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Biomedical subjects

K Arndt

Publications and source records attributed to K Arndt.

At least 19 recordsLinked to original sources
PubMed2004

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.

Animals↗
PubMed2002

Development and potential of non-peptide antagonists for calcitonin-gene-related peptide (CGRP) receptors: evidence for CGRP receptor heterogeneity.

Calcitonin-gene-related peptide (CGRP) is a 37-amino-acid vasodilatory peptide, of which two isoforms, alpha CGRP and beta CGRP, have been described. The use of C-terminal fragments of CGRP peptide, such as human alpha CGRP-(8-37), has led to the pharmacological subdivision of CGRP receptors into CGRP-1 [high potency for binding of human alpha CGRP-(8-37)] and CGRP-2 (lower potency) receptors. We have recently developed BIBN4096BS, the first non-peptide CGRP antagonist, which has sub-nanomolar affinity for primate CGRP receptors. The use of BIBN4096BS has led to the discovery of further functional CGRP receptor heterogeneity in rat tissues. To further exploit BIBN4096BS as a pharmacological tool, we used BIBN4096BS in pig left anterior descending coronary vessels and cerebral basilar arteries, and compared functional with molecular data, characterizing CGRP receptor components. Our data show that, apart from a subdivision into CGRP-1 and -2 receptors, BIBN4096BS reveals additional functional differences between the actions of alpha CGRP and beta CGRP. However, evidence for CGRP receptor heterogeneity on a molecular level is scarce.

Animals↗
PubMed2001

Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity.

Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC(50) = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of 1a led to 1c, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC(50) of 1.2 nM in the Src enzymatic assay, an IC(50) of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.

Animals↗
PubMed2001

The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution.

We report the purification of a presynaptic "particle web" consisting of approximately 50 nm pyramidally shaped particles interconnected by approximately 100 nm spaced fibrils. This is the "presynaptic grid" described in early EM studies. It is completely soluble above pH 8, but reconstitutes after dialysis against pH 6. Interestingly, reconstituted particles orient and bind PSDs asymmetrically. Mass spectrometry of purified web components reveals major proteins involved in the exocytosis of synaptic vesicles and in membrane retrieval. Our data support the idea that the CNS synaptic junction is organized by transmembrane adhesion molecules interlinked in the synaptic cleft, connected via their intracytoplasmic domains to the presynaptic web on one side and to the postsynaptic density on the other. The CNS synaptic junction may therefore be conceptualized as a complicated macromolecular scaffold that isostatically bridges two closely aligned plasma membranes.

Animals↗
PubMed2001

Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles.

Screening of a directed compound library in a yeast-based assay identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (2a) as a Src inhibitor. An enzymatic assay established that 2a was an ATP-competitive inhibitor of the kinase activity of Src. We present here SAR data for 2a which shows that the aniline group at C-4, the carbonitrile group at C-3, and the alkoxy groups at C-6 and C-7 of the quinoline are crucial for optimal activity. Increasing the size of the C-2 substituent of the aniline at C-4 of 2a from chloro to bromo to iodo resulted in a corresponding increase in Src inhibition. Furthermore, replacement of the 7-methoxy group of 2a with various 3-heteroalkylaminopropoxy groups provided increased inhibition of both Src enzymatic and cellular activity. Compound 25, which contains a 3-morpholinopropoxy group, had an IC(50) of 3.8 nM in the Src enzymatic assay and an IC(50) of 940 nM for the inhibition of Src-dependent cell proliferation.

Aniline Compounds↗
PubMed2001

A prospective clinical and urodynamic study of bladder function during and after pregnancy.

The aim of the study was to determine whether clinical and/or urodynamic changes in bladder function occur during pregnancy. Assessment consisted of a urinary symptom questionnaire, urogynecological examination and urodynamic investigations, which were repeated 6 weeks after pregnancy. Sixty-six patients had the initial and 40 the follow-up assessments. Statistical analysis was done by 95% confidence intervals (95% CI). Nocturia, frequency, dysuria, urgency and stress incontinence occurred significantly more frequently during pregnancy. Urinary tract infection was diagnosed in 18% of patients during pregnancy and asymptomatic bacteriuria in 9%. Genuine stress incontinence was diagnosed in 12% during pregnancy and in none after pregnancy (95% CI 1% to 24%). An unstable detrusor was diagnosed in 23% of patients during pregnancy and in 15% after pregnancy (95% CI -8% to 23%). Strong desire to void, urgency, maximum cystometric capacity, maximum flow rate and average flow rate were all statistically significantly decreased during pregnancy. It is concluded that significant changes occur in bladder function during pregnancy.

Adult↗
PubMed2000

Functional cis-heterodimers of N- and R-cadherins.

Classical cadherins form parallel cis-dimers that emanate from a single cell surface. It is thought that the cis-dimeric form is active in cell-cell adhesion, whereas cadherin monomers are likely to be inactive. Currently, cis-dimers have been shown to exist only between cadherins of the same type. Here, we show the specific formation of cis-heterodimers between N- and R-cadherins. E-cadherin cannot participate in these complexes. Cells coexpressing N- and R-cadherins show homophilic adhesion in which these proteins coassociate at cell-cell interfaces. We performed site- directed mutagenesis studies, the results of which support the strand dimer model for cis-dimerization. Furthermore, we show that when N- and R-cadherins are coexpressed in neurons in vitro, the two cadherins colocalize at certain neural synapses, implying biological relevance for these complexes. The present study provides a novel paradigm for cadherin interaction whereby selective cis-heterodimer formation may generate new functional units to mediate cell-cell adhesion.

Animals↗
PubMed2000

Molecular modification of N-cadherin in response to synaptic activity.

The relationship between adhesive interactions across the synaptic cleft and synaptic function has remained elusive. At certain CNS synapses, pre- to postsynaptic adhesion is mediated at least in part by neural (N-) cadherin. Here, we demonstrate that upon depolarization of hippocampal neurons in culture by K+ treatment, or application of NMDA or alpha-latrotoxin, synaptic N-cadherin dimerizes and becomes markedly protease resistant. These properties are indices of strong, stable, enhanced cadherin-mediated intercellular adhesion. N-cadherin retained protease resistance for at least 2 hr after recovery, while other surface molecules, including other cadherins, were completely degraded. The acquisition of protease resistance and dimerization of N-cadherin is not dependent on new protein synthesis, nor is it accompanied by internalization of N-cadherin. By immunocytochemistry, we found that high K+ selectively induces surface dispersion of N-cadherin, which, after recovery, returns to synaptic puncta. N-cadherin dispersion under K+ treatment parallels the rapid expansion of the presynaptic membrane consequent to the massive vesicle fusion that occurs with this type of depolarization. In contrast, with NMDA application, N-cadherin does not disperse but does acquire enhanced protease resistance and dimerizes. Our data strongly suggest that synaptic adhesion is dynamically and locally controlled, and modulated by synaptic activity.

2-Amino-5-phosphonovalerate↗
PubMed1999

Inadvertent hypothermia in the OR.

Hypothermia is one of the most common problems that patients experience in the perioperative environment. Hypothermia causes more problems for the patient than the mere unpleasant experience of feeling cold. Additional nursing interventions are required for a patient suffering from inadvertent hypothermia, which often delays the patient's discharge from the perioperative setting. Many of the nursing interventions that are successful in preventing hypothermia and restoring body heat to surgical patients, such as applying a warmed blanket to a patient's body, seem straightforward. Understanding the cause and effects of inadvertent hypothermia, however, is essential in recognizing it and implementing the most effective nursing interventions.

Aged↗
PubMed1998

Development of cadherin-defined parasagittal subdivisions in the embryonic chicken cerebellum.

The expression of three cadherins (cadherin-6B, cadherin-7, and R-cadherin) was analyzed by immunohistochemistry at early to intermediate stages of chicken cerebellar development (4.5-12 days of incubation [E4.5-E12]). Expression was first detected at approximately E5. On the cerebellar surface, expression of cadherin-6B and cadherin-7 is initially observed in transverse domains that subsequently elongate into parasagittal stripes. The sequence of emergence, the borders, and the orientation of these expression domains suggest a parcellation of the cerebellum into distinct medial, lateral, and caudal embryonic subdivisions. These subdivisions relate to histologic features, to the expression of gene regulatory proteins, and, possibly, to patterns of clonal restriction. Individual cadherin-expressing cell clusters can be observed to split into cortical and nuclear subdivisions, which are connected by nerve fibers expressing the same cadherin, thus establishing the parasagittal corticonuclear connectivity pattern found at later developmental stages. Our results suggest that cadherins may play a role in the transition from the early embryonic to the later functional organization of the cerebellum by providing a scaffold of potential adhesive cues.

Afferent Pathways↗
PubMed1998

Cadherin-defined segments and parasagittal cell ribbons in the developing chicken cerebellum.

In the developing chicken cerebellar cortex, three cadherins (Cad6B, Cad7, and R-cadherin) are expressed in distinct parasagittal segments that are separated from each other by ribbons of migrating interneurons and granule cells which express R-cadherin and Cad7, respectively. The segment/ribbon pattern is respected by the expression of other types of molecules, such as engrailed-2 and SC1/BEN/DM-GRASP. The cadherin-defined segments contain young Purkinje cells which are connected to underlying nuclear zones expressing the same cadherin, thereby forming parasagittal cortico-nuclear zones of topographically organized connections. In addition, R-cadherin-positive mossy fiber terminals display a periodic pattern in the internal granular layer. In this layer, Cad7 and R-cadherin are associated with synaptic complexes. These results suggest that cadherins play a pivotal role in the formation of functional cerebellar architecture by providing a three-dimensional scaffold of adhesive information.

Animals↗
PubMed1998

15N investigation into the effect of a pollutant on the nitrogen metabolism of Tetrahymena pyriformis as a model for environmental medical research.

A pilot study was performed to examine the potential of stable isotope techniques for monitoring the impact of a harmful substance on the cellular nitrogen metabolism in the ciliate species Tetrahymena pyriformis. After identical cultivation periods of control cells and toluene-exposed cells in a defined culture medium enriched with [guanidino-15N2]l-arginine, a number of nitrogen-containing pools were analyzed: 1) quantity and 15N abundance of ammonia as the end product of nitrogen metabolism in the system; 2) pattern and 15N abundances of the protein-bound amino acids in the cells; 3) pattern and 15N abundances of free amino acids in the cells; and 4) pattern and 15N abundances of the amino acids in the culture medium. In addition to 15N emission spectrometry, a new gas chromatography/combustion interface-isotope ratio mass spectrometry/mass spectrometry analytical system was used. The production and 15N content of ammonia were higher in the toluene-exposed system by 30% and 43%, respectively, indicating higher deamination rates and greater arginine consumption. The toluene-exposed cells exhibited increased 15N abundances of protein-bound amino acids in alanine, aspartic acid, glutamic acid, and tyrosine. Furthermore, structural analyses revealed the presence of N[Omega]-acetylarginine and pyrrolidonecarboxylic acid--compounds that had not previously been detected in Tetrahymena pyriformis. Differences in the 15N-enrichment of free amino acids were also evident. This new effect-monitoring system designed to investigate the impact of a pollutant on protein metabolism by using a stable isotope-labeled cell culture is a powerful tool for environmental medical research.

Amino Acids↗
PubMed1997

Expression of the cell adhesion molecule axonin-1 in neuromeres of the chicken diencephalon.

Axonin-1/TAG-1, a member of the immunoglobulin (Ig) superfamily of adhesion molecules, has been shown to be selectively expressed by a subset of neurons and fiber tracts in the developing nervous system of vertebrates. Axonin-1/TAG-1 is thought to play a role in the outgrowth, guidance, and fasciculation of neurites. In the present study, we map the expression of axonin-1 in the diencephalon of the chicken brain at early and intermediate stages of development [2-8 days of incubation; embryonic day (E)2-E8] by immunohistochemical methods. Results show that axonin-1 is first expressed at about E2.5 by postmitotic neurons scattered throughout most of the diencephalon. During the neuromeric stage of brain development (about E3-E5), axonin-1+ nerve cell bodies are predominantly found in two neuromeric subdivisions: 1) in the alar plate of the precommissural pretectum and dorsal thalamus and 2) in the posterior preoptic region of the hypothalamus. The axonin-1+ fiber bundles emerging from these areas grow across segmental boundaries. For example, axonin-1+ neurites originating in the dorsal thalamus cross the zona limitans intrathalamica at a right angle to project to the striatum. Later, the axonin-1+ neuromere areas give rise to particular axonin-1+ gray and white matter structures. Most of these structures correspond to the structures described to express TAG-1 in rodents. In conclusion, axonin-1 can be used as a marker to study aspects of the transition from the early neuromeric structure to the mature anatomy of the chicken brain.

Animals↗
PubMed1997

Cloning and expression analysis of cadherin-10 in the CNS of the chicken embryo.

A full-length cDNA of a novel cadherin of chicken (cad10) was cloned. The deduced amino acid sequence of the putative cytoplasmic domain of this molecule is highly homologous to a previously published cytoplasmic fragment of human cadherin-10, a type II cadherin. An in situ hybridization analysis in chicken embryos shows that cad10 expression starts at about 4 days' incubation (E4) and persists at least until the hatching stage. In the central nervous system (CNS), cad10 expression is spatially restricted at all stages of development. At early stages, expression reflects the neuromeric organization of the brain. For example, in the alar plate of the diencephalon, cad10 expression is restricted to the dorsal thalamic neuromere. A number of cad10-expressing brain nuclei are formed in this neuromeric domain during later development. Specific cad10-expressing gray matter structures are also found in all other major divisions of the brain. Many of these structures are known to be functionally connected to each other. The cad10 expression pattern is distinct from that of other cadherins. These results support the idea that cadherins provide a molecular code for the regionalization of the embryonic CNS at the different stages of development.

Animals↗
PubMed1997

Winning market positioning strategies for long term care facilities.

The decision to develop an aggressive marketing strategy for its long term care facility has become a priority for the management of a one-hundred bed facility in the Rocky Mountain West. Financial success and lasting competitiveness require that the facility in question (Deer Haven) establish itself as the preferred provider of long term care for its target market. By performing a marketing communications audit, Deer Haven evaluated its present market position and created a strategy for solidifying and dramatizing this position. After an overview of present conditions in the industry, we offer a seven step process that provides practical guidance for positioning a long term care facility. We conclude by providing an example application.

Aged↗
PubMed1996

Restricted expression of R-cadherin by brain nuclei and neural circuits of the developing chicken brain.

Cadherins are a family of Ca(2+)-dependent cell-cell adhesion molecules regulating morphogenesis by a preferentially homophilic binding mechanism. We have previously shown that the expression of R-cadherin in the early chicken forebrain (embryonic days E3-E6) is restricted to particular neuromeres or parts of neuromeres. R-cadherin-expressing neuroblasts born in these areas accumulate in the mantle zone and aggregate in particular (pro-) nuclei (Gänzler and Redies [1995] J. Neurosci. 15:4157-4172). In the present study, these findings are extended to later developmental stages (embryonic days E8, E11, and E15). By immunohistochemical and in situ hybridization techniques, we show that, at these stages of development, R-cadherin expression remains restricted to particular developing gray matter regions and fiber tracts. The R-cadherin-positive fiber tracts connect some of the R-cadherin-positive gray matter areas to form parts of particular neural circuits in the visual, auditory, somatosensory, and motor systems. Moreover, R-cadherin expression reflects the morphologic differentiation of gray matter regions. As brain nuclei become morphologically more distinct, the expression of R-cadherin shows a clearer demarcation of the nuclear boundaries. In addition, R-cadherin expression in some nuclei becomes restricted to particular subregions or to clusters of neurons. In the cerebellum, R-cadherin is expressed in parasagittal stripes. These results suggest that R-cadherin expression reflects the functional and morphologic maturation of gray matter structures and of information processing circuits in the embryonic chicken brain.

Animals↗
PubMed1996

Implicit rationing criteria in non-small-cell lung cancer treatment.

Data collected from lung cancer patients attending the Victoria Clinic of the British Columbia Cancer Agency are used to investigate how resources are rationed in the treatment of non-small-cell lung cancer (NSCLC). An ordered logit model is estimated to analyse empirically the relationship between treatment selection and: tumour stage, size and differentiation; the Feinstein index; Karnofsky performance status (KPS); and the patient's age, gender and marital and smoking status. Implicit rationing is found to occur with respect to all of these factors except the Feinstein index, gender and marital status. With respect to age, KPS and smoker status the main empirical results are: (a) an increase in age from 50 to 85 reduces the expected treatment expenditure by 50-70%, depending on the patient's KPS and smoker status; (b) patients with a KPS less than 80 and of 80, receive 30-46% and 75-85%, respectively, of the expected treatment expenditure for patients with a KPS of 90 or 100, depending on age and smoker status; (c) the expected treatment expenditure for active smokers is about 71-86% of the expenditure for non- or former smokers depending on age and KPS.

Age Factors↗