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Biomedical subjects

U Wagner

Publications and source records attributed to U Wagner.

At least 109 records · Page 6Linked to original sources
PubMed1998

Effects of VIP and related peptides on airway mucus secretion from isolated rat trachea.

Vasoactive intestinal polypeptide (VIP) is known as an important regulator of airway function. It has been suggested that VIP is involved in the pathogenesis of asthma due to its relaxant effects on smooth muscles. The present study was designed to characterize the effects of the peptides of the VIP family on airway mucus secretion. The peptides VIP, PHI, PACAP-27, PACAP-38, GLP-I, exendin-4, helodermin, helospectin I and helospectin II were investigated using isolated rat trachea. Data show that PACAP-27 is the most potent stimulator of airway mucus secretion (225% stimulation). The rank order of potency was PACAP-27 > VIP > helospectin II > PHI > exendin-4 = helodermin = helospectin I = PACAP-38. The addition of the protease inhibitor thiorphan enhanced the effects of PHI and helodermin, but not of the other peptides. These data show that the peptides of the VIP family stimulate airway mucus secretion differently.

Animals↗
PubMed1998

Thalamocortical circuits causing remote hypometabolism during focal interictal epilepsy.

The functional circuit causing depression of cerebral glucose metabolism in brain areas remote from an epileptic focus was investigated in experiments on the cortex of the rat. Epileptic activity was induced by direct epicortical application of Na-penicillin onto the motor cortical area Fr1/Fr2. The increased neuronal activity was associated with an increase of metabolism in the focal area and a decrease in somatosensory cortical areas. Metabolism was also massively increased in the thalamus, predominantly in the posterior nucleus. Stereotactic radiofrequency lesioning of this nucleus, 30 days prior to the induction of the epileptic focus, restricted the area with increase of metabolism to the upper cortical laminae, and abolished the cortical hypometabolism in the sensory cortex. It is suggested that the primary functional circuit affected by the acute epileptic focus in the present model consists of the motor cortex, the thalamic nucleus posterior and the somatosensory cortex.

Acute Disease↗
PubMed1998

Remission of bone metastases after combined chemotherapy and radionuclide therapy with Re-186 HEDP.

A patient with disseminated osseous metastases due to breast cancer reported multifocal pain. Because of persisting pain after a first cycle of chemotherapy, 1,295 MBq Re-186 HEDP was administered intravenously. Excellent pain relief was observed. Subsequently, the patient received further combined chemotherapy and Re-186 HEDP therapy and remained pain free. Tc-99m MDP bone imaging showed a significant regression of osseous metastases. It may be speculated that the combination of Re-186 HEDP and chemotherapy results in significantly increased palliation of metastatic bone disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3beta transgenes.

In order to investigate the effect on tau of manipulating glycogen synthase kinase (GSK)-3beta activity in the brain, we created transgenic mice harbouring wild-type GSK-3beta genes or a mutant GSK-3beta that is predicted to be more active. Transgene-derived mRNAs were detected in the brains of a number of the transgenic mouse lines and several of these transgenic lines displayed transgenic GSK-3beta activity. Western blot analyses of the two lines with the highest levels of transgenic GSK-3beta activity revealed that the phosphorylation status of tau was elevated at the AT8 epitope. These observations strongly suggest that GSK-3beta is an in vivo tau kinase in the brain. Only low levels of expression of GSK-3beta were obtained and it is possible that high levels of GSK-3beta activity are lethal.

Animals↗
PubMed1997

Overexpression of the mouse dishevelled-1 protein inhibits GSK-3beta-mediated phosphorylation of tau in transfected mammalian cells.

Tau is a neuronal microtubule-associated protein whose function is modulated by phosphorylation. GSK-3beta is a tau kinase. GSK-3beta is part of the wingless signalling pathway and stimulation by wingless is predicted to down-regulate GSK-3beta activity. In Drosophila imaginal disc cells, overexpression of dishevelled, a component of the wingless pathway, mimics the wingless signal. We have therefore studied the effect that overexpression of the murine dishevelled-1 protein has on GSK-3beta-mediated phosphorylation of tau in transfected CHO cells. We find that co-transfection with dishevelled-1 is inhibitory to GSK-3beta-mediated tau phosphorylation. Tau is hyperphosphorylated in Alzheimer's disease and the possible relevance of these findings to Alzheimer's disease pathogenesis are discussed.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Phosphorylation of tau by glycogen synthase kinase 3beta affects the ability of tau to promote microtubule self-assembly.

To study the effects of phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) on the ability of the microtubule-associated protein tau to promote microtubule self-assembly, tau isoform 1 (foetal tau) and three mutant forms of this tau isoform were investigated. The three mutant forms of tau had the following serine residues, known to be phosphorylated by GSK-3, replaced with alanine residues so as to preclude their phosphorylation: (1) Ser-199 and Ser-202 (Ser-199/202-->Ala), (2) Ser-235 (Ser-235-->Ala) and (3) Ser-396 and Ser-404 (Ser-396/404-->Ala). Wild-type tau and the mutant forms of tau were phosphorylated with GSK-3beta, and their ability to promote microtubule self-assembly was compared with the corresponding non-phosphorylated tau species. In the non-phosphorylated form, wild-type tau and all of the mutants affected the mean microtubule length and number concentrations of assembled microtubules in a manner consistant with enhanced microtubule nucleation. Phosphorylation of these tau species with GSK-3beta consistently reduced the ability of a given tau species to promote microtubule self-assembly, although the affinity of the tau for the microtubules was not greatly affected by phosphorylation since the tau species remained largely associated with the microtubules. This suggests that the regulation of microtubule assembly can be controlled by phosphorylation of tau at sites accessible to GSK-3beta by a mechanism that does not necessarily involve the dissociation of tau from the microtubules.

Alzheimer Disease↗
PubMed1997

HLA markers and prediction of clinical course and outcome in rheumatoid arthritis.

OBJECTIVE: To evaluate HLA markers as early prognostic factors for disease severity in rheumatoid arthritis (RA). METHODS: HLA genotyping was carried out in a retrospective analysis of 66 RA patients and in a prospective study of 55 RA patients and 87 healthy controls using polymerase chain reaction-based methods for HLA-DRB1 specificities, DR4 alleles, and their linked DQB1 alleles, as well as HLA-B27. The clinical course of RA was assessed by clinical and radiologic scores. The impact of HLA markers was evaluated by epidemiologic means in addition to modeling using multiple logistic regression analysis. RESULTS: Shared epitope-positive (HVR3+) DR4 alleles and the HVR3 amino acid cassette QKRAA were associated with RA in both longstanding (relative risk [RR] 3.34 and 3.19) and recent-onset (RR 2.1 and 2.37) RA. In longstanding RA, radiologic evidence of severe joint destruction (Larsen score > 1.62) was seen more often in HVR3 shared epitope-positive patients than in epitope-negative patients (odds ratio [OR] = 25.67, chi 2 = 13.59, P = 0.0003). Moreover, rank sum analysis of Larsen indices indicated significantly higher ranking for the presence of the RA-associated HVR3 cassettes (QKRAA, QRRAA) when expressed on a DR4 allele (P < 0.0001). In the prospective study, DR4-positive patients had a significantly increased risk (OR = 13.75, P = 0.00083) of developing bony erosions. In addition, HVR3 epitope-positive DR4-positive individuals had significantly higher Larsen indices than did epitope-negative patients (P = 0.0083). In particular, the presence of the HVR3 epitope on DR4 resulted in an increased a posteriori likelihood (0.91) of developing early erosive disease compared with an a priori risk of 0.62. Conversely, the likelihood decreased to a minimum of 0.35 when the HVR3 epitope was absent. CONCLUSION: While the contribution of HLA typing to establishing the diagnosis of RA is limited, HLA-DR genotyping and DR4 subtype determination provide valuable markers for the prognosis of joint destruction in RA.

Adolescent↗
PubMed1997

DNA aberrations in urinary bladder cancer detected by flow cytometry and FISH.

Detection of molecular alterations is of potential significance for diagnosis and prognosis in bladder cancer. Fluorescence in situ hybridization (FISH) allows visualization and quantitation of genes and chromosomes on a cell by cell level and can easily be applied to urinary cells. To evaluate the sensitivity of FISH for detection of DNA aberrations in bladder cancer, formalin-fixed tissues of 293 tumors were examined by FISH and flow cytometry (FCM). Centromere probes for the chromosomes X, Y, 1, 7, 9, and 17 were used for FISH analysis. FISH was more sensitive for detection of quantitative DNA aberrations than FCM. An aberration of at least one chromosome was found in 107 of 108 tumors (99%), which were tetraploid, aneuploid, or multiploid, and in 29 of 49 tumors (59%), which were diploid, by FCM. The frequency of FISH aberrations showed greater differences between pTa (47%) and pT1 tumors (85%; P < 0.0001) than between stages pT1 and pT2-4 (98%). The marked genetic difference between pTa and pT1 tumors argues against the concept of grouping pTa and pT1 tumors together as "superficial bladder cancer." The frequency of tumors with chromosomal aberrations detected by FISH increased with the number of chromosomes examined. Aneusomy was seen in 68% of grade 1 tumors examined for > or = 4 chromosomes, suggesting that the cytological diagnosis of bladder cancer recurrences could be substantially improved by FISH.

Carcinoma, Transitional Cell↗
PubMed1997

The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role.

The tuberomammillary nucleus (TM), a cluster of magnocellular cells in the posterior hypothalamus, is the main source of neuronal histamine in the brain. Although this nucleus is well described in terms of anatomy and neurochemistry, only little is known about its function. Our earlier work showed that the TM projection system may be involved in behavioral asymmetries and behavioral recovery after unilateral manipulations of the brain. Using horseradish peroxidase (HRP) labeling we found an increase in strength (structure and/or activity) in the crossed and uncrossed tuberomammillary-striatal projections in the course of recovery from behavioral asymmetries produced by unilateral removal of the rats' vibrissae, which were in the same direction as the asymmetries found in projections from the substantia nigra to the striatum. Experiments performed with unilateral lesions of the TM region provide evidence for an involvement of the TM system in reinforcement mechanisms. Unilateral destruction of the TM with direct current (DC) or ibotenic acid was found to increase the rate of lateral hypothalamic self-stimulation ipsilateral to the lesion site, suggesting that the TM (particularly the E2 subgroup in its rostral part) may function as a reinforcement inhibiting neural substrate. Experiments performed with bilateral DC or ibotenic acid lesions of the TM region suggest a role of the nucleus in learning and mnemonic processes. A bilateral electrolytic or neurotoxic lesion of the TM region was found to facilitate the performance of adult and behaviorally impaired aged rats in a variety of learning tasks, including a habituation paradigm, aversively motivated learning tasks and water mazes. Examination of the site of the neurotoxic lesion in the TM region with immunohistochemical techniques revealed a marked decline of histamine-staining neurons mainly in the rostral part of the TM nucleus, suggesting that the facilitatory effects on reinforcement and mnemonic processes might be related to the destruction of TM intrinsic histaminergic cells. In summary, the present results indicate that the TM nucleus is involved in neural plasticity and functional recovery following damage to the CNS and may function as an inhibitory neural substrate in the control of reinforcement and mnemonic processes.

Animals↗
PubMed1997

Lateralized attenuation of hypothalamic self-stimulation after injecting histamine synthesis blocker alpha-FMH into the E2 tuberomammillary subnucleus.

The tuberomammillary nucleus (TM), located in the posterior hypothalamic region, is the only known source of neuronal histamine. Unilateral lesions in the rostroventral part of this nucleus enhanced ipsihemispheric lateral hypothalamic self-stimulation behavior, suggesting that this region exerts inhibitory control over the neuronal systems related to reward or reinforcement processes. To examine whether the amplification of reinforcing stimulation following lesions of histamine synthesizing neurons is indeed histamine mediated, we blocked histamine synthesis unilaterally by injection of 200 microg alpha-fluoromethylhistidine into the E2 region of the TM, and assessed the effects on electrical self-stimulation behavior in the lateral hypothalamus (LH) of rats. Based on the finding that TM lesions facilitated such self-stimulation behavior, we hypothesized that this treatment would have similar effects. Unexpectedly, there was a sharp decrease in the rate of ipsihemispheric lateral hypothalamic self-stimulation following the injection of alpha-FMH compared to the contralateral hemisphere of treated animals as well as compared to the vehicle group. Response rates were most strikingly attenuated 1 h postinjection, but remained low over the whole 7 days of testing. Opposite behavioral effects of TM lesions and alpha-FMH application have been reported previously, and the effectiveness of alpha-FMH in reducing brain histamine levels is known to differ between brain regions. The fact that the alpha-FMH injection affected self-stimulation only in the ipsilateral hemisphere rules out an interpretation of the results in terms of unspecific effects of the treatment on arousal and other performance variables, and, instead, indicates a functional interaction with a subsystem linked to lateral hypothalamic reinforcement processes.

Animals↗
PubMed1997

Unilateral lesion of dorsal hippocampus enhances reinforcing lateral hypothalamic stimulation in the contralateral hemisphere.

Whereas convincing evidence exists for an important role of the hippocampus in mechanisms underlying memory and encoding of location in space, the contribution of the hippocampus to the system underlying central processes of reinforcement is less well established. Scattered data suggesting that hippocampal ablation increases the effectiveness of positive reinforcers have alternatively been interpretated in terms of general and unspecific behavioral disinhibition, which results in higher levels of activity and rates of responding. In the present experiment, 22 Wistar rats were either given a neurotoxic or a sham lesion in the CA1 region of the hippocampus, and the effect on lateral hypothalamic self-stimulation behavior was assessed. To control for nonspecific performance effects rates of lever pressing were assessed ipsi- and contralateral to the lesioned hemisphere as well as under condition of extinction (current set to zero). Following the neurotoxic lesion the animals displayed significant higher rates of self-stimulation at the electrode sites in the hypothalamus situated contralateral but not ipsilateral to the hemisphere with the lesion compared with controls. The increase in self-stimulation commenced on the third day postlesion and was maintained over the 8 days of testing. The lesion did not change the animals' behavior under extinction. Thus, the hippocampal lesion led to an amplification of rewarding lateral hypothalamic self-stimulation behavior, indicative of a lesion induced disinhibition of the brain's reinforcement system.

Animals↗
PubMed1997

Immunological responses to the tumor-associated antigen CA125 in patients with advanced ovarian cancer induced by the murine monoclonal anti-idiotype vaccine ACA125.

We have generated an immunoglobulin G1 (IgG1) murine monoclonal anti-idiotype antibody (Ab2) designated ACA125, which mimics a specific epitope on the tumor-associated antigen CA125. This antigen is expressed by most of malignant ovarian tumors. Patients with CA125-positive tumors are immunologically tolerant to CA125. We used ACA125 as a surrogate for the tumor-associated antigen CA125 for vaccine therapy of 16 patients with advanced epithelial ovarian cancer or recurrences. Each of the patients received a minimum of 3 injections up to 19 injections of the complete anti-idiotype MAb ACA125 at a dosage of 2 mg per injection. Nine of 16 patients developed anti-anti-idiotypic (Ab3) responses to the ACA125. All 9 patients generated specific anti-CA125 antibody demonstrated by reactivity with purified CA125. Nine of 16 patients developed a CA125-specific cellular immune response by their peripheral blood lymphocytes (PBL) and 3 of 16 showed an increase in gamma-interferon concentrations accompanied by Ab3 responses. Toxicity was limited to abdominal pain in one case, which led to the withdrawal of further immunizations. The median progression free survival in those patients, who showed a specific immune response to the tumor-associated antigen CA125, was 11.0 +/- 5.6 months without any other therapy, in contrast to 8.0 +/- 4.2 months in the anti-anti-idiotype negative group. This is the first report of the induction of a specific active immunity to the tumor-associated antigen CA125 in patients with advanced ovarian cancer treated with an anti-idiotype antibody that "mimics" CA125. Patients showed the development of a specific humoral and cellular immune response to an otherwise nonimmunogenic tumor antigen. The immune responses in patients treated with this anti-idiotype vaccine, the low rate of side effects, and the improved time to progression after the induction of a specific immune response against the tumor-associated antigen CA125 justify follow-up clinical trials in advanced ovarian cancer patients with minimal residual disease in an adjuvant approach.

Animals↗
PubMed1997

Production of a single-chain fragment of the murine anti-idiotypic antibody ACA125 as phage-displayed and soluble antibody by recombinant phage antibody technique.

The F(ab')2 fragment of the murine monoclonal anti-idiotypic antibody ACA125 mimicking the tumor-associated antigen CA125 is used as a vaccine for the induction of an anti-tumoral immunity in patients with ovarian carcinoma. We tried to generate a single-chain fragment (ScFv) composed of ACA125 heavy- and light-chain variable domains connected by a polypeptide linker as an alternative to the corresponding F(ab')2 fragment. Heavy- and light-chain genes of antibody-producing mouse hybridoma cell line were amplified separately and assembled into a ScFv gene with linker DNA by the polymerase chain reaction (PCR). The ScFv gene was ligated into the phagemid vector pCANTAB5E, which allows the production of both phage-displayed and soluble ScFv. Transformed Escherichia coli TG1 cells were infected with M13K07 helper phage to yield recombinant phage, which display ScFv fragments as a g3p fusion protein on the surface of the filamentous phage M13. Recombinant phages could be selected by binding to the idiotypic antibody OC125 after one round of panning and directly used to reinfect E. coli TG1 cells. The E. coli nonsuppressor strain HB2151 was infected with an antigen-positive phage clone, previously screened by enzyme-linked immunosorbent assay (ELISA), to express soluble ScFv fragments. Functional soluble ScFv binding to the idiotypic antibody OC125 F(ab')2 could be detected in the bacterial periplasm by Western blot and ELISA. The variable heavy- and light-chain genes of the ACA125 ScFv fragment were further sequenced and compared with known antibody sequences.

Amino Acid Sequence↗
PubMed1997

Anti-TAG-72 antibody B72.3--immunological and clinical effects in ovarian carcinoma.

Based on the network theory, anti-tumor antibodies (Ab1) can trigger the immune system of the host into a response against tumor cells. Through an immunological cascade, anti-idiotypic antibodies bearing the internal image of epitopes of the nominal antigen (Ab2 beta) are produced that themselves can induce cellular and humoral cytotoxic effects against the antigen-expressing tumor cell. Formation of such antibodies has been shown to be associated with prolonged survival of melanoma, colorectal, and ovarian carcinoma patients. We studied anti-idiotypic antibody (Ab2) responses and clinical outcome of 31 ovarian cancer patients receiving the monoclonal antibody (MAb) B72.3, which targets the ovarian carcinoma associated antigen TAG-72. All patients were treated by surgery and polychemotherapy, which was followed by repeated (mean of 4) injections of 1 mg of the MAb B72.3. A remarkable anti-idiotypic anti-B72.3 response arose in 19 patients, with 9 of them showing a major response with Ab2 serum concentrations greater than 1,000 U/ml ("high-responders"). The median disease-free survival time, as well as the median survival time of these high-responders, was increased as compared to the low- or no responders. Evaluating our data, we conclude that monoclonal antibody treatment with the MAb B72.3 may induce humoral immunological responses in about two-thirds of our study group, although a positive clinical effect may only be expected in patients with excessive anti-idiotypic antibody formation.

Animals↗
PubMed1997

Chromosome 8p deletions are associated with invasive tumor growth in urinary bladder cancer.

Alterations of chromosome 8, including deletions of 8p, occur frequently in many tumors. In this study, fluorescence in situ hybridization was used to study the relationship between 8p deletions, 8q gains, and phenotype in bladder cancer. Cells from 87 tumors were examined by dual-labeling fluorescence in situ hybridization with a centromere 8 probe (pJM12) and P1 probes for 8p22, 8p12, 8q12, and 8q24. Both 8p22 deletions and 8q24 gains were strongly associated with tumor phenotype. There was a marked difference in 8p22 deletions between noninvasive (pTa) tumors (3/33) and minimally invasive (pT1) tumors (8/19; P = 0.005) whereas there was no significant difference between pT1 and muscle-invasive (pT2-4) tumors (19/35; P = 0.3926). Six tumors with 8p22 deletion were examined at 8p12. Three of these tumors showed no 8p12 deletion, narrowing down the site of a putative tumor suppressor gene distal to 8p12. In one other case, there was a marked increase in 8p12 copy number (> 40 per cell; amplification), suggesting the presence of an oncogene involved in bladder cancer at 8p12. The marked difference in 8p22 deletions between noninvasive (pTa) and minimally invasive (pT1) tumors is consistent with a role of a putative tumor suppressor gene on 8p for development of invasive tumor phenotype.

Chromosome Aberrations↗
PubMed1997

[Criteria for successful outcome of external fetal version from breech presentation to cephalic presentation].

The technique of external version of breech presentations has been proposed as a tool to reduce morbidity of fetus and mother. 79 cases of a 3 year period were evaluated aiming at identification of risk factors improving the success rate of the intervention. A total of 48% of attempts was successful. The most frustrating single factor was identified to be the oligohydramnion. Posterior implantation of the placenta improved the rate to 61%. The umbilical cord being localized by coloured Doppler had little influence even if positioned around the neck as neither success nor complications were predictable in this case. Maternal adipositas had a negative influence on the success rate. Perinatal morbidity war not increased in the group of external versions.

Breech Presentation↗
PubMed1997

[Genomic changes in urinary bladder cancer].

Recent molecular studies on transitional cell carcinomas (TCC) of the urinary bladder suggest two genetically different tumor types with a varying degree of genomic instability-pTa (grade 1 and 2) tumors are usually "genetically stable". These tumors have rarely p53 alterations and contain only few genomic alterations (deletions, DNA sequence copy number gains, amplifications). Genomic changes in these tumors typically include losses of the chromosomes Y and 9 as well as 1q gains. TCC's with invasive growth pattern (pT1-4) are mostly "genetically instable". They have p53 alterations in about 50% of tumors, and often numerous DNA sequence copy number changes including deletions of 2q, 5q, 6q, 8p and 11p as well as gains at 1q, 3p, 3q, 5p, 6p, 8q und 10p. High level amplifications at various sites of the genome are also frequent in these "instable tumors". They may pinpoint the localization of overexpressed oncogenes. Further studies will have to investigate whether genetic analyses can add useful information to the currently used pathological (pTNM) and clinical (superficial/invasive) classifications of urinary bladder cancer.

Carcinoma, Transitional Cell↗