[Backache as main symptom of unknown primary cancer syndrome with a particularly severe course].
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Acute Disease↗
Biomedical subjects
C Ruf
Publications and source records attributed to C Ruf.
Improved limits on nu(e) emission from mu+ decay.
We investigated mu(+) decays at rest produced at the ISIS beam stop target. Lepton flavor (LF) conservation has been tested by searching for nu(e) via the detection reaction p(nu(e),e(+))n. No nu(e) signal from LF violating mu(+) decays was identified. We extract upper limits of the branching ratio (BR) for the LF violating decay mu(+)-->e(+)+nu(e)+nu(-) compared to the standard model (SM) mu(+)-->e(+)+nu(e)+nu(mu) decay: BR<0.9(1.7) x 10(-3) (90% C.L.) depending on the spectral distribution of nu(e) characterized by the Michel parameter rho=0.75(0.0). These results improve earlier limits by one order of magnitude and restrict extensions of the SM in which nu(e) emission from mu(+) decay is allowed with considerable strength. The decay mu(+)-->e(+)+nu(e)+nu(mu) often proposed as a potential source for the nu(e) signal observed in the LSND experiment can be excluded.
Journal Article↗
Molecular basis for nonanaphylactogenicity of a monoclonal anti-IgE antibody.
IgE Abs mediate allergic responses by binding to specific high affinity receptors (FcepsilonRI) on mast cells and basophils. Therefore, the IgE/FcepsilonRI interaction is a target for clinical intervention in allergic disease. An anti-IgE mAb, termed BSW17, is nonanaphylactogenic, although recognizing IgE bound to FcepsilonRI, and interferes with binding of IgE to FcepsilonRI. Thus, BSW17 represents a candidate Ab for treatment of IgE-mediated disorders. By panning BSW17 against random peptide libraries displayed on phages, we defined mimotopes that mimic the conformational epitope recognized on human IgE. Two types of mimotopes, one within the Cepsilon3 and one within the Cepsilon4 domain, were identified, indicating that this mAb may recognize either a large conformational epitope or eventually two distinct epitopes on IgE. On the basis of alignments of the two mimotopes with the human IgE sequence, we postulate that binding of BSW17 to the Cepsilon3 region predominantly blocks binding of IgE to FcepsilonRI, leading to neutralization of IgE. Moreover, binding of BSW17 to the Cepsilon4 region may explain how BSW17 recognizes FcepsilonRI-bound IgE, and binding to this region may also interfere with degranulation of IgE sensitized cells (basophils and mast cells). As a practical application of these findings, mimotope peptides coupled to a carrier protein may be used for the development of a peptide-based anti-allergy vaccine by induction of anti-IgE Abs similar to the current approach of using humanized nonanaphylactogenic anti-IgE Abs as a passive vaccine.
Amino Acid Sequence↗
Mimicry of human IgE epitopes by anti-idiotypic antibodies.
According to Jerne's network hypothesis, the binding site of an anti-idiotypic antibody also represents the internal image of an epitope present on a foreign, or even a self antigen. In recent years, antigen mimicry has been defined at the molecular level for some xeno-antigens. However, until now there has been no demonstration of structural mimicry between a human anti-idiotypic antibody and a self structure. To address this question, we used human IgE as the self structure and a well-defined anti-human IgE mAb (BSW17). We describe the isolation of two anti- idiotypic antibodies specific for the anti-IgE antibody BSW17 from a non-immune human Fab phage display library. Interestingly, these two anti-idiotypic antibodies mimic the same molecular surface region as a previously described IgE peptide mimotope isolated by panning on BSW17, but they cover a much larger epitope on the IgE molecule. Accordingly, immunisation of rabbits with the two anti-idiotypic antibodies induced high-affinity antibodies with the same characteristics as BSW17. Thus, our data demonstrate that it is possible to isolate anti-idiotypic antibodies derived from the human genome without the need for hyperimmunization, and confirm Jerne's hypothesis that both foreign antigens and self structures can be mimicked by our own immunoglobulins.
Amino Acid Sequence↗
Thermal gains through collective metabolic heat production in social caterpillars of Eriogaster lanestris.
We investigated thermal characteristics of aggregations of social, tent-building caterpillars of the small eggar moth Eriogaster lanestris (Lepidoptera: Lasiocampidae). The highly synchronous behavior of individuals of the colony has important consequences for their thermal ecology. Air temperature in the tent fluctuates according to the caterpillars' activity: air temperature slowly rises about 2.5-3 degrees C above the surroundings when caterpillars aggregate in the tent after feeding and decreases rapidly when the larvae leave the tent. Thermal energy can be stored for a few hours when ambient temperature drops. Experiments show that metabolic heat production sufficiently explains this effect. As even minor additional heat gain may reduce developmental time, aggregating in the tent may thus confer selective advantages under overcast weather or at night, when behavioral thermoregulation through basking is not possible.
Animals↗
Effects of complement inactivation and IgG depletion on skin reactivity to autologous serum in chronic idiopathic urticaria.
BACKGROUND: Intradermal injection of autologous serum elicits a wheal-and-flare response in about 60% of patients with chronic idiopathic urticaria (CIU). This reactivity has been attributed to the presence of IgG autoantibodies directed against IgE or the alpha-chain of the high-affinity IgE receptor (FcepsilonRIalpha) expressed on basophils and mast cells, leading to the hypothesis that at least some forms of CIU could be sustained by an autoimmune process. OBJECTIVES: The aim of this study was to investigate the relationship between the presence of anti-IgE or anti-FcepsilonRI antibodies and the ability to induce wheal-and-flare responses in CIU sera selected for the capacity to give a positive skin test response. METHODS: Fifteen patients with CIU and a positive skin test response to autologous serum were injected intradermally with native serum and with serum heated at 56 degrees C for 30 minutes and then adsorbed on Sepharose-protein G to obtain IgG depletion. Serum levels of anti-IgE and anti-FcepsilonRIalpha antibodies were measured by ELISA by using purified IgE and recombinant RIalpha-soluble double-fusion protein RIalpha-human serum albumin-RIalpha, respectively. The histamine-releasing activity of sera was tested by using ELISA with whole human blood from a healthy donor. RESULTS: All patients had positive cutaneous responses to native serum injection. Anti-FcepsilonRIalpha antibodies were present in 14 of 15 native sera, only two of which were able to induce in vitro basophil degranulation. On the contrary, detectable amounts of anti-IgE antibodies were not found in any serum. IgG depletion by protein G resulted in complete (10/14 samples) or considerable (4/14 samples) removal of anti-FcepsilonRIalpha antibodies. The two sera endowed with functional activity lost their capacity to trigger histamine release from basophils after heating and protein G adsorption. Nonetheless, heat-decomplemented/IgG-depleted sera elicited wheal-and-flare reactions comparable with those observed with untreated sera. CONCLUSIONS: These results strongly suggest that skin reactivity to autologous serum could be due to as yet unidentified non-Ig reactants present in the sera of patients with CIU.
Adult↗
Interaction of human IgE with Fc epsilon RI alpha exposes hidden epitopes on IgE.
BACKGROUND: Binding of human IgE via the heavy-chain constant region domain 3 (Cepsilon3) to the alpha-chain of its high affinity receptor (FcepsilonRIalpha) is a key event in mediating allergic reactions. We wanted to identify epitopes within Cepsilon3 that are stable to denaturation and to evaluate whether such structures are involved in receptor binding. The existence of stable epitopes would facilitate the generation of compounds that inhibit the IgE-FcepsilonRIalpha interaction. METHODS: Monoclonal anti-human IgE-antibodies against recombinant bacterially synthesized Cepsilon3, which is known to be partly misfolded, were raised in mice. These antibodies were probed for binding to native, immobilized and receptor-bound IgE, respectively, providing tools for the identification of the indicated stable epitopes. RESULTS: Two of the generated antibodies (8E7, 3G9) discriminate between IgE in solution and IgE attached to FcepsilonRIalpha, pointing towards a steric rearrangement within Cepsilon3 induced upon receptor binding. The described antibodies represent tools for studying the mechanism of the Fcepsilon-FcepsilonRIalpha interaction and may be of diagnostic value since serum IgE from various human donors was differently recognized by 8E7, which is indicative for naturally occurring IgE molecules with different steric conformation. CONCLUSION: The presented data support the hypothesis of a conformational change within IgE Cepsilon3 upon receptor binding by showing that monoclonal antibodies raised against recombinant Cepsilon3 differently recognize soluble and receptor-bound IgE. The presence of an IgE portion in sera of human donors that is recognized by 8E7 indicates the existence of IgE molecules in different steric conformations in human blood, which may be related to pathologic parameters.
Antibodies, Monoclonal↗
Epitope-specific antibody response to IgE by mimotope immunization.
We have previously described a mouse monoclonal anti-human IgE antibody (BSW17) capable of recognizing receptor-bound IgE without inducing mediator release from human basophils or mast cells. Moreover, immune complexes of IgE and BSW17 are not able to bind to the IgE receptor. An initial attempt to map the precise epitope recognized by this mAb by using Fc epsilon-derived peptides of variable length was unsuccessful. However, by screening random peptide phage display libraries we isolated circular nona- and octapeptides specifically recognized by BSW17. These constrained peptides mimic at least a part of a conformational epitope and are thus called mimotopes. These mimotopes, either phage displayed or synthetically synthesized, did not react with any other anti-human IgE antibody tested, but efficiently inhibited the binding of human IgE to BSW17 only. The use of Rhodol-Green-labeled free cyclic peptide proved that these interactions were not carrier dependent. Immunization of rabbits with phage clones displaying the specific peptides on the surface induced an anti-human IgE response specific for the epitope of BSW17. Therefore, we conclude that such mimotopes or mimotope-derived peptides might be used for vaccination to induce in vivo a beneficial anti-IgE response as a novel immunotherapy.
Amino Acid Sequence↗
[Strategy and outcome of interdisciplinary therapy of ovarian carcinomas].
In this retrospective trial we analyzed the data for 200 patients with serous papillary ovarian cancer. The patients were treated with various operation strategies following an interdisciplinary conference among a surgeon, a gynecologist, and an oncologist. Mean overall survival was 26 months. It was significantly better in patients with primary and secondary debulking operations in combination with sufficient postoperative chemotherapy. The morbidity rate reached 16.8%, the overal mortality rate was 5.7%. The mortality for the first surgical intervention was 0%.
Adult↗
Suppression of in vivo IgE and tissue IL-4 mRNA induction by SDZ 280.636, a synthetic muramyl dipeptide derivative.
Modulation of IgE isotype expression on B cells is one of the numerous effects of muramyl peptides on the regulation of the immune system. A non toxic diacyl glycerol derivative of muramyl dipeptide (MDP), in which the L-alanine is replaced by L-threonine (MDP-Threo-GDP; SDZ 280.636), is currently under investigation as lead compound for the development of an anti-allergic drug. In this report, the modulatory effect of orally administered SDZ 280.636 in a murine model on polyclonally induced IgE levels is described. In this model, mice are injected i.v. with goal anti mouse IgD (GAMD) and challenged three to four weeks later with goal IgG (GIG). Both the primary and secondary immune responses lead to an increase of serum IgE levels. We demonstrate the efficacy of this muramyl dipeptide derivative in selectively inhibiting a polyclonal IgE response in GAMD-primed, GIG challenged mice without affecting the levels of other immunoglobulin classes. It is further shown that the induction of interleukin 4 (IL-4) gene transcript levels in lymphoid organs, which is observed as a consequence of boosting GAMD pretreated mice with GIG, is selectively suppressed in gut associated lymphoid tissues (GALT) and mesenteric lymph nodes but not in spleen. In contrast, interleukin 13 (IL-13) mRNA levels are not affected by SDZ 280.636. The findings that SDZ 280.636 inhibits polyclonal IgE responses and suppresses IL-4, but not IL-13 mRNA expression point towards differences in the regulatory pathways of IL-4 and IL-13 gene transcription in lymphoid organs. Thus the mechanism of action appears to involve a specific suppression of IL-4 gene transcription in cells occurring in Peyer's patches and mesenteric lymph nodes which are among the first constituents of the immune system encountered by an orally administered drug.
Animals↗
[Instrumental diagnosis for therapy decision making in abdominal injuries].
The aim of diagnostic procedures following abdominal injuries is rapid assessment of the necessity for surgical intervention and specification of the organ lesion, thus reducing the number of negative laparotomies. The extent of the diagnostic approach must be reduced in unstable patients. Sonography is the standard procedure in stable as well as in unstable patients, both in the initial period and the subsequent follow-up. CT-scan is complementary to sonography in detecting organ lesions. Sonographically guided puncture has replaced diagnostic peritoneal lavage. Laparoscopy following blunt abdominal injuries is not useful; however, it may be helpful following penetrating abdominal trauma.
Abdominal Injuries↗
[Strategy and outcome in bowel injuries after blunt abdominal trauma].
In this retrospective trial, we examined 215 patients with bowel lesions following abdominal injuries. We analyzed the diagnostic procedures, the time to diagnosis, the subsequent surgical therapy, and complications. The diagnosis of bowel lesions remains a diagnostic challenge. All apparative diagnostic procedures (sonography, CT-scan, lavage, laparoscopy, X-ray) fail to diagnose bowel lesions. In our trial, most patients showed clinical signs of peritonitis leading to diagnosis. Ultrasonographically guided puncture was important, if clinical signs remained unclear. This study underlines the importance of repeated clinical examination for early diagnosis and treatment of bowel injury.
Abdominal Injuries↗
[Strategy and results of advanced tumors in emergency situations].
In this retrospective trial we examined 142 patients with advanced unresectable cancer, who had bowel obstruction, bleeding, bowel lesion and abscesses and who were treated with different surgical procedures (resection, bypass, enterostomy). Mean survival rate was 8.6 months (range: 0-57 months). The mortality rate reached 21.7%. Surgical reintervention was necessary in 15.8% because of bowel obstruction and did not influence the survival rate. Despite advanced tumor disease and intestinal obstruction most patients had a good quality of life after surgical intervention.
Abdominal Abscess↗
Induction in mice of serum IgE levels after treatment with anti-mouse IgD antibodies is preceded by differential modulation of tissue cytokine gene transcription.
Injection of mice with purified goat anti-mouse IgD (GAMD) leads to an interleukin (IL)-4-dependent increase of serum IgE levels. Challenge of GAMD-primed mice with goat IgG (GIG) initiates a secondary immune response with elevated serum IgE. In this report, kinetic cytokine transcript profiles of murine lymphoid tissues in response to primary i.v. GAMD treatment, as well as GIG challenge are presented. For the first time, gene transcription patterns of the recently described cytokines IL-12 and IL-13 are shown and compared with the corresponding patterns for other cytokine genes involved in IgE regulation, i.e. IL-4, and interferon (IFN)-gamma. After GAMD injection, two groups of induction profiles were observed in spleen, mesenteric lymph nodes and Peyer's patches: while IL-4 and IL-12p35 gene transcription was strongly enhanced, IFN-gamma, IL-12p40 and IL-13 mRNA were only moderately induced. Generally, maximal mRNA induction was measured on days 3 to 4 after GAMD treatment. The data demonstrate a clear-cut difference between the IL-4 and IL-13 response on the transcriptional level although both gene products show similar biological activities. The cytokine mRNA profiles support the assumption of IL-4 playing the central role in generating an IgE response. However, they do not reflect a strict Th1 versus Th2 cytokine gene transcription pattern but rather point towards a concerted action of various, partially antagonizing cytokines with respect to the regulation of IgE synthesis. IL-12 may, possibly via stimulation of IFN-gamma synthesis, represent a counterbalancing factor in the IL-4-mediated IgE response.
Animals↗
A new pharmophoric model for 5-HT reuptake-inhibitors: differentiation of amphetamine analogues.
A pharmacophoric model for 5-HT reuptake-inhibitors was developed using the pharmacophore elements geometry and MEP (Molecular Electrostatic Potential) by the method of active analogue approach. This model is characterized by: (1) a protonated basic nitrogen separated by 610 pm from the center of an aromatic system and 920 pm from an electronegative substituent of this aromatic system, (2) a region with n- and/or pi-electrons along the axis substituent-aromatic system-nitrogen atom, (3) an aliphatic side chain which joins the region of the n- and/or pi-electrons with the nitrogen atom, (4) an additional aromatic group at right angles to the pharmacophoric aromatic group below the protonated nitrogen and (5) a forbidden region on the pharmacophore which leads to a deviation of the allowed tubular orientation of the ligand. The pharmacophore model enables a differentiation of the entactogenic, hallucinogenic and stimulating arylalkanamines. The theoretical considerations are confirmed by a postulated intramolecular H-bonding in the active conformation of the selective 5-HT reuptake-inhibitor, citalopram (12 in Fig. 2), which could be proved by NMR- and IR-spectroscopic measurements.
Amphetamines↗
Arterial, portal or combined arterio-portal regional chemotherapy in experimental liver tumours?
The most appropriate route for regional administration of chemotherapeutic drugs to liver tumours was studied in a standardized rodent model: cells of Novikoff hepatoma were transplanted into the central liver lobe of Sprague-Dawley rats. From day 5 to day 12 after transplantation, the liver was continuously perfused with 420 mg/kg 5'-fluoro-2-deoxyuridine by subcutaneous osmotic micropumps via the hepatic artery (n = 20), the portal vein (n = 20) or both vessels together (n = 12). The tumour multiplication factor (TMF) and the vascularization of the tumour were evaluated. Arterial and combined infusion led to a highly significant reduction in TMF, but combined infusion was not more effective than arterial alone. Portal infusion had no significant effect. There was no correlation between vascularization and tumour response in arterial infusion, but a strong correlation in portal infusion. Thus chemotherapy via the portal route may be effective in selected tumours with considerable portal vascularisation.
Animals↗
Hybrid genes expressing fusion peptides. A strategy for bacterial production of recombinant human interleukin-3 with a defined NH2-terminus.
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Amino Acid Sequence↗
Phonon-drag effect in GaAs-AlxGa1-xAs heterostructures at very low temperatures.
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Journal Article↗