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Biomedical subjects

U Müller

Publications and source records attributed to U Müller.

At least 91 records · Page 5Linked to original sources
PubMed2001

Mechanisms that regulate mechanosensory hair cell differentiation.

Hair cells of the vertebrate inner ear are mechanosensors that detect sound, gravity and acceleration. They have a specialized cytoskeleton optimized for the transmission of mechanical force. Hair cell defects are a major cause of deafness. The cloning of disease genes and studies of model organisms have provided insights into the mechanisms that regulate the differentiation of hair cells and their cytoskeleton. The studies have also provided new insights into the function of receptors such as integrins and protocadherins, and cytoplasmic proteins such as Rho-type GTPases and unconventional myosins, in organizing the actin cytoskeleton.

Actins↗
PubMed2001

[Treatment of anaphylactic shock].

Anaphylaxis is a life-threatening allergological emergency: it has to be recognized and treated immediately by the physician. Most often anaphylaxis is caused by drugs, foods and insect stings. Emergency treatment consists in intramuscular application of adrenaline and volume substitution. Only afterwards antihistamines and corticosteroids should be administered. All patients have to be hospitalized immediately and treated on an intensive care unit. After anaphylaxis the following preventive measures are most important: consultation with an allergist, including instruction for allergen avoidance and emergency medications. In anaphylaxis induced by insect stings specific immunotherapy should be started.

Adrenal Cortex Hormones↗
PubMed2001

Identification of molecular determinants required for interaction of ubiquitin-conjugating enzymes and RING finger proteins.

Recent results from several laboratories suggest that the interaction of E2 ubiquitin-conjugating enzymes with the RING finger domain has a central role in mediating the transfer of ubiquitin to proteins. Here we present a mutational analysis of the interaction between the E2 enzyme UbcM4/UbcH7 and three different RING finger proteins, termed UIPs, which, like Parkin, contain a RING1-IBR-RING2 motif. The results show that the E2 enzyme binds to the RING1 domain but not to the other cysteine/histidine-rich domains of the RING1-IBR-RING2 motif. Three regions within the UbcM4 molecule are involved in this interaction: the H1 alpha helix, loop L1, connecting the third and fourth strand of the beta sheet, and loop L2, located between the fourth beta strand and the second alpha helix. Loop L2 plays an important role in determining the specificity of interaction. The effects of L2 mutations on UbcM4/UIP interaction are different for each UIP, indicating that RING finger domains can vary considerably in their structural requirements for binding to E2 enzymes. The result that single amino-acid changes can regulate binding of E2 enzymes to different RING finger proteins suggests a novel approach to experimentally manipulate proteolytic pathways mediated by RING finger proteins.

Amino Acid Sequence↗
PubMed2001

[Malnutrition in COPD].

During the last years our knowledge about the malnutrition of patients with COPD has grown. Weight loss is a problem of some patients with COPD, but, as we know today by techniques of body composition measurement much more patients have reduced muscle mass. The reason for this is complex and involves many body systems. Nutritional intervention alone is not successful in many patients. We have to accept that COPD is a kind of systemic disease which does not only involve the lung. Thus, future therapies have to include not only treatment of the bronchial system.

Body Composition↗
PubMed2001

[Synaesthesia - towards a cognitive neuroscience of coloured hearing].

This review is about synaesthesia, a well known but still poorly investigated phenomenon. The most common form of synaesthesia is coloured hearing. Epidemiological and genetical studies show that synaesthesia has a higher prevalence in the normal population than previously stated. Most subjects are female and there is a clear heritability. Psychophysical investigations of synaesthetic mechanisms in normal subjects show reliable colour-tone-attributions. Single case studies with paradigms from experimental psychology found a high consistency of synaesthetic associations and observed behaviourally relevant interferences between primary perception and secondary synaesthetic sensations. The first studies using functional neuroimaging methods found specific neuronal correlates of synaesthesia. Neuropsychiatric studies analyze synaesthesia-like phenomena in patients with optical nerve lesions, upper limb amputation or severe depression and as induced by hallucinogenic drugs. Data-based and more speculative theories and models of synaesthesia are presented and critically discussed.

Auditory Perception↗
PubMed2001

Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy.

BACKGROUND: Antihistamine premedication has been used to increase safety of specific-allergen immunotherapy. Its influence on the efficacy of this treatment has not been studied so far. OBJECTIVE: The goal was to analyze the influence of antihistamine premedication on long-term efficacy of specific-allergen immunotherapy. METHOD: Patients included in a double-blind, placebo controlled trial who received premedication with terfenadine or placebo during initial rush immunotherapy with honeybee venom in 1988/1989 were assessed in a retrospective analysis for the long-term protective effect, as indicated by the tolerance of a bee sting challenge or field sting during immunotherapy. RESULTS: Of the 52 patients who had participated in the 1988/1989 trial, 47 could be reassessed after an average of 3 years. Of these, 45 were still receiving bee venom immunotherapy. A total of 41 patients were stung by bees while receiving immunotherapy (20 of the terfenadine-premedicated group and 21 of the placebo-premedicated group), 17 with in-field stings and 24 with in-hospital sting challenge. Six (29%) of the patients receiving placebo had a mild-to-moderate systemic allergic reaction, whereas none of the patients receiving terfenadine reacted to the bee sting (P =.012). CONCLUSIONS: These results indicate that antihistamine premedication during the initial phase of specific-allergen immunotherapy may enhance the efficacy of this treatment.

Adolescent↗
PubMed2001

Interferon-stimulated response element (ISRE)-binding protein complex DRAF1 is activated in Sindbis virus (HR)-infected cells.

To elucidate the host cell defense mechanisms in response to Sindbis viral infection, we have started to characterize interferon (IFN)-stimulated response element (ISRE)-binding proteins activated in infected cells that are involved in the transcriptional induction of IFN type I-inducible genes. Using electromobility shift assays (EMSA), we detected several protein complexes with a human IFN-stimulated gene 15 (ISG15) ISRE in extracts from virus-infected L929 cells that were absent in extracts from uninfected cells. Comigration with Newcastle disease virus-activated ISRE-binding complexes, ISRE-binding specificity, supershift experiments, and conditions of formation indicate that the complexes activated by Sindbis viral infection in L929 cells correspond to DRAF1 and ISG factor 3 (ISGF3). Transfection of L929 cells with poly rI:rC induced only ISGF3. DRAF1 could be detected in Sindbis virus-infected mouse embryo fibroblasts derived from IFNR type I and type II KO mice. Viral RNA synthesis is required for activation of DRAF1.

Animals↗
PubMed2001

In vivo evidence for differential association of striatal dopamine and midbrain serotonin systems with neuropsychiatric symptoms in Parkinson's disease.

Parkinson's disease affects various neurotransmitter systems. Using SPECT, the authors measured [(123)I]beta-CIT binding ratios of the caudate, putamen, medial thalamus, and dorsal midbrain over cerebellum in 16 patients with Parkinson's disease, and examined correlations with clinical ratings. Whereas striatal binding ratios (reflecting regional dopamine transporter densities) were associated with motor symptoms, dorsal midbrain binding ratios (reflecting regional serotonin transporter densities) were significantly correlated with the mentation, behavior, and mood subscale of the Unified Parkinson's Disease Rating Scale. These findings indicate that degeneration of the nigrostriatal dopaminergic neurons and a dysfunctional serotonergic raphe system contribute differentially to motor deficits and neuropsychiatric symptoms in Parkinson's disease.

Adult↗
PubMed2000

Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group.

Analysis of the gene GCH1 in 58 patients with dystonia and a positive response to L-dopa revealed mutations in 30 individuals from 22 families. Thirteen of the mutations observed were familial, three occurred de novo, and inheritance could not be determined in six cases. There was no mutation in the promoter region of GCH1 in any patient. The doses of L-dopa given to members of the two groups were not significantly different.

Adult↗
PubMed2000

Disruption of the gene encoding the ubiquitin-conjugating enzyme UbcM4 has no effect on proliferation and in vitro differentiation of mouse embryonic stem cells.

The ubiquitin-conjugating enzyme UbcM4, which is identical to the human enzyme UbcH7, was previously shown to be essential for normal mouse development. In order to study the possible role of UbcM4 for cell proliferation and in vitro differentiation, we here describe the establishment and characterization of fibroblast and embryonic stem cell lines with partial or complete inactivation of the UbcM4 gene. ES cell lines in which both alleles of the gene were inactivated by targeted mutagenesis showed no differences in growth rates, cell cycle progression and in vitro differentiation when compared to wild-type ES cells. Fibroblast cell lines with a partially inactivated UbcM4 gene were derived from embryos of the previously described A6 mouse mutant, where retrovirus integration has resulted in a recessive lethal mutation. As in the mutant embryos, steady levels of RNA and protein in the cell lines were reduced by about 70%. The mutant cell lines showed no differences in immortalization kinetics, growth rates and cell cycle progression when compared to wild-type fibroblasts. Taken together, our results strongly suggest that UbcM4-mediated ubiquitination and degradation are not necessary for proteins involved in the maintenance and growth of cells.

Animals↗
PubMed2000

Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.

The amyloid precursor protein (APP) involved in Alzheimer's disease is a member of a larger gene family including amyloid precursor-like proteins APLP1 and APLP2. We generated and examined the phenotypes of mice lacking individual or all possible combinations of APP family members to assess potential functional redundancies within the gene family. Mice deficient for the nervous system-specific APLP1 protein showed a postnatal growth deficit as the only obvious abnormality. In contrast to this minor phenotype, APLP2(-/-)/APLP1(-/-) and APLP2(-/-)/APP(-/-) mice proved lethal early postnatally. Surprisingly, APLP1(-/-)/APP(-/-) mice were viable, apparently normal, and showed no compensatory upregulation of APLP2 expression. These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1(-/-)/APP(-/-)/APLP2(+/-) mice display postnatal lethality. In addition, they provide genetic evidence for at least some distinct physiological roles of APP and APLP2 by demonstrating that combinations of single knock-outs with the APLP1 mutation resulted in double mutants of clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnormalities in the brain or any other organ examined. Moreover, cortical neurons from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitotoxicity in vitro.

Amyloid beta-Protein Precursor↗
PubMed2000

Crystal structure of hyaluronidase, a major allergen of bee venom.

BACKGROUND: Hyaluronic acid (HA) is the most abundant glycosaminoglycan of vertebrate extracellular spaces and is specifically degraded by a beta-1,4 glycosidase. Bee venom hyaluronidase (Hya) shares 30% sequence identity with human hyaluronidases, which are involved in fertilization and the turnover of HA. On the basis of sequence similarity, mammalian enzymes and Hya are assigned to glycosidase family 56 for which no structure has been reported yet. RESULTS: The crystal structure of recombinant (Baculovirus) Hya was determined at 1.6 A resolution. The overall topology resembles a classical (beta/alpha)(8) TIM barrel except that the barrel is composed of only seven strands. A long substrate binding groove extends across the C-terminal end of the barrel. Cocrystallization with a substrate analog revealed the presence of a HA tetramer bound to subsites -4 to -1 and distortion of the -1 sugar. CONCLUSIONS: The structure of the complex strongly suggest an acid-base catalytic mechanism, in which Glu113 acts as the proton donor and the N-acetyl group of the substrate is the nucleophile. The location of the catalytic residues shows striking similarity to bacterial chitinase which also operates via a substrate-assisted mechanism.

Allergens↗
PubMed2000

Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children (Dagher, R., and Helman, L. (1999) Oncologist 4, 34-44), whereas medulloblastoma, a highly malignant tumor of the cerebellum, accounts for 20% of childhood brain tumors (Goodrich, L. V., and Scott, M. P. (1998) Neuron 21, 1243-1257). Both tumors are associated with a deficiency in the tumor suppressor Patched (PTCH) in Gorlin syndrome (Gorlin, R. J. (1987) Medicine (Baltimore) 66, 98-113), and they are present in the corresponding murine models. RMS in Ptch mutant mice consistently contain elevated levels of the tumor growth-promoting insulin-like growth factor 2 (Igf2). We have investigated the mechanism of Igf2 overexpression and its significance in medulloblastoma and RMS tumorigenesis. Here we report that Igf2 is indispensable for the formation of medulloblastoma and RMS in Ptch mutants. Overexpression of Igf2 in RMS in these mice does not involve loss of imprinting, uniparental disomy, amplification of the Igf2 locus, or polyploidy. Since Igf2 is also overexpressed in non-tumor tissue deficient in Ptch, these observations suggest that Ptch regulates Igf2 levels through a transcriptional mechanism. They also identify Igf2 as a potential target for medulloblastoma and RMS.

Animals↗
PubMed2000

Association of an interleukin 1 alpha polymorphism with Alzheimer's disease.

BACKGROUND: Retrospective epidemiologic studies suggest that individuals exposed to anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs have a lower probability of developing AD as well as an older age at onset for the illness. Neuroinflammation may play an important role in the pathogenesis of AD. Interleukin 1 (IL-1), a potent proinflammatory cytokine, is colocalized immunohistochemically to neuritic plaques, a requisite neuropathologic feature for AD. A polymorphism in the 5'-flanking regulatory region at -889 of the IL-1 alpha gene (a C-to-T transition designated as IL-1A[-889] allele 2) may cause an overexpression of IL-1 alpha, a finding shown to be associated with inflammatory diseases. The IL-1A(-889) allele 2 polymorphism may be associated with AD pathogenesis. METHODS: A total of 259 patients with AD and 192 nondemented control subjects were included from two different centers (Indianapolis, IN, and Munich, Germany). Genotyping for APOE alleles and IL-1A(-889) allele 2 was performed by PCR-based amplification followed by restrictive endonuclease digestion. Statistical analyses were conducted by center-, gender group-, and age group-stratified Mantel-Haenszel odds ratios, CI, and p values. RESULTS: The allele frequency of IL-1A(-889) allele 2 was 46% in clinically diagnosed patients with probable AD versus 34% in control subjects from the combined centers. CONCLUSION: The authors found an increased risk for AD with an estimated Mantel-Haenszel odds ratio of 1.68 (95% CI 1.1 to 2.6; p = 0.022) for heterozygous carriers and 7.2 (95% CI 2.0 to 24.5; p = 0.003) for individuals homozygous for IL-1A(-889) allele 2. They found no evidence for an interaction between the IL-1A and the apoE epsilon 4 polymorphisms (carriers and homozygotes), age, or gender with regard to conferred risk. The data strongly support an association between the IL-1A(-889) allele 2, especially in homozygotes, and later-onset AD.

Aged↗
PubMed2000

Transcription mapping of the 5q- syndrome critical region: cloning of two novel genes and sequencing, expression, and mapping of a further six novel cDNAs.

The 5q- syndrome is a myelodysplastic syndrome with the 5q deletion ¿del(5q) as the sole karyotypic abnormality. We are using the expressed sequence tag (EST) resource as our primary approach to identifying novel candidate genes for the 5q- syndrome. Seventeen ESTs were identified from the Human Gene Map at the National Center for Biotechnology Information that had no significant homology to any known genes and were assigned between DNA markers D5S413 and D5S487, flanking the critical region of the 5q- syndrome at 5q31-q32. Eleven of the 17 cDNAs from which the ESTs were derived (65%) were shown to map to the critical region of the 5q- syndrome by gene dosage analysis and were then sublocalized by PCR screening to a YAC contig encompassing the critical region. Eight of the 11 cDNA clones, upon full sequencing, had no significant homology to any known genes. Each of the 8 cDNA clones was shown to be expressed in human bone marrow. The complete coding sequence was obtained for 2 of the novel genes, termed C5orf3 and C5orf4. The 2.6-kb transcript of C5orf3 encodes a putative 505-amino-acid protein and contains an ATP/GTP-binding site motif A (P loop), suggesting that this novel gene encodes an ATP- or a GTP-binding protein. The novel gene C5orf4 has a transcript of 3.1 kb, encoding a putative 144-amino-acid protein. We describe the cloning of 2 novel human genes and the sequencing, expression patterns, and mapping to the critical region of the 5q- syndrome of a further 6 novel cDNA clones. Genomic localization and expression patterns would suggest that the 8 novel cDNAs described in this report represent potential candidate genes for the 5q- syndrome.

Amino Acid Sequence↗
PubMed2000

[Effect of logistic and medical emergency resources on fatal outcome of severe trauma].

122 cases of patients who died in sequel of an accident (recruitment period 1993/94, mean ISS 40 +/- 19) in reach of air rescue base Dresden, Germany, were examined. Data were assessed from autopsy protocol and the protocol of the physician who treated on scene. We analyzed the time course of the emergency, the scheduled emergency medical service and the quality of prehospital diagnosis and therapy by the emergency team. The mean response time was 8.1 +/- 5.9 min, the mean distance between EMS bases und incident location 5.9 +/- 5.7 km. In 94.4% of all cases a mobile intensive care unit--with an emergency physician as crew member--was on scene, in 5.6% a paramedic car. Air rescue by helicopter, including an emergency physician, was performed only in 8.7% of all cases although a helicopter was available in 54% of all accidents. Mechanisms of injury were traffic accident (71.4%), fall (14.3), 5.9% accident on building site, shot and stab injuries (5.9%) and burns (1.7%). 82 patients reached the emergency room alive (67.2% mean ISS 37 +/- 18). Only 26% of all patients were transported directly to a level I trauma center. Mean survival time of all 122 patients was 146 +/- 30.4 h. Severe head injury described by autopsy protocol was diagnosed on scene in 82%. Preclinical treatment was:intubation and ventilation (63%), O2 insufflation (17.4%), no specific treatment (19.6%). Severe thoracic trauma was diagnosed in 54%. Preclinical treatment was:intubation and ventilation (64.8%), O2 application (18.8%), no specific treatment (16.2%). Severe thoracic trauma with hemato-pneumothorax (n = 26) was recognized by the emergency physician in 65.6%, specific therapy (application of chest drain) was performed in 7.1%. Preclinical diagnosis rates concerning abdominal trauma were 29% and 27.8% in case of unstable pelvis fracture. Hemorrhagic shock related to these injuries was found in 44.2%, mean resuscitation volume applicated in these cases was 960 +/- 610 ml. Typical faults in diagnosis and treatment were underestimating of severe trunk trauma and non-consistent use of invasive treatment procedures. Primary transport of the severely injured patient to a level I trauma center by helicopter was performed only rarely.

Adult↗