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Biomedical subjects

G König

Publications and source records attributed to G König.

At least 19 recordsLinked to original sources
PubMed1999

Synthesis and structure activity relationships of novel small molecule cathepsin D inhibitors.

Cathepsin D, a lysosomal aspartyl protease, has been implicated in the pathology of Alzheimer's disease as well as breast and ovarian cancer. A weakly active cathepsin D inhibitor was identified by high throughput screening. Subsequent optimization led to the discovery of a new class of small molecule inhibitors of this enzyme, culminating with the sulfonamide 13 (IC50 = 250 nM).

Cathepsin D↗
PubMed1999

[Lesional pattern and clinical symptoms in rheumatoid flexor tendon disease].

OBJECTIVES: To assess complaints and clinical findings of rheumatoid hand flexor tendon disease in relationship to the anatomical site and the type of lesion in order to improve the diagnosis and enable early operative treatment with preservation of hand function. METHODS: 123 patients of the hands of 78 patients (66 female, 12 male) with a mean age of 57 years were analyzed retrospectively. Preoperative complaints and clinical findings were recorded according to their frequency. Three different types of flexor tendon disease were distinguished intraoperatively: isolated tenosynovitis, tenosynovitis with tendon lesion, and complete tendon rupture. RESULTS: 188 tendons showed isolated synovitis, 208 had a tendon lesion with synovitis, and 30 tendons a rupture. Tenosynovitis was found in the palm and wrist mainly. The 2nd, 3rd and 4th finger were most frequently involved. 81 tendon adhesions, 12 nodules, 63 superficial lesions and 52 defects were detected. These lesions were found mainly in the palm and the second and third ray. The profundus tendon was affected most often. Ruptures were detected most often in the wrist caused by bony spurs and tenosynovitis. A clinical difference between tenosynovitis with and without tendon lesion was not found. However, complaints and findings were different in the digit, palm, wrist and forearm. Ruptures had characteristic clinical findings. CONCLUSIONS: Rheumatoid flexor tendon disease is common. Tenosynovitis is often accompanied by tendon lesions. Ruptures occur as disease progresses. Exact assessment of complaints and clinical findings is mandatory to diagnose and localize flexor tendon disease. Early operative intervention helps to preserve the function of the hand.

Adult↗
PubMed1998

Preventable causative factors leading to hospital admission with decompensated heart failure.

OBJECTIVE: To determine the distribution and importance of various factors, especially the preventable ones, that contribute to cardiac decompensation and subsequent hospital admission for heart failure. METHODS: During a one year period patients were prospectively recruited and evaluated during their hospital stay by means of a structured personal interview by trained medical staff and through clinical examination and laboratory investigation. SETTING: The cardiological department at a teaching affiliated general community hospital in Berlin, Germany. PATIENTS: Consecutive sample of 179 patients admitted to hospital with acute decompensation of pre-existing heart failure. MAIN OUTCOME MEASURES: Proportional distribution of causative factors leading to hospital admission for heart failure; relative importance of preventable factors; details of patient compliance with diet and medication, and knowledge about medication. RESULTS: Mean (SD) age was 75.4 (9.9) years. Potential causative factors for decompensated heart failure were identified in 85.5% of patients. Lack of adherence to the medical regimen was the most commonly identified factor and was regarded as the cause of the cardiac decompensation in 41.9% of cases. Non-compliance with drugs was found in 23.5% of patients. Other factors related to hospital admission were coronary ischaemia (13.4%), cardiac arrhythmias (6.1%), uncontrolled hypertension (5.6%), and inadequate preadmission treatment (12.3%). In all, 54.2% of admissions could be regarded as preventable. CONCLUSIONS: Many hospital admissions for decompensation of chronic heart failure in patients at a district hospital in Berlin are preventable. Measures are necessary to improve this situation and evaluation of programmes that include patient education, patient follow up, and physician training is needed.

Aged↗
PubMed1997

Bcl-xl-specific antibody labels activated microglia associated with Alzheimer's disease and other pathological states.

This report describes the production of a monoclonal antibody raised against Bcl-xl, and includes an initial study of bcl-xl expression in neuropathology including Alzheimer's disease (AD). Bcl-xl is a potent apoptotic inhibitor and is known to be the predominant Bcl-x isoform in brain. To examine the expression of bcl-xl in aged brain and neurodegenerative disease, we raised a Bcl-xl-specific monoclonal antibody. In aged human brain, the highest bcl-xl expression was observed in cerebellum. By immunohistochemistry, significant bcl-xl expression was detected in reactive microglia of patients with AD and other neurological diseases such as progressive supranuclear palsy. Bcl-xl-positive microglia frequently colocalized with beta-amyloid plaques in AD and with activated astrocytes in non-AD and AD brains, suggesting a general role for Bcl-xl in regions of pathology. High levels of Bcl-xl protein might render microglia more resistant to cytotoxic environments such as areas of neurodegeneration and astrogliosis.

Aging↗
PubMed1997

Blastocystis hominis in animals: incidence of four serogroups.

In toto, 520 faecal samples from mammals, birds, reptiles, amphibians, fish, and snails were investigated (see Table 1). 91 strains of Blastocystis hominis could be isolated by culture. However, only 48 of them were suitable for axenisation. 96 percent of samples belonged to four serogroups detected in humans but two strains, one from a pig and another from a duck, could not be classified, suggesting the existence of one or two further serogroups. While humans showed mainly serogroups I and II, pigs harboured serogroups III and IV. Four serogroups were isolated from monkeys. The question whether the genus Blastocystis consists of one or more species is discussed.

Amphibians↗
PubMed1996

Development and characterization of a monoclonal antibody 369.2B specific for the carboxyl-terminus of the beta A4 peptide.

The beta-amyloid deposits in Alzheimer's diseased (AD) brain are made up mainly of beta A4 peptides which show both N- and C-terminal heterogeneity. The predominant C-terminal species, identified by peptide sequencing of purified beta-amyloid, end either at position 40 or 42 of the beta A4 peptide. The distribution of these two beta A4 species in postmortem tissue as well as their generation in vitro could not be addressed previously due to the lack of specific antibodies that could differentiate them. This report describes the generation of a highly specific monoclonal antibody, MAb 369.2B which was raised against a synthetic peptide consisting of the C-terminus of the 1-42 beta A4 species. MAb 369.2B does not recognize the shorter beta A4 species 1-40 in solution or in solid phase. Furthermore, both beta A4 1-40 and 1-43 were unable to absorb out the antibody when used immunocytochemically. The regional distribution of MAb 369.2B immunoreactivity in AD and non-AD brain samples were compared to MAb 286.8A, an antibody raised against the N-terminal region of beta A4. Overall, the staining patterns were very similar. In AD cases with extreme vascular involvement, the N-terminal (MAb 286.8A) antibody was more likely to label the vascular basement membrane of affected vessels, and to label them more uniformly. In addition, preliminary quantitative analyses revealed that the C-terminal antibody labeled fewer, larger plaques than the N-terminal antibody. Qualitative analyses revealed that these smaller plaques were typically subregions of the larger plaques. The data corroborate the biochemical findings of N-terminal raggedness in beta A4 plaques. Further studies are required to explain this differential pattern of deposition.

Aged↗
PubMed1996

Immunohistochemical detection of factor XIIIa and factor XIIIs in synovial membranes of patients with rheumatoid arthritis or osteoarthritis.

In spite of differences in etiology, RA and OA lead to astonishingly similar synovitic alterations. Fibroblastic transformation of the synovial membrane and an increase in monocytes constitute a rare but highly characteristic feature of RA. Monocytes synthesize factor (F) XIII, implying that FXIII (a and s) in synovial tissue might help to differentiate between RA and OA. Biopsies were obtained at open surgery from 98 unselected patients with the clinical diagnosis of RA (n = 54) or OA (n = 44). In a three-stage (ABC) immunoperoxidase technique, polyclonal antisera against factor XIIIa and factor XIIIs were investigated. Compared to OA sections. RA synovium showed more FXIIIa-positive cells-monocytes, fibrocytes, fibroblasts and synovial lining cells. In the subsynovial layer, band-like structure of FXIIIa-stained cells was observed in 27.8% of the RA patients, but in only one OA specimen. Higher proportions of FXIIIa-positive monocytes, macrophages, histiocytes and fibroblasts, as well as positive Langhans giant cells and vascular wall regions (except endothelial cells), were observed in RA. OA specimens revealed more intense FXIIIa labeling of these cells with a lower percentage of stained cells. Overall, labeling with FXIIIs antibody resulted in less intense staining. In conclusion, distinction between synovitis caused by RA and synovitis due to OA is possible, as the former show higher numbers of FXIIIa-positive cells, including monocytes, fibroblasts, fibrocytes and synovial lining cells. Further more, RA tissue is stained less intensely than OA tissue. There is evidence for continuous excretion of FXIII in the synovial membrane by the above-mentioned cell systems.

Adolescent↗
PubMed1996

Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung.

Fibrosing alveolitis (FA) is a frequent and often fatal complication of systemic sclerosis (SSC). Alveolar inflammation has been recognized as a primary event in the pulmonary manifestation of SSC. To evaluate the significance of the alveolitis in SSC, we performed bronchoalveolar lavage (BAL) and correlated the generated data with changes in lung function over time. Seventy nine SSC patients with pulmonary involvement were followed for 56.8 +/- 3.1 wk (mean +/- SEM) with a repeat lung function test at the end of the follow-up period. During follow-up, 38 patients were treated with a systemic immunosuppressive regimen. For evaluation, patients were assigned to two groups according to whether their BAL cell differential was normal (inactive BAL) or abnormal (active BAL: i.e., polymorphonuclear leukocytes > 5% and/or lymphocytes > 15%). Active BAL was associated with more severe lung function impairment than was inactive BAL, and patients with active BAL deteriorated during follow-up if untreated. In contrast, treated patients with active BAL stabilized or improved. In summary, active alveolitis as characterized by BAL is associated with progressive pulmonary disease in SSC patients, and a significant positive effect of immunosuppressive therapy on the course of pulmonary disease was observed in patients with active BAL.

Bronchoalveolar Lavage↗
PubMed1995

The effect of the JE (MCP-1) gene, which encodes monocyte chemoattractant protein-1, on the growth of HeLa cells and derived somatic-cell hybrids in nude mice.

To investigate the effect of tumor-associated macrophages on the in vivo growth properties of cervical carcinoma cells, tumorigenic human papilloma virus (HPV) 18-positive HeLa cells were transfected with an expression vector harboring the cDNA for the macrophage chemoattractant protein-1 JE (MCP-1). Although the endogenous gene is present and not structurally rearranged, its expression seems to be negatively affected by a still unknown mechanism. Inoculation of JE (MCP-1)-negative HeLa cells into nude mice led to rapidly growing tumors, where macrophage infiltration into the inner tumor mass was not detectable immunohistochemically. The activity that attracted mononuclear cells under both in vitro and in vivo condition was reconstituted in HeLa cells after transfection with the JE (MCP-1) expression vector. Heterotransplantation of those cells into immunocompromised animals resulted in significant growth retardation that was accompanied by a strong infiltration of macrophages. On the other hand, in vivo selection of nonmalignant hybrids made between wild-type HeLa cells and normal human fibroblasts in nude mice resulted in tumorigenic segregants 4 mo after inoculation into the animals. Monitoring JE (MCP-1) expression directly within those nodules, we found that transcription was either absent or only weakly detectable. Recultivation of JE (MCP-1)-positive tissue grafts under in vitro conditions revealed that the gene was only marginally inducible by tumor necrosis factor-alpha, a cytokine that normally induces a very strong activation of transcription in nontumorigenic cells. These findings suggest that functional JE (MCP-1) expression and in turn activated macrophages may play a pivotal role in controlling the proliferation rate of HPV-positive cells in vivo.

Animals↗
PubMed1995

Technetium-99m mercaptoacetyltriglycine clearance: reference values for infants and children.

Six hundred and thirty-nine clearance studies performed in children aged 7 days to 19 years utilizing technetium-99m mercaptoacetyltriglycine (MAG 3) were retrospectively analysed. Standardized conditions for the investigation included: parenteral hydration (60 ml/hxm2 body surface) in addition to normal oral fluid intake, weight-related dose of 99mTc-MAG 3 (1 MBq/kg body weight, minimum 15 MBq) and calculation of clearance according to Bubeck et al. Of the 513 children, 169 included in this analysis could be classified as "normal" with regard to their renal function. Normal kidney function was judged by the following criteria: normal GFR for age, normal tubular function (absence of proteinuria and glucosuria), normal renal parenchyma (on ultrasonography, MAG 3 scan and intravenous pyelography), absence of significant obstruction and gross reflux (>grade I), no single kidney and no difference in split renal function >20%. Results showed increasing MAG 3 clearance values for infants during the first months of life, reaching the normal range for older children and adults between 7 and 12 months.

Adolescent↗
PubMed1994

Processing of the pre-beta-amyloid protein by cathepsin D is enhanced by a familial Alzheimer's disease mutation.

A major pre-beta-amyloid protein695 (APP695) processing activity from Alzheimer's disease brain extracts was identified and found to be indistinguishable from the activity of cathepsin D.APP695 processing activity cleaved APP695 into a series of fragments that reacted on immunoblots to a monoclonal antibody (C286.8a) against beta-amyloid-(1-7)-peptide and cleaved N-dansyl-APP-(591-601)-amide at the Glu-Val and Met-Asp bonds. Fragments of 5.5 kDa and 10-12 kDa were formed from the cleavage of APP695 by cathepsin D at the Glu593-Val594 bond, and had the same N-terminus as a minor form of beta-amyloid released by cells. The Lys595-->Asn and Met596-->Leu substitutions found in a pedigree of familial Alzheimer's disease, increased the cathepsin D-catalyzed rate of accumulation of 5.5 kDa and 10-12 kDa C286.8a-reactive fragments 5-10fold. This substitution also increased the rate of N-dansyl-APP-(591-601)-amide cleavage at the Xaa-Asp bond by up to 41-fold. These observations suggest a role of cathepsin D in beta-amyloid formation under certain circumstances.

Alzheimer Disease↗
PubMed1994

Short-term and long-term effects of serial bronchoalveolar lavages in a nonhuman primate model.

Bronchoalveolar lavage (BAL) has gained widespread use as a tool for investigating human lung diseases. In certain cases, it can be useful to obtain BAL material in a serial manner. There is convincing evidence from experimental and clinical studies that BAL can cause influx of neutrophils into the bronchoalveolar space. However, conflicting data have been reported on whether this side effect of BAL also affects previously nonlavaged lung areas. In addition, there is little information available on whether multiple repetitive BAL procedures cause damage to lung tissue. To reexamine the short-term effects of serial BAL procedures, the left lung of 10 cynomolgus monkeys was lavaged with five 20-ml aliquots of saline four times at 24-h intervals (Group A). 72 h after the initial BAL, the right lung was lavaged as a control. The percentage of neutrophils increased significantly (p < 0.05), with the greatest effect seen at 48 h (30.7 +/- 5.8 versus 0.8 +/- 0.3%, mean +/- SEM). No significant changes were observed in the control BAL of the right lung at 72 h. A multidisciplinary approach was used to assess the long-term effects of multiple BAL procedures. BAL was performed 14 times over 26 mo at 2-mo intervals (Group B, n = 5). The right lung was lavaged as a control 25 mo after the initial BAL. In addition to standard cellular BAL parameters, the concentrations of fibronectin, procollagen III amino-terminal peptide-related antigen, total phospholipids, and lactate dehydrogenase activity were measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗