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Biomedical subjects

Ulrich Müller

Publications and source records attributed to Ulrich Müller.

69 records · Page 4Linked to original sources
PubMed2003

Glomerular and renal vascular structural changes in alpha8 integrin-deficient mice.

Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the alpha8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. alpha8-deficient (alpha8-/-) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of alpha8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of alpha8-/- mice would be completely normal. Therefore, the renal phenotype of adult alpha8-/- mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. alpha8-/- mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and alpha8-/- mice. Quantitative morphologic analyses revealed that the glomeruli of alpha8-/- mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the alpha8 ligand fibronectin) was expanded in alpha8-/- mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of alpha8-/- mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor alpha2 integrin in alpha8-/- mice. The glomerular capillary length density was significantly greater in alpha8-/- mice than in wild-type mice. Cortical arterial vessel walls were not altered in alpha8-/- mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of alpha8, glomerular and renal vascular alterations in alpha8-/- mice were relatively mild. Only aged alpha8-/- mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of alpha8 can be largely compensated for, at least in younger alpha8-/- mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor alpha2 contribute to maintaining the glomerular structure in alpha8-/- mice. The compensatory mechanisms involved will be the subject of future research.

Animals↗
PubMed2003

The development of executive function in early childhood.

According to the Cognitive Complexity and Control (CCC) theory, the development of executive function can be understood in terms of age-related increases in the maximum complexity of the rules children can formulate and use when solving problems. This Monograph describes four studies (9 experiments) designed to test hypotheses derived from the CCC theory and from alternative theoretical perspectives on the development of executive function (memory accounts, inhibition accounts, and redescription accounts). Each study employed a version of the Dimensional Change Card Sort (DCCS), in which children are required first to sort cards by one pair of rules (e.g., color rules: "If red then here, if blue then there"), and then sort the same cards by another, incompatible pair of rules (e.g., shape rules). Study 1 found that although most 3- to 4-year-olds failed the standard version of this task (i.e., they perseverated on the preswitch rules during the postswitch phase), they usually performed well when they were required to use four rules (including bidimensional rules) and those rules were not in conflict (i.e., they did not require children to respond in two different ways to the same test card). These findings indicate that children's perseveration cannot be attributed in a straightforward fashion to limitations in children's memory capacity. Study 2 examined the circumstances in which children can use conflicting rules. Three experiments demonstrated effects of rule dimensionality (uni- vs. bidimensional rules) but no effects of stimulus characteristics (1 vs. 2 test cards; spatially integrated vs. separated stimuli). Taken together, these studies suggest that conflict among rules is a key determinant of difficulty, but that conflict interacts with dimensionality. Study 3 examined what types of conflict pose problems for 3- to 4-year-olds by comparing performance on standard, Partial Change, and Total Change versions of the DCCS. Results revealed effects of conflict at the level of specific rules (e.g., "If red, then there"), rather than specific stimulus configurations or dimensions per se, indicating that activation of the preswitch rules persists into the postswitch phase. Study 4 examined whether negative priming also contributes to difficulty on the DCCS. Two experiments suggested that the active selection of preswitch rules against a competing alternative results in the lasting suppression of the alternative. Taken together, the results of these studies provide the basis for a revision of the CCC theory (CCC-r) that specifies more clearly the circumstances in which children will have difficulty using rules at various levels of complexity, provides a more detailed account of how to determine the complexity of rules required in a task, takes account of both the activation and inhibition of rules as a function of experience, and highlights the importance of taking intentionality seriously in the study of executive function.

Attention↗
PubMed2003

Erbb2 regulates neuromuscular synapse formation and is essential for muscle spindle development.

Neuregulins and their Erbb receptors have been implicated in neuromuscular synapse formation by regulating gene expression in subsynaptic nuclei. To analyze the function of Erbb2 in this process, we have inactivated the Erbb2 gene in developing muscle fibers by Cre/Lox-mediated gene ablation. Neuromuscular synapses form in the mutant mice, but the synapses are less efficient and contain reduced levels of acetylcholine receptors. Surprisingly, the mutant mice also show proprioceptive defects caused by abnormal muscle spindle development. Sensory Ia afferent neurons establish initial contact with Erbb2-deficient myotubes. However, functional spindles never develop. Taken together, our data suggest that Erbb2 signaling regulates the formation of both neuromuscular synapses and muscle spindles.

Actins↗
PubMed2002

The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions.

Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness, vestibular dysfunction, and visual impairment. Several genetic loci have been linked to USH1, and four of the relevant genes have been identified. They encode the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative adhesion receptors cadherin 23 (CDH23) and protocadherin 15 (PCDH15). We show here that CDH23 and harmonin form a protein complex. Two PDZ domains in harmonin interact with two complementary binding surfaces in the CDH23 cytoplasmic domain. One of the binding surfaces is disrupted by sequences encoded by an alternatively spliced CDH23 exon that is expressed in the ear, but not the retina. In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer. Because CDH23-deficient mice have splayed stereocilia, our data suggest that CDH23 and harmonin are part of a transmembrane complex that connects stereocilia into a bundle. Defects in the formation of this complex are predicted to disrupt stereocilia bundles and cause deafness in USH1 patients.

Amino Acid Sequence↗
PubMed2002

Reelin, Disabled 1, and beta 1 integrins are required for the formation of the radial glial scaffold in the hippocampus.

The extracellular matrix molecule Reelin is required for the correct positioning of neurons during the development of the forebrain. However, the mechanism of Reelin action on neuronal migration is poorly understood. Reelin is assumed to act on neurons directly, but it may also affect the differentiation of glial cells necessary for neuronal migration. Here we show that a regular glial scaffold fails to form in vivo in the dentate gyrus of mice deficient of Reelin or Disabled 1, a neuronal adaptor protein in the Reelin signaling pathway. A subset of these defects is observed in mice that lack beta(1)-class integrins, known to bind Reelin. Moreover, recombinant Reelin induced branching of glial processes in vitro. Our data suggest that Reelin affects glial differentiation via Disabled 1 and beta(1)-class integrin-dependent signaling pathways.

Animals↗
PubMed2002

[Symmetry in perovskite variants].

The relationships among the huge number of derivative structures of the perovskite type are rationalized in a concise manner using group-subgroup relations between space groups. One family tree of such relations is given for perovskites having tilted coordination octahedra. Further group-subgroup relations are concerned with distortions of the octahedra, such as Jahn-Teller distortions or with atoms shifted from the octahedron centres. In these cases, the space-group symmetry reductions must allow site symmetry reductions of the occupied sites in the perovskite structure. On the other hand, subgroups in which the perovskite sites split into different independent sites are necessary for derivative structures with atom substitutions, such as in the elpasolites A(2)EMX(6). In addition, substitutions and distortions can be combined in adequate subgroups. Substitutions may also involve the occupation of atom sites of perovskite by molecular groups such as N(CH(3))(4)(+) or other organic cations, or by molecules like acetonitrile. If they are ordered, their molecular symmetry requires further space-group symmetry reductions. The anions can be replaced by cyanide ions or by NO(2)(-) ions; space-group symmetry then depends on the temperature-dependent degree of order. The relationships can be used to predict if and what kind of twinning may occur in phase transitions and whether second-order phase transitions are possible.

English Abstract↗
PubMed2002

Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment.

Type I allergy is an immunoglobulin E (IgE)-mediated hypersensitivity disease affecting more than 25% of the population. Currently, diagnosis of allergy is performed by provocation testing and IgE serology using allergen extracts. This process defines allergen-containing sources but cannot identify the disease-eliciting allergenic molecules. We have applied microarray technology to develop a miniaturized allergy test containing 94 purified allergen molecules that represent the most common allergen sources. The allergen microarray allows the determination and monitoring of allergic patients' IgE reactivity profiles to large numbers of disease-causing allergens by using single measurements and minute amounts of serum. This method may change established practice in allergy diagnosis, prevention, and therapy. In addition, microarrayed antigens may be applied to the diagnosis of autoimmune and infectious diseases.

Allergens↗
PubMed2002

The balance beam in the balance: reflections on rules, relational complexity, and developmental processes.

The lead articles by Jansen and van der Maas (2002, this issue) and Halford, Andrews, Dalton, Boag, and Zielinski (2002, this issue) raise numerous questions concerning the development of rule use and how best to assess it. In this Reflection, we focus on the following: (a) When can one infer the use of a rule? (b) What are the mechanisms underlying the development of rule use? and (c) What is the relation between understanding and execution? In addressing these questions, we contrast relational complexity theory with cognitive complexity and control (CCC) theory.

Adolescent↗
PubMed2002

The alpha8 integrin chain affords mechanical stability to the glomerular capillary tuft in hypertensive glomerular disease.

In the kidney, the alpha8 integrin chain is expressed in glomerular mesangial cells. The alpha8 integrin plays a role in early nephrogenesis but its functional role in the adult kidney is unknown. We tested the hypothesis that alpha8 integrin-mediated cell-matrix interactions are important to maintain the integrity of the glomerulus in arterial hypertension. Desoxycorticosterone (DOCA)-salt hypertension was induced in mice homozygous for a deletion of the alpha8 integrin chain and wild-type mice. Blood pressure, albumin excretion, total renal mass, and glomerular filtration in DOCA-treated alpha8-deficient mice were comparable to DOCA-treated wild types. DOCA-treated wild types showed increased glomerular immunostaining for alpha8 integrin compared to salt-loaded and untreated controls, whereas the glomeruli of alpha8-deficient mice always stained negative. Morphometric studies revealed similar degrees of glomerulosclerosis in DOCA-treated alpha8-deficient and DOCA-treated wild-type mice. However, DOCA-treated alpha8-deficient mice had a higher score of capillary widening (mesangiolysis) than DOCA-treated wild-type mice, which was confirmed in two additional wild-type strains. Moreover, in DOCA-treated alpha8-deficient mice, glomerular fibrin deposits were more frequent than in DOCA-treated wild types. The results show that lack of alpha8 is associated with increased susceptibility to glomerular capillary destruction in DOCA salt hypertension, whereas it does not seem to play a major role in the development of fibrosis or glomerulosclerosis. Our findings indicate that mesangial alpha8 integrin contributes to maintain the integrity of the glomerular capillary tuft during mechanical stress, eg, in hypertension.

Animals↗
PubMed2002

[A case of kleptomania?].

We report on a case of kleptomania with manifestation as deceptive ordering by catalogue. The patient is additionally suffering from severe agoraphobia.

Agoraphobia↗
PubMed2002

The Adaptive Digit Ordering Test: clinical application, reliability, and validity of a verbal working memory test.

In the face of ample experimental evidence on the importance of working memory capacity for everyday life, there is a growing need for measures suited for clinical assessment of working memory. For this purpose, the Adaptive Digit Ordering Test (DOT-A), a new version of a digit ordering test introduced by Cooper et al. [Brain 114 (1991) 2095], was developed in analogy to the Digit spans. In Study 1, we investigated DOT-A performance in patients with Parkinson's disease (PD) and patients with frontal lobe damage, as these groups often exhibit working memory impairments within the framework of executive dysfunctions. In comparison with matched controls, both patient groups showed reduced performance in DOT-A but not in Digit span performance. This pattern was found to be particularly sensitive for patients with PD. In Study 2, DOT-A performance was assessed in 50 healthy subjects carefully selected according to demographic criteria in order to ensure representativity. Parallel test and split-half correlations indicated sufficient reliability of the DOT-A. Concurrent validity was confirmed by significant correlation with a well-established working memory test (two-back task). We conclude that DOT-A is a promising diagnostic instrument, and its economy and direct comparability to the Wechsler Digit spans and high sensitivity for patient populations make it especially well-suited for assessment in clinical practice.

Journal Article↗
PubMedDate not supplied

Interference control in a new rule use task: age-related changes, labeling, and attention.

Three experiments examined 3- to 6-year-olds' interference control using a task in which children saw 2 corresponding sets of colored cards, a large set in front of them and a small set behind them. A colored candy (Smartie) was placed on a large card with mismatching color, and children could win the Smartie by selecting the small card that matched the color of the large card. Three-year-olds performed poorly whereas older children performed well. Having children label the correct color before responding improved 3-year-olds' performance (Experiment 2), as did pointing to the large card (Experiment 3); decreasing the affective salience of the stimuli (colored beads vs. Smarties) did not (Experiment 3). Results reveal the role of selective attention in action control.

Attention↗
PubMedDate not supplied

The role of negative priming in preschoolers' flexible rule use on the dimensional change card sort task.

Four experiments examined the development of negative priming (NP) in 3-5-year-old children using as a measure of children's executive function (EF) the dimensional change card sort (DCCS) task. In the NP version of the DCCS, the values of the sorting dimension that is relevant during the preswitch phase are removed during the postswitch phase. The experiments showed that the NP effect observed in the DCCS decreased during the preschool years, and they clarified the circumstances in which NP occurs. Taken together, the findings suggest that the development of EF in early childhood consists in part in disinhibiting attention to information that has previously been suppressed.

Affect↗