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Biomedical subjects

A Walser

Publications and source records attributed to A Walser.

At least 19 recordsLinked to original sources
PubMed2004

Long-term persisting interferon beta-1b neutralizing antibodies after discontinuation of treatment.

OBJECTIVES: Neutralizing antibodies (NAB) against interferon beta (IFNB) with presumably negative impact on treatment outcome have been described in up to 42% of patients undergoing IFNB treatment. However, in most cases NAB decrease despite continuation of IFNB therapy. Observations on NAB after discontinuation of IFNB therapy are lacking. Here, we report for the first time on NAB which now persist for several years following discontinuation of IFNB treatment. MATERIALS AND METHODS: We present two multiple sclerosis patients followed over 8 and 10 years. NAB have been measured repeatedly and are presented together with clinical data. NAB developed after 2 years of treatment and persisted despite discontinuation of treatment at high titers for more than 4 years. CONCLUSION: Our data indicate that IFNB therapy may induce long-term NAB production which persists even after discontinuating IFNB treatment. Possible immunological mechanisms are discussed.

Adjuvants, Immunologic↗
PubMed2001

[Ileocecal invagination of a mucocele of the appendix].

HISTORY AND CLINICAL FINDINGS: A 39-year-old patient was admitted because of pain in the right mid and lower abdomen of 2 weeks duration with vomiting and postprandial nausea. He complained of changing stool habits with diarrhoea and constipation. Clinically he showed a slight tenderness in the right lower abdomen. INVESTIGATIONS: Routine laboratory test were normal including CRP and WBC. Ultrasound showed a non-compressible mass with low intensity echoes, 3.6 x 4.6 cm in diameter in the right mid abdomen, slightly tender, surrounded by a circular, intestine-like structure. A gastrografin-swallow didn't reveal any obstacle in the proximal small intestine and was inconclusive further distal. A CT scan demonstrated a ileocoecal invagination extending in the colon ascendens to the right flexure with suspicion of a tumor. At the colonoscopy on the next day the invagination was not apparent any more, but a well-rounded tumour in the appendix region was seen. DIAGNOSIS, TREATMENT AND COURSE: Suspecting a coecal tumour with remitting ileocoecal invagination a ileocoecal resection was performed on the third day. The tumour proved to be a mass of mucus with parts of a villo-mucinous cystadenoma of the UMP type. Recovery was uneventful. CONCLUSION: Mucoceles of the appendix can cause ileocoecal invagination in the adult.

Adult↗
PubMed1994

Neutralizing interferon beta antibodies in melanoma patients treated with recombinant and natural interferon beta.

The incidence and clinical significance of therapy-induced neutralizing interferon beta (IFN beta) antibodies was studied in a group of 21 melanoma patients treated with natural IFN beta and 7 patients treated with recombinant IFN beta. They were treated subcutaneously with 3 x 10(6) IU three times per week in an adjuvant open trial for 24 weeks after surgical removal of all detectable metastases. Of the 21 patients treated with natural IFN beta, 95% developed significant levels of neutralizing antibodies after 24 weeks. In comparison, 28% of the 7 patients treated with recombinant IFN beta developed neutralizing IFN beta antibodies. Cross-reactivity of the antibodies could be demonstrated. Persistence of antibody titers was seen in 80% of the patients 24 weeks after cessation of treatment with natural IFN beta. No correlation between the maximum antibody titers and the antibody persistence after cessation of therapy could be established. We detected a clear correlation between the formation of neutralizing antibodies and the decrease in beta 2-microglobulin and 2',5'-oligoadenylate synthetase and therefore the drop in biological activity. In this adjuvant trial there was no difference in relapse rate and time until relapse between antibody-positive and antibody-negative patients. No difference in clinical outcome could be established between the patients treated with natural IFN beta and recombinant IFN beta.

2',5'-Oligoadenylate Synthetase↗
PubMed1994

Severe inflammatory upper airway stenosis in ulcerative colitis.

Severe upper airway stenosis was diagnosed in a 23 year old woman who presented with hoarseness, cough and dyspnoea 8 yrs after initial diagnosis of ulcerative colitis. The respiratory symptoms worsened over the next few months, the patient eventually developing dysphagia and ultimately severe upper airway obstruction. The narrowest site was the glottis, which was severely stenosed by inflammatory swellings. Systemic corticosteroids led to rapid clinical improvement and restoration of normal airway patency within a few months. Ulcerative colitis is frequently associated with extraintestinal inflammatory manifestations. In the respiratory tract these usually take the form of chronic bronchitis, which occasionally develops into bronchiectasis. This case confirms that the inflammation can also involve the larynx and large airways.

Adult↗
PubMed1993

Differential antagonism of platelet activating factor-induced neutrophilia and gastric hemorrhage in the rat.

Intravenous injection of platelet activating factor (PAF) in rats produced hypotension, neutrophilia, gastric congestion, and sloughing of the gastric epithelium. The congestion was quantified by measuring hemoglobin in the gastric mucosa. Other lesions were quantified by scores of gross pathology and histopathology. PAF-induced changes in neutrophil levels were prevented by pretreatment with the PAF-antagonist Ro24-4736, but not by the PAF-antagonist CV-3988. Both PAF antagonists reduced the hypotension, the amount of hemoglobin in the gastric mucosa, and the PAF-induced gastric pathology. These results suggest that PAF receptors involved in PAF-induced neutrophil mobilization respond differently from PAF receptors in the gastrointestinal and cardiovascular systems.

Animals↗
PubMed1993

Imidazenil: a new partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors.

Positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors, including benzodiazepines and congeners, can be classified into three categories: 1) full allosteric modulators (i.e., triazolam and alprazolam) that act with high potency and efficacy at many GABAA receptors; 2) selective allosteric modulators (i.e., diazepam) that act with high potency and high efficacy at selected GABAA receptors; and 3) partial allosteric modulators (i.e., bretazenil) that act with high potency but low efficacy at many GABAA receptors. Imidazenil, an imidazobenzodiazepine carboxamide, has been characterized as a novel representative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABAA receptors, imidazenil positively modulates the GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of diazepam, and it antagonizes the effects of the latter drug. Imidazenil in vitro (Ki = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [3H]flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-punishment test and is 10 times more potent than bretazenil and 100 times more potent than diazepam or alprazolam in antagonizing bicuculline- and pentylenetetrazol-induced seizures. Unlike diazepam and alprazolam, which induce sedation and ataxia and potentiate the effects of ethanol and thiopental at doses similar to those that produce anticonflict effects and occupy 50% of brain flumazenil binding sites, imidazenil does not produce ataxia or sedation in rats nor does it potentiate the effects of ethanol or thiopental in doses 30- to 50-fold higher than those required for the anticonflict effect and for 100% occupancy of brain flumazenil binding sites. Furthermore, when administered with diazepam, imidazenil blocks in a dose-related fashion the sedative, ataxic effects of this drug and thus acts on these unwanted responses as an antagonist (i.e., like flumazenil). In all tests, imidazenil has the pharmacological profile of a partial allosteric modulator, but is more potent than bretazenil, has a longer biological half-life and, in rodents, is virtually unable to cause sedation, ataxia or to potentiate ethanol toxicity.

Allosteric Regulation↗
PubMed1991

Triazolobenzo- and triazolothienodiazepines as potent antagonists of platelet activating factor.

A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.

Animals↗
PubMed1991

Thienotriazolodiazepines as platelet-activating factor antagonists. Steric limitations for the substituent in position 2.

The preparations of thienotriazolodiazepines bearing a substituted ethynyl group at the 2-position, and the corresponding cis-olefins and fully saturated analogues are described. The compounds were evaluated as potential antagonists of platelet-activating factor (PAF) in in vitro and in vitro test models. The new thienotriazolodiazepines are compared with known related compounds such as WEB 2086 (compound 6) and the phenylethyl derivatives 27 and 28.

Animals↗
PubMed1989

[Selective vitamin B 12 malabsorption in a 19-year-old patient].

Selective malabsorption of vitamin B12, or Imerslund-Gräsbeck disease, is a rare congenital condition. The normal ileal uptake of intrinsic-factor-bound vitamin B12 is deficient. Inheritance is autosomal recessive. Megaloblastic anemia generally appears in infancy and is usually accompanied by mild proteinuria. The case is presented of a 19-year-old woman with megaloblastic anemia due to selective vitamin B12 malabsorption. As far as we know this is the only patient in whom the disease appeared so late. Of special interest are also the marginally low Schilling tests of the patient's parents. Further conditions which may lead to vitamin B12 deficiency are also discussed. A hypothesis is put forward concerning the late appearance of the disease in this particular case. Pathophysiologic, nephrologic and genetic aspects of selective vitamin B12 malabsorption are briefly reviewed.

Adult↗
PubMed1989

Ethological studies in animals and man, their use in psychiatry.

Ethology is concerned with the observation, description and measurement of the acts and postures which make up the behavioural repertoire of animals. Man too, exhibits analogous patterns of non-verbal behaviour, many of which serve social interactions. It is shown how ethological profiles of psychiatric patients can be constructed using the same methods as are used to analyse the social behaviour of rodents. It is argued that deficits in social behaviour are a key feature of the mentally ill patient and arise when flight, i. e. escape-oriented behaviour predominates. This notion is supported by an ethological study which shows that compared to healthy subjects, depressed patients exhibit fewer facial expressions and gestures which instigate or invite social interactions. These patterns serve to isolate the depressive patients from the group. With its emphasis upon objective analysis of behaviour, the ethological approach can provide a useful adjunct to conventional but largely subjective, clinical assessment schemes. It can also help to integrate findings in man and animals since in both, the behaviour is assessed in the same kind of units according to a common conceptual framework.

Animals↗
PubMed1989

Only a minor fraction of plasma membrane-associated large T antigen in simian virus 40-transformed mouse tumor cells (mKSA) is exposed on the cell surface.

The bulk of simian virus 40 (SV40) large T antigen in SV40-infected and -transformed cells localizes within the cell nucleus, while a minor fraction specifically associates with the plasma membrane (PM) and is exposed on the cell surface. PM-associated large T seems to span the lipid bilayer but, on the other hand, does not display typical features of a transmembrane protein. To further characterize the postulated transmembrane orientation of large T, we asked whether all large T molecules associated with the plasma membrane indeed are exposed on the cell surface. We compared the amount of cell surface-exposed large T, determined on living cells by a sensitive 3H-protein A-binding assay and by external immunoprecipitation, with that of total PM-associated large T extracted from isolated PM. We demonstrate that in mKSA cells (SV40-transformed BALB/c mouse fibroblasts), total PM-associated large T accounted for a substantial portion (ca. 2%) of total cellular large T. However, only 0.1 to 0.2% of it could be detected on the cell surface. Thus, only a minor fraction of PM-associated large T (less than 10%) is exposed on the surface of these cells. Interior PM-associated large T is stably associated with the plasma membrane, while the small fraction of surface-exposed large T is rapidly released from the cell surface.

Adenoviridae↗
PubMed1989

A novel mechanism for covalent attachment of fatty acid to SV40 large T antigen.

The plasma membrane associated subclass of simian virus 40 large T antigen is specifically acylated with palmitic acid in vivo. To further analyze possible biological functions of fatty acid acylation, we developed a target-bound cell free in vitro acylation assay, in which immunopurified large T, bound to protein A-sepharose, was incubated with [3H]fatty acid. In this assay, large T was efficiently labeled with [3H]palmitic acid, but not with [3H]myristic acid. Thus the specificity of the in vivo labeling was preserved in vitro, too. The specific acylation of large T in vitro seemed to occur by an autocatalytic reaction, since it was found to be independent of added acyltransferases and exogenous energy. The energy for this reaction must be provided by the large T molecule itself, probably by an energy-rich internal ester bond. Our results provide evidence for a novel mechanism for the covalent attachment of fatty acids to proteins, which might also operate in vivo.

Acylation↗
PubMed1988

A subclass of the adenovirus 72K DNA binding protein specifically associating with the cytoskeletal framework of the plasma membrane.

We have analyzed by immunofluorescence microscopy and by biochemical cell fractionation the subcellular distribution of the adenovirus type 2 72K DNA binding protein (DBP) during the course of infection in HeLa cells. Early in infection, the 72K DBP was strictly localized in the cell nucleus. However, as infection progressed, the 72K DBP was additionally found in other subcellular fractions, notably in association with the cytoskeletal framework of the plasma membrane, the plasma membrane lamina. Pulse-chase experiments demonstrated that this association was specific. Control experiments excluded the possibility of an artificial redistribution of the 72K DBP during cell fractionation. Our data, therefore, demonstrate that a significant portion of the 72K DBP during late times of infection associates specifically with the cytoskeletal framework of plasma membranes of infected cells.

Adenoviridae Infections↗
PubMed1986

The kinase activity of SV40 large T antigen is mediated by a cellular kinase.

Large T antigen (large T) extracted from SV40-infected or transformed cells exhibits an in vitro protein kinase activity, whose origin and biological significance up to now had been obscure. We have addressed the questions of whether this activity is intrinsic to large T or arises by association with a cellular kinase, and, furthermore, whether this activity might play a biological role in vivo. Instead of analyzing large T from whole-cell lysates, where non-specific association of a cellular kinase(s) with large T might easily occur, we analyzed individual cellular subclasses of large T, isolated from their in vivo locations. In contrast to large T isolated from whole-cell lysates which was always kinase positive, none of the cellular subclasses of large T prepared by in situ fractionation of SV40-transformed mKSA cells exhibited detectable in vitro kinase activity. We could demonstrate that our fractionation conditions neither inactivated the large T-associated kinase activity nor dissociated it from large T when they were applied to kinase-positive large T isolated from whole-cell lysates. We conclude that large T does not contain an intrinsic kinase activity. This conclusion was further supported by our finding that it was possible to remove the large T-associated kinase activity from kinase-positive large T preparations and to reconstitute it by incubating the kinase-negative large T with cell lysates from various cell lines. Therefore, the simplest way of interpreting our results is that the in vitro kinase activity measured with large T preparations from whole-cell lysates is the result of an in vitro association of a cellular kinase(s) with large T during certain conditions of cell lysis.

Animals↗