Cough, dyspnoea and purulent sputum in a 66-yr-old nonsmoking female.
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Aged↗
Biomedical subjects
K M Müller
Publications and source records attributed to K M Müller.
Increasing dose of methylprednisolone pulse therapy treats desquamative interstitial pneumonia in a child.
A 10 yr old male with hypoxaemia, progressive infiltration on the chest radiograph and biopsy-proven desquamative interstitial pneumonia was treated with daily oral prednisolone for 6 months. Intravenous methylprednisolone pulses were concomitantly administered in doses averaging 10 mg x kg body weight(-1) on three consecutive days every 4-6 weeks. After 6 months improvement could be noted and oral steroids were stopped, while pulse therapy continued. Three months later, when seven pulses had been administered, a relapse occurred and the clinical status deteriorated. Instead of reinstating daily systemic steroids, the dose of methylprednisolone pulses was increased to 20 mg x kg body weight(-1) i.v. given on three consecutive days and repeat pulses every 4 weeks. This was followed by continuous improvement. After 24 months corticosteroid pulses were terminated. Normal lung function, serum lactate dehydrogenase, blood gases upon exertion and regular development was achieved. During the course of treatment, the child has grown 10 cm. It is concluded that the effect of corticosteroid pulse therapy on interstitial lung disease in childhood is dose-dependent and that the dose can be adjusted to the effect observed.
Anti-Inflammatory Agents↗
[Aspiration pneumonia caused by vertebrae of a dove in a 39 year old patient with Down syndrome].
Undetected foreign body aspiration is a well-known problem not only in children and patients with predisposing conditions like mental retardation, seizures or brain tumours, but also in healthy subjects. The clinical signs are quite different. Haemoptysis, cough, recurrent or chronic penumonia and bronchitis may occur. These symptoms are often accompanied by fever, weight loss and night sweat. Atelectasis, respiratory distress or death have been described. We demonstrate the case of a 39-year old man with Down syndrome who was transferred to our hospital because of pneumonia in the left lower lobe that had been lasting for about two months. It had been resistant to several antibiotic regimens. Computerised tomography led to the suspicion of a bronchial carcinoma with poststenotic infiltration of the lower lobe. Fibreoptic bronchoscopy and biopsy confirmed the diagnosis of a foreign body in the distal part of the left main bronchus. After two weeks of treatment with ciprofloxacin regression of the acute inflammation occurred. During a second bronchoscopy we could extract the foreign body (a 1 x 1.7 cm vertebra of a dove). It is concluded that undetected foreign body aspiration can occur in various clinical settings and fibreoptic bronchoscopy is a suitable approach providing an exact diagnosis.
Adult↗
German uranium miner study--historical background and available histopathological material.
Mining activities in the former German Democratic Republic were documented as early as 1168 in the ore mountains (Erzgebirge) of Saxony. Silver, bismuth, cobalt, nickel and tungsten were mined from then up to the end of the 19th century. After the Second World War, the Soviet Occupation Authorities reopened the old silver mines in Saxony to mine uranium for the Soviet nuclear industry. About 400, 000 workers produced a total of 220,000 tons of uranium during the years 1946 to 1990. After the reunification of Germany, the archive of the Institute of Pathology of the mining area was opened for research. It contains protocols of 28,975 autopsy cases and about 400,000 slides collected from 1957 to 1992, about 66,000 tissue blocks, and 238 whole lungs. From the autopsy cases, 17,466 could be identified as workers of the uranium mining company. The remainder of the cases were in the population of the mining area. A comparison of the frequencies of malignancies of male workers older than 15 years with those of the population of the mining area for the years 1957 to 1989 demonstrates a significantly higher percentage of lung cancer among the uranium miners. There was no significant difference for other solid cancers and leukemias.
Cause of Death↗
German uranium miner study--pathological and molecular genetic findings. German Uranium Miner Study, Research Group Pathology.
Uranium miners of the former Wismut company in Germany form the largest cohort of workers exposed to (222)Rn and dust in the world. The German Uranium Miner Study, Research Group Pathology, is evaluating the central pathology archive of the Wismut company. The main tasks of our study are pathological-anatomical and molecular genetic investigations of 28,975 autopsy cases and the evaluation of mining pollutants in the lungs by neutron activation analysis. As part of an observer agreement study, lung tumors are classified according to the WHO/IASLC classification and nontumorigenic lung disorders are registered. Lung tumors were analyzed for the presence of a proposed radon-specific mutation in the TP53 gene (formerly known as p53). Interim results are: (a) In the years 1957 to 1965, a high rate (69%) of small cell carcinomas was found which had declined to 34% by 1990. (b) The percentage of the deceased who suffered from silicosis is not higher in the group of lung tumors than in other tumor groups or the nontumor group. (c) The hypothesis of a radon-characteristic hotspot mutation in the TP53 tumor suppressor gene is not supported by our investigations. (d) Neutron activation analysis demonstrates that uranium, arsenic, chromium, cobalt and antimony can be found in tissue samples from the miners even when they had stopped working more than 20 years before death.
Genes, p53↗
[New aspects of lung tumor pathology].
The "new" 3rd WHO classification of lung tumors 1999 is described in nine groups of malignant broncho-pulmonary neoplasias. In recent years, our knowledge of the quite variable biology of tumors has been significantly increased by the use of immunohistochemical methods and molecular biology. These methods facilitated an improved qualitative and quantitative characterization of heterogeneously differentiated long tumors (e.g., neuroendokrine/blastomatoid portions etc.). The detection of genetic alterations of tumor suppressors (Rb/p53/FIHT/TGF beta R-2 etc.) and oncogenes (e.g., myc/fos/blc-2/ras/erbB etc.) is, at the moment, only of scientific interest. The genetic heterogeneity of tumors is emphasized by results obtained with the comparative genomic hybridization (CGH). In small-cell carcinomas of the lung more than seven variable chromosomal alterations--especially loss of genetic material in the regions 3p, 10q, and 4q--can be detected in a tumor. Adenocarcinomas show losses of genetic material on chromosomes 9 and 19, and/or gains on chromosome 1. Squamous cell carcinomas frequently exhibit losses on chromosome 2 and gains on chromosome 3. A connection between the detected genetic anomalies and histomorphological growth patterns can not be seen. At the present time, the validity of individual findings for a correlation between operability, tumor progress, chemotherapy and prognosis is not sufficiently elucidated by investigations nor secured. The histopathological, immunohistochemical, and genetic characterization of specimens of, mostly advanced, lung tumors that show variable phenotypes in biopsies of just 1-2 mm does not allow conclusions regarding causal factors (e.g., smoking, radon, asbestos etc.) or further progress of the disease. Therapeutical approach and the still unfavourable prognosis remain essentially, as in the last thirty years, to be characterized by TNM and performance status of the individual patient and, to a lesser extent, by the main histological type of tumor.
Genes, Tumor Suppressor↗
Factors influencing the dimer to monomer transition of an antibody single-chain Fv fragment.
Antibody single-chain Fv (scFv) fragments are able to form dimers under certain conditions, and the extent of dimerization appears to depend on linker length, antibody sequence, and external factors. We analyzed the factors influencing dimer-monomer equilibrium as well as the rate of interconversion, using the scFv McPC603 as a model system. In this molecule, the stability of the VH-VL interaction can be conveniently varied by adjusting the ionic strength (because of its influence on the hydrophobic effect), by pH (presumably because of the presence of titratable groups in the interface), and by the presence or absence of the antigen phosphorylcholine, which can be rapidly removed due to its very fast off-rate. It was found that the monomer is the thermodynamically stable form with linkers of 15 and 25 amino acids length under all conditions tested (35 microM or less). The dimer is initially formed in periplasmic expression, presumably by domain swapping, and can be trapped by all factors which stabilize the VH-VL interface, such as the presence of the antigen, high ionic strength, and pH below 7.5. Under all other conditions, it converts to the monomer. Predominantly monomer is obtained during in vitro folding. Monomer is stabilized against dimerization at very high concentrations by the same factors which stabilize the VH-VL interaction. These results should be helpful in producing molecules with defined oligomerization states.
Animals↗
Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common beta chain in children with acute myeloid leukemia associated with respiratory failure.
Deficiency of the granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin-3 (IL-3)/IL-5 receptors common beta chain (betac) is a cause of fatal respiratory failure. betac deficiency manifests as pulmonary alveolar proteinosis (PAP). PAP has heterogenous etiologies that may be genetic or aquired. Some cases of PAP have been reported to be associated with hematologic malignancies such as acute myeloid leukemia (AML). In mice, the PAP phenotype was generated by targeted deletion of the gene for betac and can be treated by transplantation of wild-type bone marrow into betac -/- mice. Thus, our findings in betac -/- mice provide evidence for a causal relationship between the lung disease and the hematopoietic system. We describe here expression defects of betac or betac plus GM-CSF receptor alpha chain (GM-CSFR alpha) in 3 pediatric patients with AML and PAP symptoms. All of the patients' leukemic cells failed to express normal levels of betac. The leukemic cells of patients no. 2 and 3 additionally lacked the expression of GM-CSFR alpha, as shown by flow cytometry. Strikingly reduced or absent function of betac was demonstrated in clonogenic progenitor assays with absent colony-forming unit (CFU) growth after GM-CSF or IL-3 stimulation. The response to growth factors acting via a growth factor receptor distinct from the GM-CSF/IL-3/IL-5 system (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was normal. After antileukemic treatment, the pulmonary symptoms resolved and betac or betac plus GM-CSFR alpha expression was normal. Our findings provide evidence that a defect in the expression of betac or betac plus GM-CSFR alpha on AML blasts can be associated with respiratory failure in patients with AML.
Acute Disease↗
Model and simulation of multivalent binding to fixed ligands.
A model to quantitate the principal aspects of multivalent binding was developed. It describes the random distribution of an immobilized component (the ligand) taking into account local densities. The binding of a bivalent molecule (the analyte) to the ligand is described as occurring in two steps, the second of which is driven by the local concentration of neighboring ligands. The model was used to simulate the kinetics of bivalent binding in surface plasmon resonance biosensors such as BIAcore. The simulations are compared with measured data. The simulation quantitates the influence of bivalent binding on the sensor signal, as a function of ligand density, analyte concentration, and binding site distance. Such simulations will be helpful for understanding and designing experiments to assess avidity effects as well as for developing molecules with high avidity. Furthermore, they help to analyze the inherent complexity in seemingly simple sensorgrams.
Antibody Affinity↗
A dimeric bispecific miniantibody combines two specificities with avidity.
Bispecific antibodies extend the capabilities of nature and might be applied in immunotherapy and biotechnology. By fusing the gene of a single-chain Fv (scFv) fragment to a helical dimerization domain, followed by a second scFv fragment of different specificity, we were able to express a functional protein in E. coli, which is bispecific and has two valencies for each specificity. The dimeric bispecific (DiBi) miniantibody preserves the natural avidity of antibodies in a very small-sized molecule of only 120 kDa. The generality of the principle was shown with a scFv fragment binding the EGF-receptor (named scFv 425) in three combinations with scFv fragments either directed against CD2 (ACID2.M1), phosphorylcholine (McPC603) or fluorescein (FITC-E2). Binding was analyzed by sandwich surface plasmon resonance biosensor (BIAcore) measurements.
Amino Acid Sequence↗
Tandem immobilized metal-ion affinity chromatography/immunoaffinity purification of His-tagged proteins--evaluation of two anti-His-tag monoclonal antibodies.
A tag comprising four to six histidines genetically fused to the protein of interest (His-tag) has been widely used to purify proteins by immobilized metal-ion affinity chromatography (IMAC). Here we report the utilization of the same tag twice in series, first for IMAC and subsequently for immunoaffinity purification. Both steps are based on completely different physical principles and can therefore remove different contaminants. Two anti-His-tag antibodies (3D5 and PentaHis) were characterized for their binding and elution properties using the BIAcore surface plasmon resonance biosensor. The dissociation constant of the PentaHis antibody was determined to be 1 x 10(-8) M and for the 3D5 antibody 3.4 x 10(-7) M at pH 7.4. Imidazole in the sample did interfere with binding, whereas chelating agents such as EDTA and high salt did not. The antibody 3D5 was coupled to a column matrix and used for a coupled two-step purification, in which the IMAC column is eluted with EDTA and the eluent is loaded directly on the immunoaffinity column. This method may constitute a very general procedure to purify proteins to near homogeneity without the need to tailor conditions individually, and it may thus be very attractive for high-throughput screening programs and for developing general protocols for clinical grade material.
Amino Acid Sequence↗
The first constant domain (C(H)1 and C(L)) of an antibody used as heterodimerization domain for bispecific miniantibodies.
Bispecific miniantibodies were constructed by genetically fusing the C(H)1 domain of an IgG1 to the C-terminus of a single-chain Fv fragment (scFv-425), specific for the EGF receptor, and fusing the C(L) domain of a kappa light chain to the C-terminus of a scFv specific for CD2 (scFv-M1). An efficient dicistronic gene arrangement for functional expression in Escherichia coli was constructed. Immunoblots demonstrated correct domain assembly and the formation of the natural C(H)1-C(L) disulfide bridge. Gel filtration confirmed the correct size, sandwich ELISAs demonstrated bispecific functionality, and SPR biosensor measurements determined binding to EGF-R in comparison to bivalent constructs. Bispecific anti-EGF-R/anti-CD2 miniantibodies are candidates for the immunotherapy of cancer.
Amino Acid Sequence↗
Lung cancer risk and welding: results from a case-control study in Germany.
In a case-control study, 839 male hospital-based cases of primary lung cancer and the same number of population-based controls--matched by sex, age, and region of residence--were personally interviewed for their job and smoking histories. The study allows to quantify occupational asbestos exposure that was thought to be a welding-associated risk: 6% of cases and 2% of controls were classified into the occupational category "welders or burners# (odds ratio [OR] = 2.65). This OR was reduced to 1.93 (95% confidence limit [CL]: 1.03-3.61) after adjustment for smoking and asbestos. In contrast, a history of welding in general for at least a half-year is 28% among cases and 23% among controls, yielding an OR of 1.25 (95% CL: 0.94-1.65) after adjustment for both confounders. The OR of welding for more than 6,000 hr is 1.45 (95% CL = 1.04-2.02), reduced to 1.10 after adjustment for smoking and asbestos. Oxyacetylene welding for more than 6,000 hr lifelong is associated with an OR of 1.86 (95% CL = 1.01-3.43) reduced to 1.46 (n.s.) after adjustment for smoking and asbestos. The risk of oxyacetylene welding seems to be highest for oat cell carcinoma with an adjusted OR for ever-exposure of 1.46 (95% CL = 0.69-3.10). Therefore, the present study supports the hypothesis that some, but not all, of the excess risk of welders observed in the literature may be due to a history of cigarette smoking and occupational asbestos exposure. The elevated risk for the subgroup of employees in the aircraft industry reported for the midterm evaluation of the study still prevails, though no longer statistically significant. However, employees in this industry who ever welded show an OR of 2.29 (95% CL = 1.19-4.42) after adjustment for smoking and asbestos.
Adult↗
Chelidonium majus: a rare reason for severe hepatotoxic reaction.
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Journal Article↗
[Placentoid malformation of the lung].
The differential diagnosis of bullous and cystiform lung alterations comprises a relatively calculable number of various diseases, in which the most important are rare cystic tumors and congenial malformations, such as adenomatoid cystic malformation. We report on a rare clinical picture. In this case, the clinical diagnosis of localized unilateral emphysema caused by local displacement and with subsequent complications had led to "bullectomies" and pneumonectomy. Macroscopically, spongiform solid areas in association with areas of physaliform transformation were seen, corresponding histomorphologically to villous, placentalike formations. The "villous stroma" revealed focally regressive alterations, fatty islets and leiomyomatous areas. So far, the pathogenesis of this lesion, described as "placentoid malformation" due to its pathognomonic histological appearance, remains unclear. In contradiction to the much discussed hypothesis that this lesion may develop from pre-existing lung emphysema, our results suggest that this may be an independent lesion, possibly congenital hamartous malformation with self-developing progression. The clinically predominant emphysematic alterations are considered to be caused by a valve mechanism due to unphysiological traction forces, the lymphatic pathways regularly found in the border areas towards the original lung tissue, possibly playing an important etiological part.
Adult↗
[Pleural reaction pattern after talc pleurodesis].
Because of the rising importance of talcum pleurodesis in the therapeutic management of malignant and benign pleural effusions in Germany, pleural samples after talcum pleurodesis were compared to microscopic, immunohistochemical, and scanning electron microscopy findings after Tetracyclin and Novantron pleurodesis in 24 patients up to 18 months after intrapleural therapy. The histomorphological findings after talcum pleurodesis show an early phase of up to 4 weeks, characterized by the presence of talcum-containing granulation tissue with giant-cell foreign-body reaction, and a subsequent late phase with organization of the granulation tissue and connective tissue formation and obliteration of the pleura sheets. The resulting characteristic linear talcum zone in the pleural connective tissue is missing in cases with tumorous infiltration of the pleura. Continuous fibroblast activation, e.g., by macrophage or foreign-body giant-cell-released mediators, seems to be the decisive factor in the fibrosing process. No therapy-related tumor growth alterations could be demonstrated.
Follow-Up Studies↗
[Myositis proliferans: a pseudosarcomatous lesion in soft tissue].
Myositis proliferans is a reactive, intramuscular soft tissue disease characterized by fibroblast and myofibroblast proliferation, showing similarities to the phase-like development seen in the general pathology of wound healing and hypertrophic scars. Immunohistochemically, a combined expression of vimentin and alpha-sm actin is seen in the spindle-shaped cell formations. The decisive histological preparations is supported by immunohistochemical techniques, especially in the differentiation from sarcoma. If a definite diagnosis is made, incomplete excision may suffice.
Actins↗
[Bronchopulmonary preneoplasia. Diagnosis using LIFE system and pathology panel of the European Early Lung Cancer Study Group (EELCSG)].
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Bronchial Neoplasms↗