe pain in the epigastrium and haematemesis. Acute pancreatitis was diagnosed on the basis of an increased serum amylase concentration (642 U/l). Abdominal ultrasound and computed tomography demonstrated a necrotic zone with central liquefaction in the tail of the pancreas adjoining the stomach wall. Gastroscopy revealed as source of the bleeding an extensive mucosal necrosis at the greater curvature of the stomach. At laparotomy, partial resection of the pancreas, gastrectomy and splenectomy were performed. Histological examination of the resected specimens showed multiple cholesterol emboli in the small arteries of the pancreas and the gastric submucosa.

Acute Disease↗
PubMed1993

Primary gastric lymphoma is rarely associated with Epstein-Barr virus.

Recently, the association of Epstein-Barr virus (EBV) with undifferentiated lymphoepithelioma-like carcinoma and adenocarcinoma of the stomach has been described. In this study of 55 primary gastric lymphomas, most of them belonging to the group of MALT lymphomas, the question of possible EBV involvement has been addressed using in-situ hybridization (ISH) and blot techniques. EBV DNA and/or DNA sequences were found in only two of 24 centroblastic and B-immunoblastic lymphomas and in one anaplastic large cell lymphoma of null cell phenotype. In a further centroblastic lymphoma, a few positive nontumorous (bystander) cells were identified by ISH. By means of ISH, no positive signals could be detected in the preserved overlying mucosa nor in regenerating epithelium adjacent to lymphoma-induced ulcerations.

Blotting, Southern↗
PubMed1993

DNA mapping of colorectal neoplasms: a flow cytometric study of DNA abnormalities and proliferation.

BACKGROUND: There is some evidence that neoplastic development and progression evolve through a multistep process associated with hyperproliferation and genetic alterations. Therefore, changes of proliferation and of cellular DNA content within the adenoma-carcinoma sequence were studied. METHODS: Using a "mapping" procedure, 12 adenomas and 18 carcinomas were analyzed flow cytometrically and histologically. In addition, normal mucosa adjacent to and distant from the tumors was assessed in the same way. RESULTS: Of 59 adenomatous fractions, 35.6% (n = 21) were aneuploid, whereas the incidence of aneuploidy was 63.5% (54/85) in the carcinomatous sites. Additional tetraploidies were identified in 5 (8.5%) and 13 (15.3%) adenomatous and carcinomatous samples, respectively. Cell proliferation, as determined by the percentage of S-phase cells, was significantly (P < 0.001) higher in the carcinomatous specimens (14.8% +/- 0.8%; mean +/- SEM) than in the adenomatous ones (8.1% +/- 0.7%). It decreased to normal mucosa adjacent to (5.1% +/- 0.5%) and distant (5.3% +/- 0.6%) from the neoplasms. DNA mapping of the tumors revealed both distinct regions and extended areas of aneuploidy and tetraploidy. There is evidence from the mapping data that aneuploid populations arise at a single focus of the adenoma and expand over large areas before a subpopulation of cells acquires the capacity of invasion. CONCLUSIONS: These data showing consecutive DNA content abnormalities within the colorectal adenoma-carcinoma sequence provide support for genomic instability and clonal evolution as important events of tumorigenesis and progression.

Adenoma↗
PubMed1993

Osteoinductive, morphologic, and biomechanical properties of autolyzed, antigen-extracted, allogeneic human bone.

Autolyzed, antigen-extracted, allogeneic (AAA) bone was prepared from human cortical bone and its morphologic, biomechanical, and osteoinductive properties were compared with untreated (frozen) as well as lyophilized human bone. Scanning electron microscopy revealed removal of inorganic calcium phosphates and persistence of shrunken collagen fibrils on the surface of AAA bone matrix. Biomechanical testing of differently prepared bone samples showed that lyophilization increased both the modulus of elasticity (P < .00001) and the compressive strength (P < .00001). Depending on the depth of decalcification in the preparation of AAA bone, both measured values decreased in rehydrated AAA bone compared with untreated bone (P < .00001). Completely demineralized and rehydrated AAA bone was soft, flexible, and showed very little compressive strength. Differences in biomechanical behavior between samples drilled longitudinally or perpendicularly to the diaphyseal bone axis were observed. Xenogeneic human bone samples were implanted in muscle pouches of Sprague-Dawley rats for 6 weeks. AAA bone implants showed chondrogenesis and osteogenesis in 50% of the cases, while untreated or lyophilized bone implants induced no new cartilage or bone formation. As decalcification exposed xenogeneic organic matrix components, AAA bone implants provoked the highest inflammatory reaction. When AAA bone samples were implanted in immunosuppressed rats, the inflammatory reaction was suppressed and 94% of the implants showed endochondral bone formation. The chondroinductivity of the bone samples also was tested in vitro using neonatal rat muscle tissue to avoid interference with inflammatory cells and secreted cytokines. In this assay, 68% of AAA bone samples induced chondroneogenesis, while untreated as well as lyophilized bone samples failed to induce any cartilage formation. The results clearly demonstrate that AAA bone has osteoinductive properties. Biomechanical stability of AAA bone implants depends on the degree of demineralization. Thus, they can be prepared in an appropriate manner for different indications in oral and maxillofacial surgery.

Animals↗
PubMed1993

Experimental antiasthmatic activity of RWJ 22108: a bronchoselective calcium entry blocker.

RWJ 22108 (N-benzyl-N-methylaminoethyl 9-(2-chloro-6-fluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1, 1-dioxothiacyclohepteno-[3,2-b]pyridine-8-carboxylate) is a new bronchoselective calcium entry blocker with potential use as an antiasthmatic agent. Previous studies have shown that RWJ 22108 is a potent calcium entry blocker in vitro and demonstrates tissue selectivity for airway smooth muscle over vascular smooth muscle. The current study demonstrates the in vivo activity of RWJ 22108 in several different models of airway obstruction and asthma. RWJ 22108 relaxes preconstricted airways in dogs with little effect on blood pressure when administered by aerosol. In addition, it inhibits airway obstruction induced by antigen, histamine and exogenous leukotriene D4 in guinea pigs. In a conscious sheep model of allergic asthma, aerosol RWJ 22108 inhibits antigen-induced early and late phase airway obstruction and also the cellular infiltration associated with late phase. Total leukotrienes production is decreased in the guinea pig model probably as a result of fewer inflammatory cells infiltrating the lungs as shown in the sheep model of late phase. These data suggest that RWJ 22108 may have pharmacological potential in the clinical management of asthma.

Airway Obstruction↗
PubMed1993

[Pathogenesis of autoimmunity in thymoma].

The analysis of thymic epithelial tumors (TET) with and without myasthenia gravis (MG) has identified both a residual organotypic differentiation of TETs and the aberrant expression of acetylcholine receptor (AChR)-epitopes in TET epithelial cells to be associated with MG. These findings have suggested an abnormal selection of helper T cells as a mechanism of paraneoplastic MG. Here we show by electronmicroscopy that epithelial cells of TETs and normal thymus exhibit the morphological features (autophagic vacuoles) thought to be necessary to process endogenous proteins for presentation by MHC class II molecules to immature T cells.

Autoimmune Diseases↗
PubMed1993

B-cells in thymic epithelial tumours. An immunohistochemical analysis of intra- and extraepithelial B-cell compartments.

A total of 26 thymomas and thymic carcinomas were studied by immunohistochemistry to determine the presence and distribution of intratumoural B-cells. Double staining experiments revealed two distinct B-cell populations in the thymic epithelial tumours. One was found within the perivascular space (PVS), which is separated from the neoplastic epithelium by a basement membrane. In all tumours the PVS contained lymphocytes with the immunophenotype of peripheral B-cells. Large numbers of B-cells with germinal centre formation were found almost exclusively in myasthenia gravis (MG)-associated tumours, mainly in cortical thymomas and well differentiated thymic carcinomas. A second population of B-cells was located in the neoplastic epithelial meshwork, mostly in areas of organoid medullary differentiation characterized by epidermoid cells or Hassall's corpuscules. This population frequently comprised large, CD23+ cells with dendritic features resembling the special type of intramedullary B-cells of the normal human thymus. In contrast, B-cells were uncommon in areas of mixed thymoma showing spindle celled medullary differentiation, and were almost completely absent from tumour areas composed of cortical type epithelium. Hence a medullary microenvironment with epidermoid cells corresponding to Hassall's corpuscules seems to be necessary for specific intrathymic B-cell homing.

Adult↗
PubMed1992

Malignant lymphomas of the upper gastrointestinal tract. Results of a prospective study in 103 patients.

BACKGROUND: There is a discrepancy between the incidence of gastrointestinal involvement by malignant lymphomas, as established in postmortem studies, and the rareness of the corresponding clinical diagnosis. METHODS: Therefore, the authors performed routine upper gastrointestinal endoscopic examination, within the framework of the usual staging examinations, in 103 consecutive patients with newly diagnosed Hodgkin disease (n = 21) and non-Hodgkin lymphoma (n = 82). RESULTS: One patient with Hodgkin disease (4.8%), 11 of 40 patients (27.5%) with non-Hodgkin lymphoma of low-grade malignancy, and 11 of 42 (26.2%) of those with highly malignant non-Hodgkin lymphoma showed involvement of the gastric and/or duodenal mucosa, as diagnosed with esophagogastroduodenoscopy. Of the 22 patients with non-Hodgkin lymphoma, 9 had involvement of other mucosa-associated lymphoid or epithelial tissue. In two patients with Stage III, two with Stage II, and two patients with presumptive Stage I disease, the disease was reclassified as Stage IV. Because of gastrointestinal involvement, treatment for two patients was changed from radiation therapy to chemotherapy and another two patients had gastric resections so that possible treatment-related complications could be avoided. CONCLUSIONS: In light of these results and the fact that a major basis for the therapeutic strategy for malignant lymphomas is tumor stage, routine esophagogastroduodenoscopic examination within the framework of the usual staging examinations is recommended. In individual cases, this procedure may be of decisive importance in the therapeutic approach to and prevention of complications.

Adolescent↗