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Biomedical subjects

F Weber

Publications and source records attributed to F Weber.

At least 163 records · Page 9Linked to original sources
PubMed1995

Recovery by splenectomy in patients with relapsed thrombotic thrombocytopenic purpura and treatment failure to plasma exchange.

Thrombotic thrombocytopenic purpura is a serious, potentially fatal disease, and conventional plasma exchange appears to be the best initial therapy. Following this approach, survival in 90% of patients is available. In patients with relapse and treatment failure to plasma exchange, splenectomy is recommended. The rationale for splenectomy and the relevant pathomechanisms involved are obscure. In the present paper two patients with TTP are reported who first responded to conventional treatment strategies but later relapsed. Resumption of previous therapy was not able to continuously maintain normal platelet levels. Thus, splenectomy was considered to be indicated. In contrast to former reports, repeated cycles of conventional plasma exchanges were performed until a transient steady state (12 hrs) of the platelet counts occurred. Then splenectomy was performed immediately and, in contrast to former reports, no reinstitution of treatment was necessary after splenectomy. In addition no postoperative complications (bleeding, neurologic impairment) have been observed. This favorable outcome might be due to the strategy of repeated conventional plasma exchange procedures. The follow-up shows now event free disease for 2 years.

Adrenal Cortex Hormones↗
PubMed1995

Acute cholecystitis after autologous bone marrow transplantation for acute myeloid leukemia.

BACKGROUND: We investigated the incidence of acute cholecystitis in patients with acute myeloid leukemia (AML) undergoing autologous bone marrow transplantation in complete remission. PATIENTS AND METHODS: Thirty-five consecutive acute myeloid leukemia patients were given oral busulfan 4 mg/kg/day for 4 days and IV cyclophosphamide 50 mg/kg/day for 4 days followed by reinfusion of autologous bone marrow purged with 4-hydroperoxycyclophosphamide. RESULTS: Five of 35 patients developed clinical evidence of acute cholecystitis, manifested by fever, nausea, vomiting, right-upper-quadrant pain, and abdominal guarding, within 18 days after autologous bone marrow infusion. Ultrasonography and CT scans of the abdomen supported the diagnosis of cholecystitis. Three patients underwent cholecystectomy, while two patients were treated medically; all recovered uneventfully. A review of 338 consecutive bone marrow transplant patients who underwent marrow transplantation for a variety of diseases and were treated with other high-dose cytotoxic regimens during the same time period revealed significantly fewer cases of cholecystitis, i.e. two, (p < 0.0001). CONCLUSIONS: Five of 35 AML patients undergoing autologous bone marrow transplant using busulfan, cyclophosphamide, and purged bone marrow developed evidence of acute cholecystitis. These findings suggest that the busulfan/cyclophosphamide preparative regimen may be associated with acute cholecystitis. The true incidence of this injury and its pathogenesis remain to be elucidated.

Acute Disease↗
PubMed1995

The role of autoimmune T lymphocytes in the pathogenesis of multiple sclerosis.

Autoimmune T cells play a key role as regulators and effectors of autoimmune disease. In multiple sclerosis (MS), activated T cells specific for myelin components or other locally expressed autoantigens enter the CNS and recognize their antigen(s) on local antigen-presenting cells. After local stimulation, the T cells produce a plethora of cytokines and inflammatory mediators that have profound effects on the local cellular environment, induce and recruit additional inflammatory cells, and contribute to myelin damage. An increasingly detailed knowledge of these processes will greatly facilitate the development of new immunotherapies. This article focuses on the role of T cells in MS. We provide a brief overview of the principles of T-cell immunology, discuss the experimental techniques available for studying T cells, address the role of T cells in the pathogenesis of MS, and highlight modern concepts for immunotherapy.

Amino Acid Sequence↗
PubMed1995

Bronchial carcinoid tumors of the lung.

The bronchial carcinoid tumor is an uncommon primary pulmonary malignancy. Biologically, it is of neuroendocrine origin. Optimal treatment consists of resection of all tumor with conservation of pulmonary tissue. Ten consecutive resections of the bronchial carcinoid are reviewed.

Adult↗
PubMed1995

[Pathogenesis and therapy of multiple sclerosis. The role of cytokines].

Multiple sclerosis (MS) is probably caused by multiple factors, but there is evidence that an autoimmunological process is relevant for the pathogenesis. Cytokines can operate in different ways in MS and the animal model "experimental allergic encephalomyelitis (EAE). "Interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interleukin-1 (IL-1) and IL-2 are important inflammation mediators within the MS plaque, whereas IFN-alpha, IFN-beta, transforming-growth-factor-beta (TGF-beta) and IL-10 exert mainly immunosuppressive functions. Application of these anti-inflammatory cytokines and the selective block of pro-inflammatory cytokines are promising new therapeutic strategies with fewer side effects than the commonly used cytostatic drugs.

Animals↗
PubMed1994

Purification and amino-terminal sequencing of the high affinity phenylalkylamine Ca2+ antagonist binding protein from guinea pig liver endoplasmic reticulum.

A high affinity phenylalkylamine Ca2+ antagonist binding polypeptide (Moebius, F. F., Burrows, G. G., Striessnig, J., and Glossmann, H. (1993) Mol. Pharmacol. 43, 139-148) was purified to homogeneity from the endoplasmic reticulum of guinea pig liver with the aid of [3H]emopamil, an antiischemic agent, and [3H]azidopamil, a photoaffinity label. The purified protein retained its high affinity for the antiischemic drugs emopamil (Kd = 4 nM), opipramol (IC50 = 15 nM), trifluoperazine (IC50 = 2 nM), and for Zn2+ (IC50 = 2 microM). Ferguson plots revealed a molecular mass of 27.2 kDa. Partial amino acid sequence information was obtained by Edman degradation and revealed no homology to known protein sequences. Antibodies raised against a synthetic peptide corresponding to the first 25 NH2-terminal amino acid residues specifically immunoprecipitated the [3H]azidopamil photoaffinity-labeled polypeptide and recognized the protein in Western blots. Cross-linking with a variety of homo- and heterobifunctional agents lead to the formation of dimers. Since in the purified preparation no other subunit could be identified with different protein stains, our results indicate that the [3H]emopamil binding site is formed by the homodimer of a novel membrane protein.

Amino Acid Sequence↗
PubMed1994

Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors.

Peripheral blood progenitor cells (PBPCs) are increasingly used for autografting after high-dose chemotherapy. One advantage of PBPCs over the use of autologous bone marrow would be a reduced risk of tumor-cell contamination. However, the actual level of tumor cells contaminating PBPC harvests is poorly investigated. It is currently not known whether mobilization of PBPCs might also result in mobilization of tumor cells. We evaluated 358 peripheral blood samples from 46 patients with stage IV or high-risk stage II/III breast cancer, small cell (SCLC) or non-small cell (NSCLC) lung cancer, as well as other advanced malignancies for the detection of epithelial tumor cells. Monoclonal antibodies against acidic and basic cytokeratin components and epithelial antigens (HEA) were used in an alkaline phosphatase-anti-alkaline phosphatase assay with a sensitivity of 1 tumor cell within 4 x 10(5) total cells. Before initiation of PBPC mobilization, circulating tumor cells were detected in 2/7 (29%) patients with stage IV breast cancer and in 2/10 (20%) patients with extensive-disease SCLC, respectively. In these patients, an even higher number of circulating tumor cells was detected after chemotherapy with VP16, ifosfamide, and cisplatin (VIP) followed by granulocyte colony-stimulating factor (G-CSF). This approach has previously been shown to be highly effective in mobilizing PBPCs. In the 42 patients without circulating tumor cells during steady state, tumor cells were mobilized in 9/42 (21%) patients after VIP+G-CSF induced recruitment of PBPCs. The overall incidence of tumor cells varied between 4 and 5,600 per 1.6 x 10(6) mononuclear cells analyzed. All stage IV breast cancer patients and 50% of SCLC patients were found to concomitantly mobilize tumor cells and PBPCs. Kinetic analyses showed two patterns of tumor cell recruitment depending on the presence or absence of bone marrow disease: (1) early after chemotherapy (between days 1 and 7) in patients without marrow infiltration, and (2) between days 9 and 16 in patients with marrow infiltration, ie, within the optimal time period for the collection of PBPCs. We show that there is a high proportion of patients with circulating tumor cells under steady-state conditions, and in addition a substantial risk of concomitant tumor cell recruitment upon mobilization of PBPCs, particularly in stage IV breast cancer patients with bone marrow infiltration. The biologic and clinical significance of this finding is unknown at present.

Adult↗
PubMed1994

Different approaches toward an automatic structural alignment of drug molecules: applications to sterol mimics, thrombin and thermolysin inhibitors.

A relative comparison of the binding properties of different drug molecules requires their mutual superposition with respect to various alignment criteria. In order to validate the results of different alignment methods, the crystallographically observed binding geometries of ligands in the pocket of a common protein receptor have been used. The alignment function in the program SEAL that calculates the mutual superposition of molecules has been optimized with respect to these references. Across the reference data set, alignments could be produced that show mean rms deviations of approximately 1 A compared to the experimental situation. For structures with obvious skeletal similarities a multiple-flexible fit, linking common pharmacophoric groups by virtual springs, has been incorporated into the molecular mechanics program MOMO. In order to combine conformational searching with comparative alignments, the optimized SEAL approach has been applied to sets of conformers generated by MIMUMBA, a program for conformational analysis. Multiple-flexible fits have been calculated for inhibitors of ergosterol biosynthesis. Sets of different thrombin and thermolysin inhibitors have been conformationally analyzed and subsequently aligned by a combined MIMUMBA/SEAL approach. Since for these examples crystallographic data on their mutual alignment are available, an objective assessment of the computed results could be performed. Among the generated conformers, one geometry could be selected for the thrombin and thermolysin inhibitors that approached reasonably well the experimentally observed alignment.

Amino Acid Sequence↗
PubMed1994

Response of multicellular tumor spheroids to liposomes containing TNF-alpha.

This publication describes a new model to investigate the influence of tumor necrosis factor-alpha (TNF-alpha) on a three-dimensional glial cell aggregate under defined, standardized, reproducible conditions using the glioma cell line A 172. The cells are initially grown as normal monolayer culture until they reach a cell density of up to 1 x 10(6). Subsequently they are grown as spheroids by the liquid overlay technique. Spheroids grown in this way were divided into ten groups of more than 50 cell aggregates. Three groups were coincubated with free TNF-alpha in increasing dosages (100 ng/ml, 200 ng/ml and 1000 ng/ml); three groups were incubated with empty liposomes (0.2 mg/ml, 0.4 mg/ml and 2 mg/ml); three groups received liposomes which had been loaded with TNF-alpha, and one group, which received no treatment, served as control. The diameter of the spheroids ranged from 80 microns to 350 microns. There was no significant difference in growth between the 3 groups treated with 'free' TNF-alpha. Comparing spheroids treated with TNF-alpha with those which had been coincubated with empty liposomes, there was a significant difference (p < 0.001) in growth, which correlated with the amount of liposomes. Similarly, free TNF-alpha had a significantly (P < 0.001) stronger growth-inhibiting effect as compared to liposomes loaded with TNF-alpha. Comparing the groups treated with liposomes only to those treated with liposomes loaded with TNF-alpha, the latter exhibited a more marked (although not significantly) growth-inhibiting effect. The preliminary conclusion is that the major growth-inhibiting effect seems to be mediated by the liposomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Aggregation↗
PubMed1994

Human astrocytes are only partially competent antigen presenting cells. Possible implications for lesion development in multiple sclerosis.

Highly purified astrocyte cultures from human embryonic brain were examined for their capacity to present antigen to human leukocyte antigen (HLA) class II compatible, cytolytic CD4+ T lymphocytes. Most astrocytes constitutively expressed HLA class I products and LFA-3 (CD58). Constitutive expression of HLA class II, LFA-1 alpha (CD11a) and ICAM-1 (CD54) was lower and varied among different cultures, while LFA-2 (CD2) was absent. IFN-gamma alone or in combination with TNF-alpha strongly enhanced expression of HLA class I, HLA-DR, -DP, -DQ, LFA-1 alpha and ICAM-1, but did not affect expression of LFA-2 (CD2) and LFA-3 (CD58). TNF-alpha alone induced only HLA class I and ICAM-1, but not HLA class II or LFA-1 alpha. Cytokine treated, but not untreated astrocytes were able to present protein (auto-)antigens to specific T lymphocyte lines. Astrocytes expressing appropriate major histocompatibility complex class II products were lysed by CD4+ T cells specific for myelin basic protein or tetanus toxoid. The lytic response was antigen dose dependent and HLA-DR restricted. It could be blocked by antibodies against HLA-DR determinants and against the adhesion molecules LFA-1 alpha and ICAM-1. In remarkable contrast to their susceptibility to T cell lysis, antigen presenting astrocytes were not only completely unable to induce T cell proliferation but even inhibited proliferation. The results indicate that, although human astrocytes have the potential to present protein antigens to CD4+ T cells, they do not induce the co-stimulatory factors required to trigger the complete T cell activation programme.

Antigen-Presenting Cells↗
PubMed1994

Multiple sclerosis. Immunomodulatory effects of human astrocytes on T cells.

Using a human culture system, we have previously shown that interferon-gamma-and tumour necrosis factor-alpha-stimulated astrocytes are capable of presenting antigens to T lymphocytes, but do not support antigen-dependent T cell proliferation. To gain further insight into the mechanisms involved in the local regulation of intracerebral T cell responses, we have investigated the effects of astrocytes on T cell proliferation induced by peripheral blood-derived mononuclear cells (PBMC). We found that astrocytes derived from human embryonic brain were able to suppress PBMC-dependent proliferation of antigen-specific, CD4+ T cell lines. Interferon-gamma production by PBMC-stimulated T cells was also suppressed by astrocytes, and this inhibition was seen as early as 6 h after initiation of co-culture. The inhibitory effect was observed in the presence of both HLA matched and mismatched astrocytes and was mediated by astrocyte-derived soluble factor(s) rather than by direct cellular contact. Inhibition of T cell proliferation was incompletely reverted by indomethacin, suggesting that prostaglandins were partially involved in the suppressive effect. The cytotoxic mediator nitric oxide was not involved in astrocyte-mediated inhibition. These observations led us to further investigate the contribution of other mediators known to down-regulate inflammatory processes. Our astrocyte cultures did not synthesize interleukin (IL)-4 or IL-10, whereas they secreted both the latent and active forms of transforming growth factor-beta 2. Transforming growth factor-beta was, however, found not to participate in astrocyte-induced inhibition in vitro. The inhibitory properties of human astrocytes may contribute to confinement of inflammatory lesions in multiple sclerosis and other inflammatory diseases of the central nervous system.

Astrocytes↗