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Biomedical subjects

P Fischer

Publications and source records attributed to P Fischer.

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

Functional topography of myelin-associated glycoprotein. II. Mapping of domains on molecular fragments.

The myelin-associated glycoprotein (MAG), an adhesion molecule of the immunoglobulin (Ig) superfamily with five Ig-like domains, was investigated with regard to its binding site(s) for the neuronal cell surface, collagen I, and heparin, using a panel of new monoclonal antibodies and cyanogen bromide cleavage fragments of MAG. All antibodies generated competed with each other for binding to MAG, indicating that they reacted with identical or closely related epitopes. Mapping of the reactive epitopes on recombinant deletion fragments of MAG expressed by Chinese hamster ovary (CHO) fibroblasts showed reactivity of monoclonal antibody 513 with domains I, II, and III, comprising the amino-terminal end of the extracellular domain. Monoclonal antibody 15 recognized domain III only. Binding of MAG-containing liposomes to neurons was blocked by antibodies 15 and 513. Cyanogen bromide (CNBr) fragments of domains I, II, and III bound to collagen type I under isotonic buffer conditions. CNBr fragments containing domains I and II were involved in binding to heparin. These observations suggest that domain III may be important for binding to the neuronal cell surface receptor for MAG, while domains I, II, and III interact with collagen type I and domains II and III with heparin.

3T3 Cells↗
PubMed1995

Increased LFA-1-mediated homotypic cell adhesion is associated with the G1 growth arrest induced by rapamycin in a T cell lymphoma.

The immunosuppressive macrolide, rapamycin, impedes the G1 to S cell cycle progression in cytokine-stimulated normal lymphocytes and in certain autonomously proliferating cell lines. Here, we found that the rapamycin-induced growth arrest augments homotypic aggregation in the YAC-1 T cell lymphoma. The growth arrest and increased aggregation were both blocked by the rapamycin antagonist, L-685,818, which interacts with the intracellular binding proteins mediating rapamycin's biochemical action. Moreover, rapamycin-induced aggregation was not seen in YAC-1 cells mutants selected for resistance to the drug's antiproliferative effect. Although the inhibition of G1/S progression induced by serum deprivation also resulted in increased cellular aggregation, cell cycle blockade in late G1 by mimosine, early S phase by hydroxyurea, or G2/M by nocodazole all failed to do so. Furthermore, the aggregation induced by rapamycin was blocked by antibodies to the alpha (CD11a) or beta (CD18) subunits of the integrin, LFA-1, or to its ligands, ICAM-1 and ICAM-2, and did not occur in LFA-1-deficient YAC mutants. However, the surface expression of LFA-1, ICAM-1, or ICAM-2 was not augmented in cells aggregated by rapamycin. Finally, the serine/threonine protein phosphatase inhibitor, okadaic acid, was found to abrogate rapamycin-induced aggregation. Therefore, rapamycin's impairment of YAC-1 cell growth in G1 is accompanied by enhanced LFA-1-mediated homotypic cell adhesion that may reflect an increase of the integrin's avidity for its ligands and may involve protein phosphorylation/dephosphorylation events. This suggests the existence of a link between cell cycle progression and "inside-out" LFA-1 signaling, possibly regulated by rapamycin's biochemical targets.

Animals↗
PubMed1995

[MRI of focal liver lesions using a 1.5 turbo-spin-echo technique compared with spin-echo technique].

AIM: The aim of our study was to evaluate a T2-weighted turbo-spinecho sequence in comparison to a T2-weighted spinecho sequence in imaging focal liver lesions. METHODS: In our study 35 patients with suspected focal liver lesions were examined. Standardised imaging protocol included a conventional T2-weighted SE sequence (TR/TE = 2000/90/45, acquisition time = 10.20) as well as a T2-weighted TSE sequence (TR/TE = 4700/90, acquisition time = 6.33). Calculation of S/N and C/N ratio as a basis of quantitative evaluation was done using standard methods. A diagnostic score was implemented to enable qualitative assessment. RESULTS: In 7% (n = 2) the TSE sequence enabled detection of further liver lesions showing a size of less than 1 cm in diameter. Comparing anatomical details the TSE sequence was superior. S/N and C/N ratio of anatomic and pathologic structures of the TSE sequence were higher compared to results of the SE sequence. CONCLUSION: Our results indicate that the T2-weighted turbo-spinecho sequence is well appropriate for imaging focal liver lesions, and leads to reduction of imaging time.

Carcinoma, Hepatocellular↗
PubMed1995

Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma.

PURPOSE: The reduced cardiac toxicity of the dextro-(d-) stereoisomer of verapamil (dexverapamil; Knoll Pharmaceuticals, Whippany, NJ) warrants its study as a potential multidrug-resistance (MDR) reversal agent. PATIENTS AND METHODS: Twenty-three patients with advanced renal cell carcinoma (RCC) were treated with vinblastine at a dose of 0.11 mg/kg intravenous (IV) bolus injection on days 1 and 2 every 21 days. Dexverapamil was added to subsequent cycles after resistance had been demonstrated. Dexverapamil treatment was begun 18 hours before day 1 of vinblastine administration and was given orally every 6 hours for 12 doses. Patients in group A were treated with a dose of 120 mg/m2, and those in group B were treated with 180 mg/m2 plus dexamethasone; plasma concentrations achieved in patients were correlated with in vitro effects. RESULTS: Toxicities included hypotension, asymptomatic bradycardia, and mild atrioventricular conduction delays, although one patient had dexverapamil discontinued for grade IV congestive heart failure. There were no partial or complete responses. The mean day-1 serum dexverapamil plus norverapamil plasma concentrations were 2,575 ng/mL (range, 697 to 6,015 ng/mL) for group A and 1,654 ng/mL (range, 710 to 4,132 ng/mL) for group B at the time of vinblastine administration. These concentrations were in the range of those that reversed vinblastine resistance in vitro. CONCLUSION: The advantage of dexverapamil as an MDR reversal agent is its potential for achieving desired blood levels with substantially less toxicity than the racemic mixture of verapamil. Based on tolerability, it is a suitable drug for further study in clinical trials of malignancies other than RCC that attempt to achieve MDR reversal. The dose of 120 mg/m2 given orally every 6 hours, with dose escalation based on individual tolerance, represents a feasible schedule to be considered for such studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Expression and localization of annexin VII (synexin) in muscle cells.

Annexin VII (synexin) is a member of the annexin family of proteins, which are characterized by Ca(2+)-dependent binding to phospholipids. We used PCR to isolate from a lambda gt11-mouse fibroblast library annexin VII cDNA fragments corresponding to the two isoforms found in both humans and Dictyostelium discoideum. The two isoforms of 47 kDa and 51 kDa differed by 22 amino acids inserted into the proximal third of the hydrophobic N terminus. Annexin VII-specific polypeptides expressed in Escherichia coli were used to generate isoform-specific monoclonal antibodies. Expression of the two isoforms during myogenesis was followed in the myogenic cell lines BC3H1 and L6. Only the 47 kDa isoform was present in undifferentiated L6 or BC3H1 myoblasts. The 51 kDa isoform appeared after myogenesis had been induced and in striated muscle only the 51 kDa isoform was observed. Immunofluorescence showed that annexin VII was located in the cytosol of mononucleated and fused polynucleated cultured cells, whereas in striated muscle, annexin VII was located preferentially at the plasma membrane and the transverse tubules. However, there was also some residual cytosolic staining, which was more abundant in type II (fast twitch) than in type I (slow twitch) fibers. Permeabilization of L6 cells with digitonin in the presence of 5 mM EGTA led to a release of annexin VII from the cells, which paralleled the loss of cytosolic lactate dehydrogenase (LDH) at low detergent concentrations (50 microM). In the presence of 100 microM extracellular Ca2+, annexin VII remained bound to the plasma membrane even in the presence of high digitonin concentrations. Incubation with the Ca(2+)-specific ionophore A23187 and 100 microM extracellular Ca2+ led to a redistribution of annexin VII from the cytosol to the plasma membrane after 30 minutes of incubation. The results obtained indicate a developmentally and Ca(2+)-regulated localization and expression of annexin VII and raise the possibility that annexin VII may play a role in excitation-contraction coupling in skeletal muscle.

Animals↗
PubMed1995

Onchocerciasis and human immunodeficiency virus in western Uganda: prevalences and treatment with ivermectin.

Epidemiologic investigations were made to assess the interaction between onchocerciasis and human immunodeficiency (HIV) type 1 infection and the efficacy of ivermectin treatment. Among 1,910 Onchocerca volvulus carriers in a hyperendemic focus, 73 (3.8%) were concurrently infected with HIV and 20 (7.2%) of 276 persons without microfilariae (mf) were HIV-seropositive. A stratified analysis showed no epidemiologic association between onchocerciasis and HIV infection. Consistently, a microfilaria density of 11.9 mf/mg of skin in HIV-positive subjects and 17.7 mf/mg in HIV-negatives ones was observed. During mass treatment of onchocerciasis with a single dose of 150 micrograms/kg of ivermectin, no difference of the efficacy was detected between persons with or without HIV and side effects in the two groups were similar. Even in HIV-positive persons with a reduced ratio of CD4+:CD8+ cells and reduced numbers of CD4+ cells, a significant reduction of their microfilaria density was observed after treatment with ivermectin. Thus, in HIV-endemic areas, the usual dose of ivermectin can be administered during mass treatment.

Adolescent↗
PubMed1995

Prevalence and risk factors of HIV-1 infection in three parishes in western Uganda.

UNLABELLED: A population-based serosurvey was conducted to determine the HIV-1 prevalence and to evaluate various risk factors in three parishes in western Uganda. Adults over 14 years were examined in all 13 villages of Kigoyera parish far from Fort Portal, in two villages of Kyamukoka parish closer to Fort Portal and in the four fishing villages of Ntoroko parish at Lake Albert with a high population mobility. Personal interviews and HIV serology using ELISA and Western blot were performed. Sera showing at least two envelope bands in the Western blot were considered as positive. The coverage of the registered eligible population was 74% in Kigoyera, 67% in Kyamukoka and 25% in Ntoroko. The prevalence of HIV was 4% (97 of 2267 persons examined, 95% CI 3.4-5.1%) in Kigoyera, a typical rural area. Whereas it was 13% (53 of 393 persons examined, 95% CI 10.1-16.9%) in Kyamukoka near to the district capital and exceptionally high with 24% (96 of 399 persons examined, 95% CI 19.9-28.3%) in the comparatively isolated fishing villages of Ntoroko. In a multivariate model the infection risk for HIV was in Kyamukoka two and in Ntoroko five times higher than in Kigoyera. Among the two main ethnic groups one had a significantly lower risk to acquire HIV infection than the other group. CONCLUSIONS: Because of their large proportion of migrating persons the fishing villages presented populations with high risks for HIV infection. The ethnic composition of the village population, representing group specific sexual behaviour, was a risk factor for HIV infection.

Adolescent↗
PubMed1994

Development of C5a receptor antagonists. Differential loss of functional responses.

C5a is a 74-amino acid glycoprotein generated on activation of the C system. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antagonist would be of considerable therapeutic importance. However, efforts at generating antagonists have so far been unsuccessful. Structure/activity studies of the C terminus of C5a have generated peptide analogues with nanomolar affinities, but all of these retain strong agonist properties. We now report hexapeptides of the form NMePhe-Lys-Pro-dCha-X-dArg in which increasing aromaticity at position 5 leads to a progressive loss of agonism with little change in binding affinity. The different responses induced by C5a are lost in the order: degranulation before Ca(2+)-flux before chemotaxis. We also describe the first full antagonist of C5a, because the peptide in which x = Trp is not only devoid of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated G protein activation.

Amino Acid Sequence↗
PubMed1994

Platelet monoamine oxidase B activity and vitamin B12 in dementia.

The activity of platelet monoamine oxidase B (MAO-B) was highly correlated with the severity of dementia in 39 patients suffering from probable dementia of the Alzheimer type and in 18 age-matched controls. There was no association between a low vitamin B12 level and high MAO-B activity in our sample of patients, who are living in a geriatric hospital where the balanced nutrition of inpatients is controlled by diet assistants.

Aged↗
PubMed1994

Autocrine stimulation of the Xmrk receptor tyrosine kinase in Xiphophorus melanoma cells and identification of a source for the physiological ligand.

The melanoma-inducing gene of Xiphophorus fish encodes the Xmrk receptor tyrosine kinase. Using a highly specific antiserum produced against the recombinant receptor expressed with a baculovirus, it is shown that Xmrk is the most abundant phosphotyrosine protein in fish melanoma and thus highly activated in the tumors. Studies on a melanoma cell line revealed that these cells produce an activity that considerably stimulates receptor autophosphorylation. The stimulating activity induces receptor down-regulation and can be depleted from the melanoma cell supernatant by the immobilized recombinant receptor protein. The fish melanoma cells can thus be considered autocrine tumor cells providing a source for future purification and characterization of the Xmrk ligand.

Animals↗
PubMed1994

Myofibrillogenesis in primary tissue cultures of adult human skeletal muscle: expression of desmin, titin, and nebulin.

To investigate the in vitro development of myofibrils in skeletal muscle cells derived from adult human muscle biopsies, immunohistochemical analysis was performed using monoclonal antibodies against desmin, titin, and nebulin. Diffuse desmin reactivity was detected 48 h after plating in about 60% of all mononucleated cells. This supports the use of desmin as a marker for undifferentiated rhabdomyosarcomas in man. Titin was visible from day 4 onwards, while nebulin was not found in mononucleated cells. After 1 week polynucleated myotubes appeared, and grew up to 30 days. Desmin was distributed diffusely throughout the cytoplasm until day 21, when the pattern became patchy. Titin began to be organized in a predominantly longitudinal orientation at day 15, while nebulin, which appeared for the first time in fusing myoblasts on the fifth to the seventh day, was almost immediately organized in a dotted longitudinal pattern, which became a Z line connected striation in matured myotubes.

Cells, Cultured↗