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Biomedical subjects

K M Müller

Publications and source records attributed to K M Müller.

At least 19 recordsLinked to original sources
PubMed1995

[Cardiac death and acute myocardial infarct after psychological or physical stress--causality questions and insurance law].

Often, it is the question to the medical expert, if there is a causality in the lawful sense from professional effort or psychical stress to acute coronary death or acute myocardial infarction. Following the German social law the connection has to be probably. Probability is well defined juridically opposite to possibility. The medical expert has to answer if the physical or psychical stress has caused the fatality or not more than manifested. Here are discussed arguments that the atheromatosis of the coronary vessels has much more importance than the manifestation of acute death or myocardial infarction caused by spasmus. There is no evidence for the existence of spastic genesis without any arteriosclerotic focus.

Causality↗
PubMed1995

P53 accumulation and proliferating-cell nuclear antigen expression in human lung cancer.

Mutations in the p53 gene are currently the commonest genetic alterations in human malignant tumors, including non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Alterations of the protein induced by gene mutations enables the mutant protein to become more stable, resulting in the accumulation of P53 in quantities detectable by immunohistochemistry. Although previous studies document the accumulation of P53 in lung cancer, there is little information regarding the usual frequency of accumulation based on a comprehensive number of lung tumors. A total of 328 paraffin-embedded lung carcinoma specimens were analyzed for P53 accumulation and for the expression of the proliferating-cell nuclear antigen (PCNA) by standard immunohistochemistry. Among 49 SCLC, 35% were positive for p53 and 51% were positive for PCNA. Out of 279 NSCLC, 43% showed a positive P53 immunoreaction and 72% displayed detectable amounts of PCNA. In squamous-cell carcinomas a statistically significant increased accumulation of P53 was found compared to adenocarcinomas (P = 0.001). Among the 233 PCNA-positive tumors the relative number of P53-positive specimens was higher compared to the total number of tumors. Since immunohistochemical investigations should contribute to the improvement of the clinical diagnosis and treatment or give information on the prognosis, we conclude from our results that it seems to be legitimate to assess the P53 status exclusively in the specimens positive for PCNA. Immunohistochemical investigations under consideration of the PCNA status yielded good and fast recognition of p53 mutations leading to intracellular P53 protein accumulation.

Carcinoma, Non-Small-Cell Lung↗
PubMed1995

Functional ablation of sensory neurons impairs healing of acute gastric mucosal damage in rats.

Healing of ethanol-injured gastric mucosa was studied in rats treated with a neurotoxic dose of capsaicin to induce functional ablation of sensory nerves. Capsaicin treatment delayed the healing of mucosal damage in the glandular region and promoted the development of deep ulcerations predominantly in the antrum. These lesions occupied 86% of the antral surface and were associated with marked invasion of inflammatory cells and 18-fold elevation of gastric myeloperoxidase activity compared with vehicle-pretreated rats. Inhibition of cyclooxygenase, 5-lipoxygenase, or nitric oxide synthase did not affect the development of antral lesions after ethanol challenge in capsaicin-pretreated rats. In vehicle-pretreated rats, inhibition of nitric oxide synthase did not mimic the effect of functional ablation of sensory neurons. The findings suggest that in the gastric mucosa sensory neurons contribute to repair processes and limit the inflammatory response to injury. These effects do not involve arachidonic acid metabolites or nitric oxide.

Acute Disease↗
PubMed1995

[Small cell bronchial carcinoma following chemotherapy. Morphological findings].

Resection specimens of 14 patients with small cell bronchial carcinoma after neoadjuvant chemotherapy were processed histologically and graded according to a three-step regression grading system: grade I, no or only slight tumor regression; grade II, incomplete tumor regression; grade III, complete tumor regression without vital tumor tissue. In five patients with either no vital tumor tissue or only small tumor remnants in the resection samples, a typical sequence of central fresh tumor necrosis, foam cell rim, vascular granulation tissue and peripheral scar formation was seen. This morphological finding may be interpreted as a characteristic, but unspecific parameter of good response to preoperative chemotherapy. The presence of vital tumor rims surrounding the capillary bed with intermingled necrotic foci, however, argues in favor of spontaneous tumor regression, which is commonly observed in small cell lung cancer.

Adult↗
PubMed1995

[Calcinosis of the meniscus. Morphologic and roentgenographic findings for zonal classification].

Primary and secondary meniscal chondrocalcinoses lead to typical changes in X-ray pictures of isolated menisci. Combined X-ray, light and electron microscopic examination of the four menisci in 70 autopsy cases showed calcifications in 13 cases (18.6%). Three types of calcification could be discriminated with the help of topographical and morphological criteria: Type 1 A: disseminated calcification. All four menisci were affected equally. Crystals of calcium pyrophosphate dihydrate (CPPD) were found on light and electron microscopy. Energy-dispersive X-ray analysis (EDX) showed the crystal deposits to consist of 46.5% calcium and 53.5% phosphorus. Type 1 B: Calcification occurring in limited areas. A calcification was found which did affected neither a whole meniscus nor all four menisci of any "quartet" observed. Crystals were found next to areas of stronger meniscal degeneration. EDX showed the same results described for type 1 A. Type 2: Confluent calcification. A cloud-like diffuse calcification was discerned on the X-ray pictures. Light and electron microscopically pseudocystic structures appeared which contained a fine granular amorphous material. No crystals were found. The structures appeared in the neighbourhood of necrotic fibres. EDX showed 44% calcium, 51.2% phosphorus, 2.8% sulphur, 0.74% magnesium and 0.6% potassium. The findings lead to the conclusion that calcification type 1 A represents primary chondrocalcinosis, whereas type 1 B corresponds to secondary chondrocalcinosis. Type 2 was identified as postnecrotic, dystrophic calcification. Careful analysis of X-ray pictures of isolated menisci can yield useful information concerning pathogenetic factors of meniscal calcification.

Calcium Pyrophosphate↗
PubMed1995

Protection by gastrin in the rat stomach involves afferent neurons, calcitonin gene-related peptide, and nitric oxide.

BACKGROUND & AIMS: Certain gut peptides exert gastroprotective effects. However, the underlying mechanism is not fully understood. This study examines the contribution of afferent neurons, calcitonin gene-related peptide, and nitric oxide to the protection conferred by gastrin 17 in the rat stomach. METHODS: Gastroprotection by gastrin 17 against ethanol-induced gross and histological damage was studied after capsaicin-induced defunctionalization of afferent neurons, pretreatment with the calcitonin gene-related peptide receptor antagonist human calcitonin gene-related peptide8-37, anti-calcitonin gene-related peptide antibodies, and the NO synthase inhibitor NG-nitro-L-arginine. RESULTS: Gastrin 17 (1-25 pmol/kg) dose-dependently prevented mucosal damage caused by ethanol. Protection was inhibited by functional ablation of afferent neurons or pretreatment with human calcitonin gene-related peptide8-37 (50% inhibitory dose, 86 pmol.kg-1.min-1), anticalcitonin gene-related peptide antibodies, or NG-nitro-L-arginine (50% inhibitory dose, 1 mg/kg). L-Arginine but not D-arginine reversed the effect of NG-nitro-L-arginine. Effects on gross damage were paralleled by histology. Protective doses of gastrin 17 increased gastric mucosal blood flow and, in addition, elevated plasma gastrin concentrations to the same extent as intragastric peptone perfusion. CONCLUSIONS: Gastrin 17 has potent gastroprotective activity that involves afferent neurons, calcitonin gene-related peptide, and NO.

Amino Acid Oxidoreductases↗
PubMed1995

Nickel and skin irritants up-regulate tumor necrosis factor-alpha mRNA in keratinocytes by different but potentially synergistic mechanisms.

A critical role of tumor necrosis factor (TNF)-alpha in irritant contact dermatitis and in the challenge phase of allergic contact dermatitis has recently been demonstrated in vivo. As in situ hybridization studies have indicated that keratinocytes were the cellular source of TNF-alpha in these reactions, we studied the mechanisms of TNF-alpha mRNA induction in keratinocytes by agents that induce contact dermatitis. Murine la-/CD3- epidermal cells were stimulated with phorbol myristate acetate (PMA), dimethylsulfoxide (DMSO), sodium dodecyl sulfate (SDS) and NiSO4, all of which up-regulated epidermal cell TNF-alpha mRNA production. In contrast, trinitrobenzenesulfonic acid and trinitrochlorobenzene did not significantly up-regulate TNF-alpha mRNA. These results were confirmed with murine keratinocyte cell lines. In keratinocytes transfected with a chloramphenicol acetyltransferase construct containing the -1059 to +138 base pair TNF-alpha promoter, increased promoter activity was observed upon stimulation with PMA and DMSO. In addition, PMA stimulation did not affect the stability of TNF-alpha mRNA. The PMA- but also the DMSO- and SDS- induced up-regulation of TNF-alpha mRNA was abolished by an inhibitor of protein kinase C (PKC). In contrast, NiSO4 up-regulated TNF-alpha mRNA by a PKC-independent mechanism, did not increase TNF-alpha promoter activity, but markedly increased the stability of the TNF-alpha mRNA. Co-stimulation with PMA and NiSO4 induced a marked increase in TNF-alpha mRNA over that obtained with each agent alone. Thus, whereas PKC-dependent irritants act by up-regulating TNF-alpha promoter activity, nickel acts via post-transcriptional regulation. Our results also establish that some irritants and irritant sensitizers directly induce TNF-alpha in keratinocytes without intermediate Langerhans cell-derived signals.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

The induction and functions of murine T-helper cell subsets.

Through the release of distinct sets of cytokines, Th1 and Th2 cells exert characteristic and often mutually exclusive or antagonistic immune effector functions. In the present report, we document and discuss several findings on the induction mechanisms of these cellular subtypes and present recent findings on their respective functions in vivo. The preferential induction of Th1 or Th2 cytokine patterns in mature CD4+ T cells is generally attributed to the action of cytokines. In addition, there is evidence that prolonged T-cell receptor occupancy may induce the development of the Th2 phenotype. Prolonged occupancy of the T-cell receptor provides enough autocrine interleukin-4 to permit induction of the Th2 phenotype. Both Th1 and Th2 cells may be derived from a single mature CD4+ T cell, providing strong evidence for post-thymic modulation of the T-cell cytokine profile and rendering the possibility of predetermined cytokine patterns in T cells unlikely. CD4+ Th1 cells mediate the tumor necrosis factor- and interferon-gamma-dependent classic delayed type hypersensitivity reaction. We found that Th2 cells were also capable of mediating local inflammatory reactions that depended on their prototypic lymphokine interleukin-4, and, in high tumor necrosis factor-producing mouse strains, upon tumor necrosis factor-alpha. Both Th-cell subsets induced cellular infiltrates that were not distinguishable on histologic grounds. In contrast to the widely accepted belief that only Th1 cells can mediate delayed hypersensitivity reactions, our results demonstrate that T cells with either lymphokine profile can cause tissue inflammation with leukocytic infiltrates.

Animals↗
PubMed1995

Involvement of granulocytes and the adhesion receptors intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in tissue inflammation induced by Th2-type helper cells.

We reported recently that subcutaneously injected, anti-CD3 epsilon-pulsed polyclonal Th2 cells mediate interleukin-4-dependent local tissue inflammation. Because a prominent polymorphonuclear infiltrate was observed in the lesions at the time of maximal tissue swelling, we investigated the involvement of polymorphonuclear leukocytes and their adhesion molecules lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) in Th2-cell-mediated inflammation. Pretreatment of recipient mice with a depleting monoclonal antibody to neutrophils or with blocking antibodies to LFA-1 or to ICAM-1 completely abrogated tissue swelling in Th2-cell-mediated inflammation. Granulocyte infiltration at 6 h was also inhibited by the antibodies to neutrophils and to ICAM-1, but not by that to LFA-1. Tissue swelling mediated by Th1 cells had different kinetics and was not prevented by administration of anti-neutrophil antibody: maximal edema formation occurred at 24-48 h, when the predominant cellular infiltrate was mononuclear. Because the Th1-cell-induced infiltrate at 6 h also consisted of granulocytes but was not associated with pronounced edema, the mere presence of infiltrating polymorphonuclear leukocytes seems not to be sufficient to induce edema. Because edema but not granulocyte infiltration was inhibited by anti-LFA-1 and because anti-LFA-1 antibodies are known to inhibit several functions of neutrophils, our results suggest that, in inflammation mediated by Th2 cells, granulocytes induce edema through their activation and/or degranulation.

Animals↗
PubMed1995

Natural vitamin D3 response elements formed by inverted palindromes: polarity-directed ligand sensitivity of vitamin D3 receptor-retinoid X receptor heterodimer-mediated transactivation.

VDR, the nuclear receptor for 1,25-dihydroxyvitamin D3 (VD), is a member of the superfamily of nuclear hormone receptors and controls multiple aspects of homeostasis, cell growth, and differentiation. VDR can function as a homodimer, but heterodimerization with the retinoid X receptor (RXR), retinoic acid receptor, or thyroid hormone receptor increases its affinity for response elements in the promoter of target genes. All natural VD response elements identified so far consist of direct repeats of a variety of hexameric core binding motifs with a preferential spacing of three nucleotides (DR3s). However, all four VD signalling pathways function also on response elements formed by inverted palindromes, although these sequences were not of natural origin. Here, we report the identification of two VD response elements consisting of inverted palindromes spaced by nine nucleotides (IP9s) in the promoters of the human calbindin D9k gene and the rat osteocalcin gene. Like most DR3-type VD response elements, both IP9s are preferentially bound by VDR-RXR heterodimers with a 5'-RXR-VDR-3' polarity, whose transcriptional activity can be enhanced by costimulation with 9-cis retinoic acid. We demonstrate that changing the response element orientation relatively to the basal promoter decreases the sensitivity of transcriptional activation by VD by about 10-fold. Our findings indicate that inverted palindromes are as functional as direct repeats. Furthermore, we suggest that the orientation of a nuclear receptor complex in relation to the basic transcriptional machinery, which is directed by heterodimer polarity and response element orientation, influences the ligand sensitivity of the respective target gene expression.

Animals↗
PubMed1995

Low specificity of cytokeratin 19 reverse transcriptase-polymerase chain reaction analyses for detection of hematogenous lung cancer dissemination.

PURPOSE: Sensitive detection of systemic tumor dissemination in lung cancer patients is important for selection of appropriate treatment modalities. Based on recent promising data that showed reverse transcriptase-polymerase chain reaction (RT-PCR) analyses for cytokeratin 19 (CK-19) expression in peripheral-blood or bone marrow samples to be a rapid and highly sensitive method for detection of hematogenous tumor dissemination in patients with breast and prostate cancer, we evaluated the specificity of this assay system in lung cancer patients and a large number of healthy controls. PATIENTS AND METHODS: We examined CK-19 mRNA expression by RT-PCR in 17 lung cancer cell lines and in peripheral-blood samples of 50 lung tumor patients and 65 healthy controls. RESULTS: Expression of CK-19 mRNA was observed in all lung cancer cell lines and in 50% of peripheral-blood samples from lung tumor patients. However, under the experimental conditions analyzed, at least 20% of the control samples were positive for CK-19 mRNA expression. CONCLUSION: Contrary to prior reports, RT-PCR may detect non-tissue-specific constitutive low-level (illegitimate) expression of CK-19 mRNA in peripheral-blood mononuclear (PBMN) cells in a significant number of healthy controls. This finding may not only hamper the use of this assay system in lung cancer patients, but also questions its proposed applicability in patients with other epithelial tumors such as breast and prostate cancer.

Adult↗
PubMed1995

[Ultrastructural findings in pleural cysts in spontaneous pneumothorax].

Lung biopsies obtained by conventional thoracotomy from five patients (mean age 33.6 years, range 21-45) following recurrence of spontaneous pneumothorax were studied by light, scanning, and transmission electron microscopy. The purpose of the study was to define abnormalities that predispose to air penetration through the intact wall of pleural blebs. Two types of blebs were identified either with a complete or with an incomplete layer of mesothelial cells. In those areas where the mesothelial cells were lacking, the walls only consisted of irregular, discontinuous collagen fibers. Increasing intraalveolar pressure may distort the net of collagen fibers and air penetration appears to be possible. The wall of pleural blebs is generally weakened by degenerative changes and may predispose to recurrence of pneumothorax. Therefore, wedge resection of the blebs including the underlying lung parenchyma is suggested for surgical therapy of pneumothorax.

Adult↗
PubMed1994

[Endoscopic diagnosis of colonic tuberculosis].

A 67-year-old woman had developed weakness, fatigue and a 10 kg weight loss over the past year. On examination a cylindrical mass was palpated in the right middle abdominal cavity. Erythrocyte sedimentation rate was increased to 87/126 mm, there was an hypochromic anaemia (haemoglobin 9.1 mg/dl) and an hypoalbuminaemia (32 g/l) with an increase in alpha 2-globulins (9.4 g/l), Cholinesterase activity was decreased to 588 U/l. X-ray film of the abdomen revealed a calcified mesenteric lymph-node and coloscopy demonstrated polypoid tumorous changes with ulcerations, extending from the pole of the caecum to the right flexure. Histological examination showed epithelioid-cell granulomas with Langhans giant cells. Culture grew Mycobacterium tuberculosis, confirming the diagnosis of intestinal tuberculosis. She was treated with oral doses of isoniazid (300 mg daily), rifampicin (600 mg daily) and pyrazinamide (2 g daily) for 2 months, followed by isoniazid and rifampicin for a further 4 months. After this the laboratory tests were within normal limits and urine as well as stool samples contained no acid-fast bacilli. As the patient felt so well she declined another coloscopy.

Aged↗
PubMed1994

[The pathology of the pulmonary arteries in lung tumors].

A study was undertaken to analyse the type and extent of pathological changes in the pulmonary arteries in non-small cell malignant tumours of the lung. Large-section histological preparations were made from 33 squamous cell carcinomas and 30 adenocarcinomas (T1 and T2 tumours) and classified according to tumour margin area (zone 1), intermediate area (zone 2) and tumour centre (zone 3). Transmural tumour growth with intraluminal cell formations in the pulmonary artery branches were found in the centre of all adenocarcinomas and 86% of squamous cell carcinomas, involving subsegment, prelobular and lobular arteries. Obstructive and obliterative changes in the pulmonary arteries as the result of tumour compression and secondary fibrosing changes predominantly occurred in the centre of all tumours. They were less common and less marked in zones 1 and 2. -Pulmonary artery branches in lung tumours of stages T1 and T2 showed marked infiltrating, obliterative and secondary inflammatory changes as far as complete vascular occlusions. These observations indicate that cytotoxic drugs, introduced via the systemic circulation, cannot reach and therefore not exert their effects in extensive areas of tumour.

Adenocarcinoma↗
PubMed1994

Vitamin D3-thyroid hormone receptor heterodimer polarity directs ligand sensitivity of transactivation.

The nuclear receptors for 1,25-dihydroxyvitamin D3 (VD) and 3,5,3'-triiodothyronine (T3), that is, VDRs and T3Rs respectively, control aspects of homeostasis, cell growth and differentiation. They activate transcription from response elements consisting of direct repeats, palindromes and inverted palindromes of a variety of hexameric core-binding motifs. VDRs bind preferentially to direct repeats spaced by three nucleotides, whereas T3Rs bind to direct repeats spaced by four nucleotides. VDRs and T3Rs can function as homodimers but heterodimerization with retinoid X or retinoic acid receptors increases their affinity for DNA in vitro and resulting transcriptional activity in vivo. We recently observed the formation of VDR-T3R heterodimers. Here we show that the polarity of the binding of such heterodimers to the VD response element of the rat 9K (relative molecular mass 9,000) calbindin gene promoter was 5'-T3R-VDR-3', whereas on the mouse 28K calbindin VD response element this polarity was reversed to 5'-VDR-T3R-3'. We also show that the ligand for the downstream receptor controls the transcriptional activity of the heterodimeric complex. Thus, polarity seems to be an important regulatory property of heterodimeric nuclear receptor complexes.

Animals↗
PubMed1994

p53 accumulation in polynuclear-giant-cells.

Accumulation of p53 has been reported in nearly all malignant human tumours. Macrophage derived giant cells of sarcoid granulomas in human lung tissue also show intense staining for p53 while normal alveolar macrophages remain unstained. Since sarcoid giant cells are not considered to be either pre-neoplastic nor to exhibit p53 gene mutations, two different physiological functions of p53 may be illustrated. Alveolar macrophages were isolated from rat lungs and cultured in vitro. Accumulation of p53 was observed by indirect immunohistochemistry after application of polyclonal rabbit serum directed against murine p53 (CM5). Antiproliferating cell nuclear antigen (PCNA) antibodies were used to study DNA synthesis. Most of the multinucleated giant cells derived from macrophages accumulated p53 in the cytoplasm, while only few nuclei were stained. PCNA was found in most giant cells nuclei. However, PCNA positivity was visible in few mononucleated macrophages. Isolated alveolar macrophages in vitro clearly divide and since nuclear division is a late event in the cell cycle, p53 may be involved in G1/S-control and in other cell-cycle-checkpoints between mitosis and cytokinesis.

Animals↗