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Biomedical subjects

K M Müller

Publications and source records attributed to K M Müller.

At least 181 records · Page 10Linked to original sources
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↗
PubMed1995

[Pleuro-mediastinitis in pulmonary actinomycosis as a rare differential bronchial carcinoma diagnosis].

A 48-year old patient complaining of immitigable coughing with purulent and sanguineous sputum and a loss of weight of 8 kg within the last three months was admitted to our hospital. Due to anamnesis and radiological findings (tumor of the right side upper lung field with infiltration of the chest wall and the mediastinum) we suspected a bronchogenic carcinoma. As bronchoscopy and histological examinations of biopsies revealed no hints to the underlying disease, we submitted the patient to a right side explorative thoracotomy. It showed a tumorous involvement of the right side upper lung field with infiltration and partial destruction of the chest wall and infiltration of the apical segment of the lower lobe of the lung and a phlegmonous infiltration of the paratracheal tissue. Histological examination confirmed chronical course of actinomycosis. Therapy consisted in resection of the affected tissue and long-term administration of antibiotics. Response to therapy was excellent concerning both radiological findings and subjective complaints.

Actinomycosis↗
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

H-2D haplotype-linked expression and involvement of TNF-alpha in Th2 cell-mediated tissue inflammation.

We recently reported that polyclonal anti-CD3 epsilon-pulsed Th2 cells mediate local tissue inflammation (DTH2) when injected into naive syngenic recipient mice, and that this response is entirely dependent on IL-4 in BALB/c (H-2d) mice. We now describe a different cytokine dependence in mice that bear a H-2b MHC haplotype. Injection of either soluble IL-4R (sIL-4R) or anti-TNF Ab partially inhibited swelling that was mediated by Th2 cells from high TNF-producing C57BL/6 mice. Anti-TNF and sIL-4R in combination were required to completely abrogate the swelling reaction and cellular infiltrate. Adoptive transfers across strain barriers showed that the TNF dependence was dictated by the origin of the transferred cells, rather than by the recipient. Experiments with intra-H-2 recombinant C57BL/10 strains indicated that TNF released by Th2 cells was correlated with the involvement of TNF in DTH2: Th2 cells from the H-2Db strains C57BL/10 and B10.A(2R) produced high amounts of bioactive TNF and mediated swelling that was partially inhibited by anti-TNF. In contrast, Th2 cells from B10.D2 and B10.A mice (H-2Dd) produced low levels of TNF, and anti-TNF had no effect on DTH2 in these strains. Our results suggest a linkage between the TNF dependence of DTH2, the capacity of Th2 cells to release TNF upon restimulation, and the donor H-2D haplotype; strain-dependent allelic expression of TNF seems to determine the involvement of this cytokine in DTH2.

Animals↗
PubMed1994

Nucleotide binding to the hydrophilic C-terminal domain of the transporter associated with antigen processing (TAP).

The gene products of tap1 and tap2 encoded in the major histocompatibility complex (MHC) class II region belong to the ATP binding cassette superfamily of transporters. They are thought to form a heterodimer for the delivery of peptides into the lumen of the endoplasmic reticulum; peptides are required for correct assembly and presentation of the MHC class I molecule peptide complex at the cell surface. To elucidate the ATP binding properties of these proteins in vitro, we expressed the hydrophilic C-terminal part of human transporter associated with antigen processing (TAP1) (nucleotide binding domain (NBD)-TAP1, amino acids 452-748) and TAP2 (NBD-TAP2, amino acids 399-686) fused to a His6 tag in Escherichia coli. The recombinant proteins accumulated exclusively in inclusion bodies and were solubilized under denaturing conditions. After purification by immobilized metal ion affinity chromatography, we were able to refold the domains for functional studies. NBD-TAP1 bound to C-8-ATP-agarose and was specifically eluted with ATP or EDTA. Photoaffinity labeling of NBD-TAP1 with the ATP analogues 8-azido-[gamma-32P]ATP and 3'-O-[(4-azido-3,5-[125I]diiodo-2-hydroxybenzoyl)-beta-alanyl]-ATP was specific. The addition of 50 microM ATP inhibited photoaffinity labeling by 8-azido-ATP down to 8% of controls. Efficiency of inhibition decreased as follows: ATP > GTP > ADP > CTP > AMP. Photolabeling of NBD-TAP2 was not observed. ATP hydrolysis by NBD-TAP1 was not detected. Until now strong but only indirect data of the TAP function existed. The described experiments demonstrate ATP binding to an isolated domain of the antigenic peptide transporter, TAP, and therefore support the theory of ATP-dependent peptide translocation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Specificity and flexibility of vitamin D signaling. Modulation of the activation of natural vitamin D response elements by thyroid hormone.

Cellular responsiveness to 1,25-dihydroxyvitamin D3 (VD) is conferred by its intracellular receptor (VDR), which belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. VDRs are known to bind to specific response elements in the promoter region of VD-regulated genes. Two types of natural VD response elements (VDREs) have been identified so far. One is bound by VDR homodimers and is found in the human osteocalcin gene promoter (DR6-type), and the other is bound by heterodimers of VDR with retinoid X receptors (RXRs) as in the mouse osteopontin promoter (DR3-type). Here, we demonstrate that VDRs directly interact in solution not only with RXR but also with retinoid acid receptors (RARs) and, interestingly, with thyroid hormone receptors (T3Rs). All three heterodimeric partners were able to enhance the in vitro DNA binding affinity of VDR as compared to VDR homodimers, but they showed different affinities for the two types of VDREs, as determined by Scatchard analysis. Moreover, functional assays showed that VDR.T3R heterodimers act differently on the two types of VDREs; on the DR3-type we observed highest induction by thyroid hormone (3,5,3'-triiodothyronine, T3) alone, whereas on a DR6-type VDRE VD and T3 together provided maximal gene activity. Our data suggest that the expression levels of VDRs, RXRs, RARs, and T3Rs and their specific ligands regulate the transcription of VD-responsive genes and illustrates the complexity of this interactive network of nuclear receptors.

Animals↗
PubMed1994

The pathology of vascular grafts.

In order to analyse the incorporation pattern of synthetic prosthesis made of Teflon and Dacron in the arterial system, 21 prostheses removed surgically and seven prostheses obtained from autopsies were examined; the duration of the implantation periods ranged from 30 min up to 10 years. Essentially the early phase of prosthetic incorporation (phase I) includes exudative inflammatory reactions as part of acute inflammatory processes. The degree of order within the tissue architecture and the mutual influence of matrix and cells in the reaction appeared to be slight. The cellular infiltrate found on the outer prosthetic surface is of local origin whereas the inner prosthetic lining contains cells of haematogenous origin. The organisation phase (phase II), which is comparable to the reparative-proliferative phase of an inflammatory reaction, showed activation of the reticulo-endothelial system together with the start of phagocytosis and a thinning of the prosthetic structures. Collagen type I and type III and fibronectin served both as a guidance and a growth tract for the cells during the cellular permeation of the prosthesis. Fibronectin and collagen type III have a special "catalytic" function. Collagen type I causes the firm anchoring of the vascular prosthesis in the periprosthetic tissue. The loss of stability of the prosthesis due to phagocytosis of fibres is balanced by the newly formed connective tissue within the wall of the vessel. The fibroblasts involved in the organisation must be derived from the flowing blood and from local mesenchymal cells. A chronic inflammatory reaction persisted during the late phase. In some cases increased proliferation of the inner mesenchymal lining of the prosthesis was observed together with regressive changes. The lack of a continuous surrounding stromal architecture on the luminal side of the vessel can be regarded as the main reason for this proliferation. Transformation of haematogenous cells into angioblasts or endothelial cells was not seen. Small endothelialised areas were only seen in the vicinity of anastomoses and following transprosthetic permeation by capillaries.

Blood Vessel Prosthesis↗
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↗
PubMed1994

Immunohistochemical characterization of the small proteoglycans decorin and proteoglycan-100 in heterotopic ossification.

Heterotopic ossification is a metabolically active process which shares several properties of orthotopic bone formation and, therefore, represents an excellent model for studying bone matrix components. Immunohistochemical methods were used to investigate the distribution pattern of the small proteoglycans decorin and proteoglycan-100 during different stages of heterotopic ossification of pressure sores of paraplegic patients. Decorin and proteoglycan-100 exhibited a substantially divergent distribution pattern. Decorin was detectable in the perivascular matrix of granulation tissue as well as in the stroma of heterotopic ossification. The ossification zone was stained most strongly. In contrast, proteoglycan-100 was predominantly detectable in fibroblasts and preosteoblasts in early areas of osteogenesis. In more mature forms of heterotopic ossification immunostaining was markedly reduced in osteoblasts and osteocytes and even absent in so-called bone-lining cells. However, at least some osteoclasts were strongly positive. These results suggest indicate that decorin and proteoglycan-100 are important components during the formal pathogenesis of heterotopic ossification. The expression of the small proteoglycans, especially of proteoglycan-100, correlates with different phases during heterotopic ossification, showing a maximum for proteoglycan-100 in matrix-forming cells in early phases of bone formation, but in osteoclasts in mature bone.

Bone and Bones↗
PubMed1994

Detection of MDM2-proto-oncogene in paraffin embedded human bronchial epithelium.

Recently a new proto-oncogene, the murine double-minute 2 (MDM2), has been described. MDM2 becomes oncogenic due to amplification and overexpression. Among other proto-oncogenes MDM2 becomes interesting since MDM2 protein can associate with both mutant and wild type p53 tumor suppressor gene products and thus inhibit p53-mediated transactivation of other genes. Loss of p53 tumor suppressor function is the most frequently observed alteration in human tumors. Immunohistochemical studies investigating the quantity of MDM2 protein in human sarcomas revealed an overexpression in 30% of the specimens. Here we describe the successful use of a monoclonal antibody (IF2) for the detection of MDM2 protein in paraffin-embedded tissue from human lung biopsies. 18 out of 44 specimens (41%), predominantly mucosal epithelial and glandular epithelial cells, stained positive for MDM2. No significant difference was observed between non-cancerogenic cells adjacent to tumor cells and those specimens without any tumor cells but altered by inflammatory processes. In general, the staining pattern was restricted not to the nuclei, but to selected subnuclear compartments, probably representing the golgi apparatus or the endoplasmatic reticulum. Our data support the hypothesis that in addition to its nuclear function of forming a complex with p53, MDM2 may also be secreted and thus have a transcellular effect.

Animals↗
PubMed1994

[Pathology of rheumatoid lung].

In the framework of rheumatic illnesses, the lungs and pleura are often observed to be involved. Dependent on the basic illness in question, conditions of the bronchoalveolar system, vessels, lymphatic system, and pleura that have developed differently inter- and intra-individually can be diagnosed in topo-regionally variable forms and combinations. In the causal pathogenesis, the initial (auto-) immunological alteration of the alveolar septa plays a role. When the monocytes, macrophages, and fibroblasts are activated, as a result of a chronic inflammatory process there is increasing reparative proliferation, which finally leads to the non-specific end stage of irreversible interstitial fibrosis. The incidence and manifestation forms of lung changes show certain differences dependent on the underlying illness (e.g., rheumatoid arthritis, systemic lupus erythematosus, progressive systemic scleroderma, dermatomyositis and polymyositis, Sjögren syndrome, and mixed connective tissue disease). In addition to vasculitis and granulomatosis of the lung, therapy-induced lung changes must also be considered in the differential diagnosis since almost all basic therapeutic agents can cause this type of lung condition. Good knowledge of the parameters from the viewpoint of possible therapeutic measures is indispensable, as is close cooperation between the treating physician and the pathologist.

Arthritis, Rheumatoid↗
PubMed1994

[Differential diagnosis of synovitis. Correlation of arthroscopic-biopsy to clinical findings].

Histological examination of 1660 biopsies (2-5 mm) of the synovial membrane of 317 patients were obtained by arthroscopic dissection; in 70% of all cases non-specific changes were revealed and in 30% specific changes. The findings included different stages of proliferation of the superficial layer, uncharacteristic inflammatory reactions of the stratum synoviale and fibrosis of the stroma, vascular proliferation and pseudopolypoid thickening of the synovial membrane. The histomorphological findings can only be interpreted reliably and a pathogenetic classification obtained, e.g., detritus synovialitis, rheumatoid arthritis or post-traumatic changes, if the arthroscopic findings conclude an exact documentation of the biopsy site and the clinical findings.

Adult↗
PubMed1994

[Malignant lymphoma and colon carcinoma 3 years after heart transplantation and immunosuppression].

Three years after heart transplantation and immunosuppressive therapy, a 66-year-old man suffered from dyspnea and showed symptoms mainly due to right heart failure. Malignant tumor cells were discovered within extensive pleural effusion. Computed tomography revealed two lesions of the liver suspicious of metastases, and recurrent blood in the stools was evident. The patient deteriorated rapidly and died 3 weeks after admission. Autopsy findings included an adenocarcinoma of the cecum (grade II) with metastases to the liver. High-grade immunoblastic non-Hodgkin's lymphoma of plasmoblastic differentiation was diagnosed, located within the mediastinal soft tissues and infiltrating the peri- and myocardium. Mesenteric lymph nodes were enlarged with histological verification of malignant lymphoma. The lymphatic tumor masses had caused considerable compression of the heart and vessels, leading to the signs of cardiac failure. The development of metastasizing colonic carcinoma and high-grade immunoblastic non-Hodgkin's lymphoma 3 years after heart transplantation and immunosuppressive therapy must be considered an unusual combination. Malignent lymphomas following heart transplantation have been described several times.

Adenocarcinoma↗