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Biomedical subjects

U Müller

Publications and source records attributed to U Müller.

At least 163 records · Page 9Linked to original sources
PubMed1998

Induction of a specific olfactory memory leads to a long-lasting activation of protein kinase C in the antennal lobe of the honeybee.

In this study we investigated the role of protein kinase C (PKC) in associative learning of Apis mellifera. Changes in PKC activity induced by olfactory conditioning were measured in the antennal lobes, a brain structure involved in associative learning. Multiple conditioning trials inducing a memory different from that induced by a single conditioning trial specifically cause an increase in PKC activity. This increase begins 1 hr after conditioning, lasts up to 3 d, and is attributable to an increased level of constitutive PKC. The increased level of constitutive PKC consists of an early proteolysis-dependent phase and a late phase that requires RNA and protein synthesis. Inhibition of the pathways resulting in constitutive PKC selectively impairs distinct phases of multiple-trial induced memory. The inhibition of the proteolytic mechanism has an instant effect on an early phase of multiple-trial induced memory but does not affect acquisition and the late phase of memory. Blocking of the transient PKC activation during conditioning does not affect the induction of memory formation. Thus, the constitutive PKC in the antennal lobe seems to contribute to the early phase of memory that is induced by multiple-trial conditioning.

Animals↗
PubMed1998

Utilization of a soluble integrin-alkaline phosphatase chimera to characterize integrin alpha 8 beta 1 receptor interactions with tenascin: murine alpha 8 beta 1 binds to the RGD site in tenascin-C fragments, but not to native tenascin-C.

The integrin alpha 8 beta 1 has been reported to bind to fibronectin, vitronectin, and tenascin-C in cell adhesion or neurite outgrowth assays. Here, we describe cDNA cloning of the murine alpha 8 subunit, purification of a recombinant soluble heterodimer consisting of the extracellular domains of the murine alpha 8 and beta1 subunits, and development of a sensitive binding assay using a modified form of this heterodimer fused to alkaline phosphatase (AP). In binding assays, the purified alpha 8 beta 1-AP chimera exhibited the same divalent ion requirements for activation and binding specificity as cell surface alpha 8 beta 1: in the presence of Mn2+ it bound to fibronectin and vitronectin in an RGDS-peptide inhibitable manner. Contrary to previous reports, we found no evidence that alpha 8 beta 1, expressed on K562 cells or as an AP chimera, interacts strongly with native tenascin-C. In binding, adhesion, and spreading assays, significant interactions were observed only to short fragments of tenascin-C containing the third fibronectin type III repeat which contains an RGD sequence. Full length tenascin-C and longer fragments containing this repeat did not appear to serve as ligands, implying that the RGD site in native tenascin-C is a cryptic binding site for this integrin, exposed by removal of adjacent domains. Soluble integrin-AP chimeras should be generally useful for identifying and characterizing integrin interactions with ligands.

Alkaline Phosphatase↗
PubMed1998

D1- versus D2-receptor modulation of visuospatial working memory in humans.

The effects of pergolide, a mixed D1/D2 receptor agonist, and bromocriptine, a selective D2 receptor agonist, were assessed in a visual delay task to further investigate the "dopamine link" of working memory in humans and to look for differential D1 versus D2 receptor contributions. Two groups of 32 healthy young adults (16 female) received either 0.1 mg of pergolide or 2.5 mg of bromocriptine in a placebo-controlled cross-over design. A pretreatment with domperidone, a peripherally active D2 antagonist, was performed in both groups to reduce side effects. Interindividual differences in pharmacokinetics were controlled by the time course of serum prolactin inhibition. The working memory paradigm was a visuospatial delayed matching task; the location of a randomly generated seven-point pattern had to be memorized and compared after 2, 8, or 16 sec with a second pattern that was either identical or slightly shifted within a reference frame. The task was designed with the intention to present unique stimuli at each trial and to require minimal motor demands. Practice effects between the two pharmacological test days were minimized by training sessions that preceded the tests. The paradigm showed significant error and reaction time increases with longer delays. After comparable doses, only pergolide, but not bromocriptine, facilitated visuospatial working memory performance as demonstrated by a significant drug-by-delay interaction. These findings are in accordance with the monkey literature as well as with neuroanatomical findings, and they confirm a preferential role of prefrontal D1 receptors for working memory modulation in humans.

Adult↗
PubMed1998

Recent developments in the molecular genetics of mitochondrial disorders.

Rapid progress has been made in the identification of mitochondrial DNA mutations which are typically associated with diseases of the nervous system and muscle. The well established mitochondrial disorders are maternally inherited and males and females are equally affected. An exception is Leber's hereditary optic atrophy (LHON) which is observed much more frequently in males than in females. There are three common point mutations in LHON which can be homoplasmic or heteroplasmic. In mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) most mutations are single base changes and lie within the tRNA-Leu gene. Point mutations in myoclonic epilepsy with ragged red fibres (MERRF) usually occur within the tRNA-Lys gene but mutations of the tRNA-Leu gene are also observed. MELAS and MERRF mutations are heteroplasmic and there is considerable clinical overlap between these diseases. Point mutations within the ATPase6 gene result in either neuropathy, ataxia and retinitis pigmentosa (NARP) or in Leigh's syndrome. The latter occurs if the mutation is present in the majority of mitochondria (extreme heteroplasmy). Finally, mitochondrial DNA deletions are the cause underlying Kearns-Sayre syndrome (KSS). Apart from the well-established mitochondrial diseases, there is increasing evidence that mitochondrial mutations may also play a role in the neurodegenerative disorders Parkinson, Alzheimer and Huntington disease. The complex I defect found in Parkinson disease is especially interesting in this respect. However, no causative mitochondrial mutation has as yet been established in any of these three common disorders.

Animals↗
PubMed1998

Molecular cytogenetic delineation of the critical deleted region in the 5q- syndrome.

The 5q- syndrome is a distinct type of myelodysplastic syndrome (MDS) characterised by refractory anaemia, morphological abnormalities of megakaryocytes, and del(5q) as the sole cytogenetic abnormality. In contrast to patients with therapy-related MDS with 5q deletions, 5q- syndrome patients have a favourable prognosis and a low rate of transformation to acute leukaemia. We have previously delineated a common deleted region of 5.6 Mb between the gene for fibroblast growth factor acidic (FGF1) and the subunit of interleukin 12 (IL12B) in two patients with 5q- syndrome and small deletions, del(5)(q31q33). The present study used fluorescence in situ hybridisation (FISH) analysis of these and a third 5q- syndrome patient with a small deletion, del(5)(q33q34), to refine further the critical deleted region. This resulted in the narrowing of the common deleted region within 5q31.3-5q33 to approximately 3 Mb, flanked by the adrenergic receptor beta 2 (ADRB2) and IL/2B genes. The common region of loss in these three 5q- syndrome patients includes the macrophage colony-stimulating factor-1 receptor (CSF1R), secreted protein, acidic, cysteine-rich (SPARC), and glutamate receptor (GR1A1) genes. This 5q- syndrome critical region is telomeric to and distinct from the other critical regions on 5q associated with MDS and acute myeloid leukaemia.

Adult↗
PubMed1998

Expression level of a transgenic lambda2 chain results in isotype exclusion and commitment to B1 cells.

Two new lambda2 chain-transgenic mouse lines were established, both of which showed stable transgene expression during aging of the mice. The line L23, which expressed the transgene at low levels, exhibited normal B cell development, antibody responses and serum Ig levels. Most of the B cells in this mouse line co-expressed the transgenic lambda2 chain together with an endogenous kappa chain, thus showing poor allelic exclusion of endogenous L chains. On the other hand, high expression of the transgenic lambda2 chain in the other mouse line, L2, resulted in nearly complete exclusion of endogenous L chain isotypes. In this line, the lambda2 transgene was already detectable in the cytoplasm of all preB-II cells and some pro/preB-I cells. Its expression during these early phases obviously inhibited development of conventional B2 cells, since the B cells in the periphery of these mice were almost exclusively of the B1 type. This finding was confirmed by adoptive transfer of transgenic bone marrow into lethally irradiated recipients. Very few B cells were present in the spleen of such recipients. The serum IgM levels of L2 mice were close to normal and the majority of these IgM were associated with the transgenic lambda2 chain. Antibody responses to thymus-dependent antigens in such mice were almost exclusively found to be of IgM class. Together, these findings indicate a developmental bias leading to a predominance of B1 cells in the L2 line.

Adoptive Transfer↗
PubMed1998

High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia.

We performed a clinical and molecular genetic analysis in members of five families with dopa-responsive dystonia. Four mutations were detected in the gene GCH1 that codes for GTP cyclohydrolase I. Two of these mutations, a delG309 in exon 1 and a C544T transition in exon 5, have not been described before. They result in inactivation of the enzyme by truncation. The remaining two mutations, both A to G transitions, a(-2)g in intron 1 and a(-2)g in intron 2, cause truncation by abnormal splicing. The genotype of family members was correlated to their clinical phenotype (obtained before molecular analysis). Clinical symptoms observed in the families included generalized and focal dystonia, abnormal gait, and subtle signs such as an abnormal writing test. High penetrance (0.8-1.0) was observed in four of five families if minor symptoms and signs were considered. A given mutation was more likely to cause symptoms in females than in males, thus confirming the well-established higher incidence of dopa-responsive dystonia in females than in males.

Adolescent↗
PubMed1998

[Electroconvulsive therapy in psychiatric clinics in Germany in 1995].

A total of 451 German psychiatric hospitals were asked in 1995 about their use of electroconvulsive therapy (ECT). As ECT nowadays is well accepted as a therapeutic tool, we wanted to compare our data with data collected in former inquiries in 1977 and 1985 and to acquire information from the new German States. Since 1977, the use of ECT has evidently increased. The psychiatric hospitals that often use ECT are for scattered throughout the whole country. ECT is mainly indicated for febrile catatonia/febrile stupor and depressive stupor, not for schizophrenia. ECT is applied especially when depressive patients are resistant or intolerant of psychopharmacotherapy. The preparation and application correspond to the standards. One focus in the present study was the attitudes of the managing directors towards ECT. Data were collected by open questionnaires. When these data were compared with data from a standardized inquiry of 1985, a similar trend was found regarding positive statements about ECT. Statements are emphasized even more when using open questionnaires. If there is a strong indication for ECT, the basic attitudes of the managing directors toward ECT are very positive. However, its application is in fact much more influenced by social factors than by indication because of negative attitudes by colleagues and nursing staff and political and stereotypic thinking of the general population.

Attitude of Health Personnel↗
PubMed1998

[Tau protein. A potential biological indicator for early detection of Alzheimer disease].

In 40 patients with Alzheimer's disease (AD), in 5 patients with non-AD dementia and in 36 cognitively normal controls the concentration of protein tau was determined in the cerebrospinal fluid (CSF). Of the AD patients, 19 were very mildly demented (MMSE score from 25 to 28). Even in these patients, CSF tau was significantly more elevated than in controls. In the non-AD patients protein tau was less increased. Among the AD patients there was no association between CSF tau and severity of cognitive impairment or deficit in cerebral blood flow, determined by SPECT. Our findings suggest that CSF tau may be elevated even at the predementia stage of AD and be useful as a biological marker for the early recognition of the disease.

Adult↗
PubMed1998

Genomic structure and complete sequence of the human FGFR4 gene.

We report the genomic structure and entire sequence of the fibroblast growth factor receptor 4 (FGFR4) gene. The gene spans approximately 11.3 kb. It is composed of 18 exons ranging in size from 71 bp to 600 bp. Exon-intron boundaries follow the GT/AG rule. Exon 1 is untranslated and preceded by structural elements characteristic of a TATA-free promoter. Although there are promoter motifs in intron 4 as well, there is currently no evidence of alternative transcription of FGFR4. Comparison of exon-intron boundaries of FGFR4 with those of FGFR1 and 3 reveals a remarkable degree of homology. With the exception of four, exon boundaries are at identical positions in all three receptor genes. Short tandem repeat polymorphisms (STRPs) were identified in introns 2 and 16 of FGFR4. The STRPs together with the sequence information will facilitate the rapid analysis of FGFR4 in those human disorders in which this gene can be considered a candidate.

Amino Acid Sequence↗
PubMed1998

The mutations in FGFR2-associated craniosynostoses are clustered in five structural elements of immunoglobulin-like domain III of the receptor.

Exons 5 and 7 of the fibroblast growth factor receptor 2 (FGFR2) gene code for immunoglobulin-like domain III (IgIII) and for the region connecting the second and the third Ig domain of the receptor. Numerous mutations in these two exons have been shown to cause various craniosynostotic syndromes. Here, we describe three previously unrecognized mutations at amino acid positions 276, 301, and 314, in one nonspecific craniosynostosis and in two Crouzon patients. We also present a polypeptide model of IgIII of FGFR2. The known mutations involve five distinct structural elements of the receptor. The changes within these elements affect receptor function by various mechanisms, including altered dimerization, truncation, increased mobility between Ig domains, disintegration of IgIII, and alteration of the ligand-binding site.

Craniofacial Dysostosis↗
PubMed1998

Clinical and molecular genetics of primary dystonias.

Primary dystonias are movement disorders with dystonia as a major symptom. They are frequently inherited as Mendelian traits. There are at least eight clinically distinct autosomal dominant and two X-linked recessive forms. In addition, pedigree analyses suggest the occurrence of an autosomal recessive variant. The clinical classification is increasingly being replaced by a genetic one. To date gene loci have been identified in at least six autosomal dominant forms, i.e., in idiopathic torsion dystonia (9q34), focal dystonia (18p), adult-onset idiopathic torsion dystonia of mixed type (8p21-q22), dopa-responsive dystonia (14q22.1-q22.2), and paroxysmal dystonic choreoathetosis (2q25-q33; 1p21-p13.3). Gene loci in the X-linked recessive forms have been assigned to Xq13.1 in the X-linked dystonia parkinsonism syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental retardation. The disease genes have been identified in two autosomal dominant forms and in one X-linked recessive form. Mutations in a gene coding for an ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the GTP cyclohydrolase 1 gene is mutated in dopa-responsive dystonia (DYT5). In sensorineural deafness, dystonia, and mental retardation, mutations were found in the gene DDP coding for a polypeptide of unknown function. This article reviews the clinical and molecular genetics of primary dystonias, critically discusses present findings, and proposes referring to the known forms, most of which can be distinguished by genetic criteria, as dystonias 1-12.

Carrier Proteins↗
PubMed1998

Paternal age is a risk factor for Alzheimer disease in the absence of a major gene.

We compared the parental age at birth of patients with Alzheimer disease (AD) with that of cognitively healthy control subjects. Within 206 carefully diagnosed AD patients, two groups were distinguished according to the likelihood of carrying a major gene for AD (MGAD). This likelihood was calculated by applying a Bayesian approach which incorporates data on aggregation of the disease, age at onset, and "censoring" ages within the family. All AD patients were ranked by MGAD probability. According to the sample's quartiles, two subgroups were defined representing the 52 individuals with the lowest and the 52 with the highest MGAD probability. Age at onset of dementia, education, and apolipoprotein E epsilon4 allele frequencies were not statistically different between the two groups. Fathers of patients with a low MGAD probability were significantly older (35.7+/-8.1 years) than fathers of both other groups (high MGAD probability 31.3+/-6.9 years, P=0.004; controls 32.6+/-6.8 years, P=0.04, n=50). The differences for mothers were less pronounced and not statistically significant. These findings suggest that increased paternal age is a risk factor for AD in the absence of a major gene, whereas increased maternal age and AD are associated only weakly and independently of genetic disposition.

Adult↗
PubMed1998

Indirect reduction with a condylar blade plate for osteosynthesis of subtrochanteric femoral fractures.

Subtrochanteric fractures frequently occur as high energy trauma usually in younger patients and may lead to severe comminution of the medial cortex. The medial cortex of the proximal femur is exposed to high compressive forces which make fracture stabilization a difficult problem. Bone healing may be seriously compromised due to extensive comminution and fragment devitalization. This requires reduction techniques which do not cause additional damage to the vitality of the bone. With indirect reduction techniques and the use of a condylar blade plate the results have been significantly improved in these fracture types in our department (1). In this report the essential aspects of indirect reduction for subtrochanteric fractures using a condylar blade plate and the treatment results from our department from earlier years (1) and from the last 2 1/2 years will be presented. In the latter period, fifteen patients with a mean age of 49 years (19-87 years) were treated with this method. Fractures resulted from traffic incidents or falls from a great height in 11 cases (73%). Union was achieved in 14 cases (93%) with full weight-bearing after a mean of 3 months (1-4 1/2 months). Malunion was seen in two cases (13%) without the need for further surgery. Non union occurred in one patient (7%) with a III B open injury due to early infection. After repeated debridements, bone grafting and decortication, the fracture was stabilized with a replacement condylar blade plate and healed uneventfully.

Accidental Falls↗
PubMed1998

Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom.

BACKGROUND: Specific immunotherapy with honeybee venom (BV) is highly effective, but allergic side effects can occur during treatment. Immunotherapy with peptides containing major T-cell epitopes of the relevant allergen or allergens provides an alternative strategy without these problems. OBJECTIVE: The study investigates the immunologic mechanisms and clinical effects of immunotherapy with T-cell epitope peptides of the major BV allergen, the phospholipase A2 (PLA). METHODS: Five patients with IgE-mediated systemic allergic reactions to bee stings were treated with a mixture of three T-cell epitope peptides of PLA. Ten patients allergic to BV receiving whole BV immunotherapy served as control subjects. Increasing doses of the peptide mixture, up to a maintenance dose of 100 microg, were administered subcutaneously within 2 months. The patients were then challenged with PLA and 1 week later with a bee sting. The cellular and humoral immune response was measured in vitro. RESULTS: No allergic side effects were caused by the peptide immunotherapy, and all patients tolerated the challenge with PLA without systemic allergic symptoms. Two patients developed mild systemic allergic reactions after the bee sting challenge. After peptide immunotherapy, specific proliferative responses to PLA and the peptides in peripheral blood mononuclear cells were decreased in successfully treated patients. The production of TH2 and TH1 cytokines was inhibited, and B cells were not affected in their capacity to produce specific IgE and IgG4 antibodies. Their levels increased after allergen challenge in favor of IgG4. CONCLUSIONS: Immunotherapy of BV allergy with short T-cell peptides of PLA induces epitope-specific anergy in peripheral T cells and changes the specific isotype ratio in a fashion similar to that of conventional immunotherapy in successfully treated patients.

Adolescent↗