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University of Washington (1977)
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American Board of Family Medicine

Publications & Research

Dr. Thomas has contributed to 191 publications.
Title Preparation and Value Assignment of Standard Reference Material 968e Fat-soluble Vitamins, Carotenoids, and Cholesterol in Human Serum.
Date April 2012
Journal Analytical and Bioanalytical Chemistry
Excerpt

Standard Reference Material 968e Fat-Soluble Vitamins, Carotenoids, and Cholesterol in Human Serum provides certified values for total retinol, γ- and α-tocopherol, total lutein, total zeaxanthin, total β-cryptoxanthin, total β-carotene, 25-hydroxyvitamin D(3), and cholesterol. Reference and information values are also reported for nine additional compounds including total α-cryptoxanthin, trans- and total lycopene, total α-carotene, trans-β-carotene, and coenzyme Q(10). The certified values for the fat-soluble vitamins and carotenoids in SRM 968e were based on the agreement of results from the means of two liquid chromatographic methods used at the National Institute of Standards and Technology (NIST) and from the median of results of an interlaboratory comparison exercise among institutions that participate in the NIST Micronutrients Measurement Quality Assurance Program. The assigned values for cholesterol and 25-hydroxyvitamin D(3) in the SRM are the means of results obtained using the NIST reference method based upon gas chromatography-isotope dilution mass spectrometry and liquid chromatography-isotope dilution tandem mass spectrometry, respectively. SRM 968e is currently one of two available health-related NIST reference materials with concentration values assigned for selected fat-soluble vitamins, carotenoids, and cholesterol in human serum matrix. This SRM is used extensively by laboratories worldwide primarily to validate methods for determining these analytes in human serum and plasma and for assigning values to in-house control materials. The value assignment of the analytes in this SRM will help support measurement accuracy and traceability for laboratories performing health-related measurements in the clinical and nutritional communities.

Title Determination of Fat-soluble Vitamins and Carotenoids in Standard Reference Material 3280 Multivitamin/multielement Tablets by Liquid Chromatography with Absorbance Detection.
Date August 2011
Journal Journal of Aoac International
Excerpt

The concentrations of selected fat-soluble vitamins and carotenoids in Standard Reference Material (SRM) 3280 Multivitamin/Multielement Tablets have been determined by two independent LC methods, with measurements performed by the National Institute of Standards and Technology (NIST). This SRM has been prepared as part of a collaborative effort between NIST and the National Institutes of Health Office of Dietary Supplements. The SRM is also intended to support the Dietary Supplement Ingredient Database that is being established by the U.S. Department of Agriculture. The methods used at NIST to determine the concentration levels of vitamins A and E, and beta-carotene in the SRM used RPLC with absorbance detection. The relative precision of these methods ranged from 2 to 8% for the analytes measured. SRM 3280 is primarily intended for use in validating analytical methods for the determination of selected vitamins, carotenoids, and elements in multivitamin/multielement tablets and similar matrixes.

Title A Hormone-dependent Module Regulating Energy Balance.
Date July 2011
Journal Cell
Excerpt

Under fasting conditions, metazoans maintain energy balance by shifting from glucose to fat burning. In the fasted state, SIRT1 promotes catabolic gene expression by deacetylating the forkhead factor FOXO in response to stress and nutrient deprivation. The mechanisms by which hormonal signals regulate FOXO deacetylation remain unclear, however. We identified a hormone-dependent module, consisting of the Ser/Thr kinase SIK3 and the class IIa deacetylase HDAC4, which regulates FOXO activity in Drosophila. During feeding, HDAC4 is phosphorylated and sequestered in the cytoplasm by SIK3, whose activity is upregulated in response to insulin. SIK3 is inactivated during fasting, leading to the dephosphorylation and nuclear translocation of HDAC4 and to FOXO deacetylation. SIK3 mutant flies are starvation sensitive, reflecting FOXO-dependent increases in lipolysis that deplete triglyceride stores; reducing HDAC4 expression restored lipid accumulation. Our results reveal a hormone-regulated pathway that functions in parallel with the nutrient-sensing SIRT1 pathway to maintain energy balance.

Title An Introgression on Wheat Chromosome 4dl in Rl6077 (thatcher*6/pi 250413) Confers Adult Plant Resistance to Stripe Rust and Leaf Rust (lr67).
Date February 2011
Journal Tag. Theoretical and Applied Genetics. Theoretische Und Angewandte Genetik
Excerpt

Adult plant resistance (APR) to leaf rust and stripe rust derived from the wheat (Triticum aestivum L.) line PI250413 was previously identified in RL6077 (=Thatcher*6/PI250413). The leaf rust resistance gene in RL6077 is phenotypically similar to Lr34 which is located on chromosome 7D. It was previously hypothesized that the gene in RL6077 could be Lr34 translocated to another chromosome. Hybrids between RL6077 and Thatcher and between RL6077 and 7DS and 7DL ditelocentric stocks were examined for first meiotic metaphase pairing. RL6077 formed chain quadrivalents and trivalents relative to Thatcher and Chinese Spring; however both 7D telocentrics paired only as heteromorphic bivalents and never with the multivalents. Thus, chromosome 7D is not involved in any translocation carried by RL6077. A genome-wide scan of SSR markers detected an introgression from chromosome 4D of PI250413 transferred to RL6077 through five cycles of backcrossing to Thatcher. Haplotype analysis of lines from crosses of Thatcher × RL6077 and RL6058 (Thatcher*6/PI58548) × RL6077 showed highly significant associations between introgressed markers (including SSR marker cfd71) and leaf rust resistance. In a separate RL6077-derived population, APR to stripe rust was also tightly linked with cfd71 on chromosome 4DL. An allele survey of linked SSR markers cfd71 and cfd23 on a set of 247 wheat lines from diverse origins indicated that these markers can be used to select for the donor segment in most wheat backgrounds. Comparison of RL6077 with Thatcher in field trials showed no effect of the APR gene on important agronomic or quality traits. Since no other known Lr genes exist on chromosome 4DL, the APR gene in RL6077 has been assigned the name Lr67.

Title Discovery and Biological Evaluation of Potent, Selective, Orally Bioavailable, Pyrazine-based Blockers of the Na(v)1.8 Sodium Channel with Efficacy in a Model of Neuropathic Pain.
Date February 2011
Journal Bioorganic & Medicinal Chemistry
Excerpt

Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration.

Title Use of the Ornstein-zernike Percus-yevick Equation to Extract Interaction Potentials from Pair Correlation Functions.
Date February 2011
Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
Excerpt

In this work, we test the ability of the Ornstein-Zernike equation in the Percus-Yevick approximation (OZPY) to generate interaction potentials from pair correlation functions (PCFs) of monatomic and diatomic Lennard-Jones fluids. The PCFs are generated by solving OZPY equation (monatomic fluid) and molecular-dynamics (MD) simulations (diatomic fluid). Since the interaction potentials are inputs in the OZPY method and the MD simulation, the extraction of the potential from the PCFs using OZPY is a test of self-consistency. This test is necessary if the procedure is to be used to generate coarse-grained (CG) potentials from PCFs. We find that the procedure is completely self-consistent for the monatomic fluid in the whole range of densities studied (reduced density up to 0.55, under reduced temperature of 2.0). In the diatomic case, we find that the procedure is generally self-consistent under both low and high densities, although there is a systematic deviation at high densities. The method is able to reproduce the two parameters (ε and σ) of the input Lennard-Jones potential model to within about 1%. This CG potential generating procedure can be straightforwardly extended to more complicated molecules.

Title Preparation and Characterization of Standard Reference Material 1849 Infant/adult Nutritional Formula.
Date October 2010
Journal Journal of Aoac International
Excerpt

Standard Reference Material (SRM) 1849 Infant/Adult Nutritional Formula has been issued by the National Institute of Standards and Technology (NIST) as a replacement for SRM 1846 Infant Formula, issued in 1996. Extraction characteristics of SRM 1846 have changed over time, as have NIST's analytical capabilities. While certified mass fraction values were provided for five constituents in SRM 1846 (four vitamins plus iodine), certified mass fraction values for 43 constituents are provided in SRM 1849 (fatty acids, elements, and vitamins) and reference mass fraction values are provided for an additional 43 constituents including amino acids and nucleotides, making it the most extensively characterized food-matrix SRM available from NIST.

Title Analogues of (3r)-7-hydroxy-n-[(1s)-1-{[(3r,4r)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (jdtic). Synthesis and in Vitro and in Vivo Opioid Receptor Antagonist Activity.
Date August 2010
Journal Journal of Medicinal Chemistry
Excerpt

The synthesis of compounds 6, 7a,b, 8a,b, 9a,b, and 10a,b where the amino -NH- group of JDTic (3) was replaced with an aromatic horizontal lineCH-, CH(2), O, S, or SO group was accomplished and used to further characterize the SAR of the compound 3 class of kappa opioid receptor antagonists. All of the compounds showed subnanomolar to low nanomolar K(e) values at the kappa opioid receptor. The most potent compound was 7a, where the amino -NH- group of 3 was replaced by a methylene (-CH(2)-) group. This compound had a K(e) = 0.18 nM and was 37- and 248-fold selective for the kappa relative to the mu and delta opioid receptors, respectively. Similar to compound 3, compound 7a antagonized selective kappa agonist U50,488-induced diuresis after sc administration in rats. In contrast to 3, where kappa antagonist activity lasted for three weeks, compound 7a did not show any kappa antagonist activity after one week.

Title "second Emerson Effect" in the Hill Reaction of Chlorella Cells with Quinone As Oxidant.
Date July 2010
Journal Science (new York, N.y.)
Excerpt

The second Emerson effect can be observed not only in photosynthesis but also in the photoreduction of quinone by Chlorella cells. This shows that this effect is not due to respiration and is not associated with the carbon dioxide-reducing phase of photosynthesis. Peaks at 650 and 670 mmicro in the action spectra of this effect, in the case of quinone reductions as well as in that of photosynthesis in Chlorella, show that light absorbed by chlorophyll b as well as that absorbed by chlorophyll a 670 can effectively supplement far-red light (> 680 mmicro) in both reactions; light absorbed by chlorophyll a 680 cannot do so.

Title Inhibition of Photosynthesis in Some Algae by Extreme-red Light.
Date July 2010
Journal Science (new York, N.y.)
Excerpt

Photosynthesis produced by far-red light (about 700 mmicro) is reversibly inhibited in some algae by extreme-red light ( approximately 750 mmicro).

Title Molecular Dynamics Simulation of Poly(ethylene Terephthalate) Oligomers.
Date March 2010
Journal The Journal of Physical Chemistry. B
Excerpt

Molecular dynamics simulations of poly(ethylene terephthalate) (PET) oligomers are performed in the isobaric-isothermal (NpT) ensemble at a state point typical of a finishing reactor. The oligomer size ranges from 1 to 10 repeat units. We report thermodynamic properties (density, potential energy, enthalpy, heat capacity, isothermal compressibility, and thermal expansivity), transport properties (self-diffusivity, zero-shear-rate viscosity, thermal conductivity), and structural properties (pair correlation functions, hydrogen bonding network, chain radius of gyration, chain end-to-end distance) as a function of oligomer size. We compare the results with existing molecular-level theories and experimental data. Scaling exponents as a function of degree of polymerization are extracted. The distribution of the end-to-end distance is bimodal for the dimer and gradually shifts to a single peak as the degree of polymerization increases. The scaling exponents for the average chain radius of gyration and end-to-end distance are 0.594 and 0.571, respectively. The values of the heat capacity, isothermal compressibility, and thermal expansivity agree well with the available experimental data, which are of much longer PET chains. The scaling exponents for the self-diffusivity and zero-shear-rate viscosity are, respectively, -2.01 and 0.96, with the latter one being close to the theoretical prediction 1.0 for short-chain polymers.

Title Synthesis and in Vitro Opioid Receptor Functional Antagonism of Methyl-substituted Analogues of (3r)-7-hydroxy-n-[(1s)-1-{[(3r,4r)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (jdtic).
Date December 2009
Journal Journal of Medicinal Chemistry
Excerpt

In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 3) was identified as the first potent and selective kappa-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor functional antagonism using a [(35)S]GTPgammaS binding assay. Compounds 8a-p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar K(e) values at the kappa receptor. The three most potent analogues were the monomethylated (3R)-7-hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8e) with K(e) values of 0.03 nM at the kappa receptor and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with K(e) = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the micro and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.

Title Markers to a Common Bunt Resistance Gene Derived from 'blizzard' Wheat (triticum Aestivum L.) and Mapped to Chromosome Arm 1bs.
Date September 2009
Journal Tag. Theoretical and Applied Genetics. Theoretische Und Angewandte Genetik
Excerpt

Common bunt, caused by Tilletia caries (DC.) Tul. & C. Tul. and T. laevis J.G Kuhn, is an economically important disease of wheat (Triticum aestivum L.) worldwide. The resistance in the winter wheat cultivar 'Blizzard' is effective against known races of common bunt in western Canada. The incorporation of resistance from Blizzard into field-ready cultivars may be accelerated through the use of molecular markers. Using the maize pollen method, a doubled haploid population of 147 lines was developed from the F(1) of the second backcross of Blizzard (resistant) by breeding line '8405-JC3C' (susceptible). Doubled haploid lines were inoculated at seeding with race T19 or T19 and L16 and disease reaction was examined under controlled conditions in 1999 and natural conditions in 2002, and 2003. Resistant:susceptible-doubled haploid lines segregated in a 1:1 ratio for bunt reaction, indicating single major gene segregation. Microsatellite primers polymorphic on the parents were screened on the population. Initial qualitative segregation analysis indicated that the wheat microsatellite markers Xgwm374, Xbarc128 and Xgwm264, located on wheat chromosome 1BS, were significantly linked to the resistance locus. Qualitative results were confirmed with quantitative trait locus analysis. The genetic distance, calculated with JoinMap, between the bunt resistance locus and overlapping markers Xgwm374, Xgwm264 and Xbarc128 was 3.9 cM. The three markers were validated on doubled haploid populations BW337/P9502&DAF1BB and Blizzard/P9514-AR17A3E evaluated for common bunt reaction in the growth chamber in 2007. These markers will be useful in selecting for the common bunt resistance from Blizzard and assist in identifying the resistance among potential new sources of resistance.

Title The Identification of Nonpeptide Neurotensin Receptor Partial Agonists from the Potent Antagonist Sr48692 Using a Calcium Mobilization Assay.
Date August 2009
Journal Bioorganic & Medicinal Chemistry Letters
Excerpt

In a search for nonpeptide agonists for the neurotensin receptor (NTR1), we replaced the adamantyl amino acid moiety found in the antagonist SR48692 (1a) with leucine and related alpha-alkylamino acids found in peptide agonists. When tested in a calcium mobilization assay, we found that both d- and l-leucine confer partial agonist activity to the pyrazole scaffold with the l-enantiomer (3a) providing a significantly greater response. A brief SAR survey demonstrated that the observed agonist activity was resilient to changes made to the dimethoxyaryl ring in 3a. The resulting compounds were less potent relative to 3a but showed greater agonist responses. The partial agonist activity was extinguished when the chloroquinoline ring was replaced with naphthalene. Thus, while l-leucine appears to possess a powerful agonist directing affect for the NTR1 receptor, its presence alone in the molecular architecture is not sufficient to insure agonist behavior.

Title The Effect of Kappa-opioid Receptor Agonists on Tetrodotoxin-resistant Sodium Channels in Primary Sensory Neurons.
Date July 2009
Journal Anesthesia and Analgesia
Excerpt

A non-opioid receptor-mediated inhibition of sodium channels in dorsal root ganglia (DRGs) by kappa-opioid receptor agonists (kappa-ORAs) has been reported to contribute to the antinociceptive actions in animals and humans. In this study, we examined structurally diverse kappa-ORAs for their abilities to inhibit tetrodotoxin-resistant (TTX-r) sodium channels in adult rat DRGs.

Title Inhibition of Photosynthesis in Certain Algae by Extreme Red Light.
Date July 2009
Journal Biophysical Journal
Excerpt

This paper shows that in Porphyridium cruentum and in Chlorella pyrenoidosa (but apparently not in Anacystis nidulans) "extreme red" light (> 720 mmu) can inhibit photosynthesis produced by "far red" light (up to 720 mmu). From the action spectrum of this phenomenon, it appears that an unknown pigment with an absorption band around 745 mmu must be responsible for it.

Title Differentially Expressed Drl and Drl-2 Play Opposing Roles in Wnt5 Signaling During Drosophila Olfactory System Development.
Date May 2009
Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Excerpt

In Drosophila, odor information received by olfactory receptor neurons (ORNs) is processed by glomeruli, which are organized in a stereotypic manner in the antennal lobe (AL). This glomerular organization is regulated by Wnt5 signaling. In the embryonic CNS, Wnt5 signaling is transduced by the Drl receptor, a member of the Ryk family. During development of the olfactory system, however, it is antagonized by Drl. Here, we identify Drl-2 as a receptor mediating Wnt5 signaling. Drl is found in the neurites of brain cells in the AL and specific glia, whereas Drl-2 is predominantly found in subsets of growing ORN axons. A drl-2 mutation produces only mild deficits in glomerular patterning, but when it is combined with a drl mutation, the phenotype is exacerbated and more closely resembles the Wnt5 phenotype. Wnt5 overexpression in ORNs induces aberrant glomeruli positioning. This phenotype is ameliorated in the drl-2 mutant background, indicating that Drl-2 mediates Wnt5 signaling. In contrast, forced expression of Drl-2 in the glia of drl mutants rescues the glomerular phenotype caused by the loss of antagonistic Drl function. Therefore, Drl-2 can also antagonize Wnt5 signaling. Additionally, our genetic data suggest that Drl localized to developing glomeruli mediates Wnt5 signaling. Thus, these two members of the Ryk family are capable of carrying out a similar molecular function, but they can play opposing roles in Wnt5 signaling, depending on the type of cells in which they are expressed. These molecules work cooperatively to establish the olfactory circuitry in Drosophila.

Title A Drosophila Model for Egfr-ras and Pi3k-dependent Human Glioma.
Date March 2009
Journal Plos Genetics
Excerpt

Gliomas, the most common malignant tumors of the nervous system, frequently harbor mutations that activate the epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling pathways. To investigate the genetic basis of this disease, we developed a glioma model in Drosophila. We found that constitutive coactivation of EGFR-Ras and PI3K pathways in Drosophila glia and glial precursors gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths, mimicking human glioma. Our model represents a robust organotypic and cell-type-specific Drosophila cancer model in which malignant cells are created by mutations in signature genes and pathways thought to be driving forces in a homologous human cancer. Genetic analyses demonstrated that EGFR and PI3K initiate malignant neoplastic transformation via a combinatorial genetic network composed primarily of other pathways commonly mutated or activated in human glioma, including the Tor, Myc, G1 Cyclins-Cdks, and Rb-E2F pathways. This network acts synergistically to coordinately stimulate cell cycle entry and progression, protein translation, and inappropriate cellular growth and migration. In particular, we found that the fly orthologs of CyclinE, Cdc25, and Myc are key rate-limiting genes required for glial neoplasia. Moreover, orthologs of Sin1, Rictor, and Cdk4 are genes required only for abnormal neoplastic glial proliferation but not for glial development. These and other genes within this network may represent important therapeutic targets in human glioma.

Title Molecular Aspects of Mucoadhesive Carrier Development for Drug Delivery and Improved Absorption.
Date February 2009
Journal Journal of Biomaterials Science. Polymer Edition
Excerpt

Although the oral route remains the most favored route of drug administration, major scientific obstacles prevent the effective and efficient delivery of low-molecular-mass drugs, peptides and proteins that exhibit poor solubility and permeability. Mucoadhesive dosage forms and the associated drug carriers have the ability to interact at a molecular level with the mucus gel layer that lines the epithelial surfaces of the major absorptive regions of the body. This interaction provides an increased residence time of the therapeutic formulation while localizing the drug at the site of administration. Such local, non-specific targeting leads to an increase in both oral absorption and bioavailability. Fundamental understanding of the biological processes encountered along the gastrointestinal tract can provide a sufficient engineer of carriers that are capable to provide this increase in residence time. Here we discuss the theoretical framework for achieving mucoadhesive systems as related to biomaterials science and the structure of the biomaterials used.

Title Control Elements in Dynamically Determined Selectivity on a Bifurcating Surface.
Date December 2008
Journal Journal of the American Chemical Society
Excerpt

The mechanism and the nature of the dynamically determined product selectivity in Diels-Alder cycloadditions of 3-methoxycarbonylcyclopentadienone (2) with 1,3-dienes was studied by a combination of product studies, experimental kinetic isotope effects, standard theoretical calculations, and quasiclassical trajectory calculations. The low-energy transition structures in these reactions are structurally balanced between [4pi(diene) + 2pi(dienone)] and the [2pi(diene) + 4pi(dienone)] modes of cycloaddition. The accuracy of these structures and their bispericyclic nature is supported by the experimental isotope effects. Trajectories passing through these transition structures can lead to both [4pi(diene) + 2pi(dienone)] and [2pi(diene) + 4pi(dienone)] cycloadducts, and the mixture of products obtained varies with the structure of the diene. The factors affecting this selectivity are analyzed. The geometry of the transition structure is a useful predictor of the major product, but the selectivity is also guided by the shape of the energy surface as trajectories approach the products and by how trajectories cross the transition state ridge.

Title Certification of Standard Reference Materials Containing Bitter Orange.
Date July 2008
Journal Analytical and Bioanalytical Chemistry
Excerpt

A suite of three dietary supplement standard reference materials (SRMs) containing bitter orange has been developed, and the levels of five alkaloids and caffeine have been measured by multiple analytical methods. Synephrine, octopamine, tyramine, N-methyltyramine, hordenine, total alkaloids, and caffeine were determined by as many as six analytical methods, with measurements performed at the National Institute of Standards and Technology and at two collaborating laboratories. The methods offer substantial independence, with two types of extractions, two separation methods, and four detection methods. Excellent agreement was obtained among the measurements, with data reproducibility for most methods and analytes better than 5% relative standard deviation. The bitter-orange-containing dietary supplement SRMs are intended primarily for use as measurement controls and for use in the development and validation of analytical methods.

Title The Insulin-regulated Creb Coactivator Torc Promotes Stress Resistance in Drosophila.
Date July 2008
Journal Cell Metabolism
Excerpt

In fasted mammals, glucose homeostasis is maintained through induction of the cAMP response element-binding protein (CREB) coactivator transducer of regulated CREB activity 2 (TORC2), which stimulates the gluconeogenic program in concert with the forkhead factor FOXO1. Here we show that starvation also triggers TORC activation in Drosophila, where it maintains energy balance through induction of CREB target genes in the brain. TORC mutant flies have reduced glycogen and lipid stores and are sensitive to starvation and oxidative stress. Neuronal TORC expression rescued stress sensitivity as well as CREB target gene expression in TORC mutants. During refeeding, increases in insulin signaling inhibited TORC activity through the salt-inducible kinase 2 (SIK2)-mediated phosphorylation and subsequent degradation of TORC. Depletion of neuronal SIK2 increased TORC activity and enhanced stress resistance. As disruption of insulin signaling also augmented TORC activity in adult flies, our results illustrate the importance of an insulin-regulated pathway that functions in the brain to maintain energy balance.

Title Discovery of Potent Furan Piperazine Sodium Channel Blockers for Treatment of Neuropathic Pain.
Date July 2008
Journal Bioorganic & Medicinal Chemistry
Excerpt

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.

Title Synthesis and in Vitro Opioid Receptor Functional Antagonism of Analogues of the Selective Kappa Opioid Receptor Antagonist (3r)-7-hydroxy-n-((1s)-1-{[(3r,4r)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (jdtic).
Date June 2008
Journal Journal of Medicinal Chemistry
Excerpt

In previous structure-activity relationship (SAR) studies, we identified (3 R)-7-hydroxy- N-((1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 1) as the first potent and selective kappa opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [ (35) S]GTPgammaS binding assay. The results from the studies better define the pharmacophore for this class of kappa opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3 R)-7-Hydroxy- N-[(1 S,2 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide ( 3) with a K e value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified.

Title Discovery and Biological Evaluation of 5-aryl-2-furfuramides, Potent and Selective Blockers of the Nav1.8 Sodium Channel with Efficacy in Models of Neuropathic and Inflammatory Pain.
Date May 2008
Journal Journal of Medicinal Chemistry
Excerpt

Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.

Title Clinical Research During Surgery Residency: the Chattanooga Approach.
Date April 2008
Journal Current Surgery
Excerpt

PURPOSE: The nontraditional clinical research rotation at the University of Tennessee College of Medicine-Chattanooga Unit is described and its efficacy evaluated by the number of peer-reviewed publications produced. METHODS: In 1988, a mandatory year of clinical research was added to the general surgery curriculum. The year is completed in 3 4-month rotations, 1 each during the PGY-2, PGY-3, and PGY-4 years. Curriculum vitae of 31 graduates of the traditional 5-year residency were evaluated for publications produced during residency and 1 year beyond training. Comparison was made to 15 subjects; 8 were 6-year graduates and 7 were PGY-4, PGY-5, or PGY-6 residents having completed the research year. Statistical analysis used the Mann-Whitney U test for nonparametric data as well as an independent t test with significance set at 0.05. Publications were verified by a MEDLINE search. Six-year graduates also completed a questionnaire regarding their research experience. RESULTS: Graduates of the 5-year program completed an average of 0.94 publications during residency, whereas 6-year graduates completed an average of 2.67 publications (p < 0.001). Opinions varied regarding desire to pursue research and the benefit of the research year. CONCLUSIONS: Our results demonstrate that basic science research is not the only model; academic productivity can be improved with an additional year devoted to clinical research. Advantages to this nontraditional approach include decreased likelihood of decline of clinical skills and knowledge, ability to maintain long-term projects, and a physical and mental break from a demanding clinical residency.

Title A New Synthesis of the Orl-1 Antagonist 1-[(3r,4r)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2h-benzimidazol-2-one (j-113397) and Activity in a Calcium Mobilization Assay.
Date February 2008
Journal Bioorganic & Medicinal Chemistry
Excerpt

A new chiral synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (2, J-113397) was developed. J-113397 has a K(e)=0.85nM in an ORL-1 calcium mobilization assay and is 89-, 887-, and 227-fold selective for the ORL-1 receptor relative to the mu, delta, and kappa opioid receptors.

Title Microsatellite Mapping of Adult-plant Leaf Rust Resistance Gene Lr22a in Wheat.
Date January 2008
Journal Tag. Theoretical and Applied Genetics. Theoretische Und Angewandte Genetik
Excerpt

This study was conducted to identify microsatellite markers (SSR) linked to the adult-plant leaf rust resistance gene Lr22a and examine their cross-applicability for marker-assisted selection in different genetic backgrounds. Lr22a was previously introgressed from Aegilops tauschii Coss. to wheat (Triticum aestivum L.) and located to chromosome 2DS. Comparing SSR alleles from the donor of Lr22a to two backcross lines and their recurrent parents showed that between two and five SSR markers were co-introgressed with Lr22a and the size range of the Ae. tauschii introgression was 9-20 cM. An F(2) population from the cross of 98B34-T4B x 98B26-N1C01 confirmed linkage between the introgressed markers and Lr22a on chromosome 2DS. The closest marker, GWM296, was 2.9 cM from Lr22a. One hundred and eighteen cultivars and breeding lines of different geographical origins were tested with GWM296. In total 14 alleles were amplified, however, only those lines predicted or known to carry Lr22a had the unique Ae. tauschii allele at GWM296 with fragments of 121 and 131 bp. Thus, GWM296 is useful for selecting Lr22a in diverse genetic backgrounds. Genotypes carrying Lr22a showed strong resistance to leaf rust in the field from 2002 to 2006. Lr22a is an ideal candidate to be included in a stack of leaf rust resistance genes because of its strong adult-plant resistance, low frequency of commercial deployment, and the availability of a unique marker.

Title Wnt4 is a Local Repulsive Cue That Determines Synaptic Target Specificity.
Date December 2007
Journal Current Biology : Cb
Excerpt

How synaptic specificity is molecularly coded in target cells is a long-standing question in neuroscience. Whereas essential roles of several target-derived attractive cues have been shown, less is known about the role of repulsion by nontarget cells. We conducted single-cell microarray analysis of two neighboring muscles (M12 and M13) in Drosophila, which are innervated by distinct motor neurons, by directly isolating them from dissected embryos. We identified a number of potential target cues that are differentially expressed between the two muscles, including M13-enriched Wnt4. When the functions of Wnt4, or putative receptors Frizzled 2 and Derailed-2 or Dishevelled were inhibited, motor neurons that normally innervate M12 (MN12s) formed smaller synapses on M12 but instead formed ectopic nerve endings on M13. Conversely, ectopic expression of Wnt4 in M12 inhibits synapse formation by MN12s. These results suggest that Wnt4, via Frizzled 2, Derailed-2, and Dishevelled, generates target specificity by preventing synapse formation on a nontarget muscle. Ectopic expression of five other M13-enriched genes, including beat-IIIc and Glutactin, also inhibits synapse formation by MN12s. These results demonstrate an important role for local repulsion in regulating cell-to-cell target specificity.

Title Anxiolytic-like Effects of Kappa-opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats.
Date December 2007
Journal The Journal of Pharmacology and Experimental Therapeutics
Excerpt

Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of kappa-opioid receptors (KORs) produces analgesia but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here, we examined whether KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (approximately 24 h) and extended time course (>3 weeks) of the prototypical KOR antagonists nor-binaltorphimine hydrochloride (norBNI) and JDTic [(3R)-7-hydroxy-N-[(1S)-1-[[(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide hydrochloride]. Rats received an i.p. injection of norBNI (3.0-30 mg/kg) or JDTic (1.0-10 mg/kg) 48 h before EPM testing. One day later, they were tested in the OF, and 5 and 7 days later, they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant- and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders.

Title Determination of Caffeine and Caffeine-related Metabolites in Ephedra-containing Standard Reference Materials Using Liquid Chromatography with Absorbance Detection and Tandem Mass Spectrometry.
Date November 2007
Journal Journal of Aoac International
Excerpt

The concentrations of caffeine and caffeine-related compounds in 2 ephedra-containing reference materials have been determined by 3 independent methods with measurements performed by the National Institute of Standards and Technology (NIST) and a collaborating laboratory. Results from the 3 methods were used for value assignment of caffeine, theobromine, and theophylline in these Standard Reference Materials (SRMs). The methods used at NIST to determine the concentration levels of caffeine, theobromine, and theophylline in SRM 3243 Ephedra-Containing Solid Oral Dosage Form and SRM 3244 Ephedra-Containing Protein Powder used reversed-phase liquid chromatography with absorbance detection and tandem mass spectrometry. These reference materials are part of the first suite in a series of NIST SRMs that provide concentration values for multiple components in dietary supplements. These SRMs are primarily intended for method validation and for use as control materials to support the analysis of dietary supplements and similar materials.

Title Preparation and Characterization of Standard Reference Material 3276, Carrot Extract in Oil.
Date October 2007
Journal Analytical and Bioanalytical Chemistry
Excerpt

The National Institute of Standards and Technology (NIST), the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and Center for Food Safety and Applied Nutrition (CFSAN), and the National Institutes of Health (NIH), Office of Dietary Supplements (ODS) are collaborating to produce a series of standard reference materials (SRMs) for dietary supplements. Standard reference material (SRM) 3276 Carrot Extract in Oil is one in this series, with values assigned for trans-alpha-carotene, trans- and total beta-carotene, delta- and gamma-tocopherol, and twelve fatty acids. Results for carotenoids and tocopherols were obtained by use of combinations of liquid chromatography (LC), on columns of differing selectivity, with absorbance and mass spectrometric (MS) detection. Fluorescence detection also was used for the tocopherols. Results for fatty acids were obtained by use of gas chromatography (GC) with both flame-ionization and mass-spectrometric detection. This material is intended for use as a primary control material when assigning values to in-house (secondary) control materials and for validation of analytical methods for measurement of these analytes in similar matrices.

Title Standard Reference Materials for Foods and Dietary Supplements.
Date October 2007
Journal Analytical and Bioanalytical Chemistry
Excerpt

Well-characterized certified reference materials are needed by laboratories in the food testing, dietary supplement, and nutrition communities to facilitate compliance with labeling laws and improve the accuracy of information provided on product labels, so that consumers can make good choices. As a result of the enactment of the Nutrition Labeling and Education Act of 1990 and the Infant Formula Act of 1980, the National Institute of Standards and Technology (NIST) worked to develop a series of food-matrix standard reference materials (SRMs) characterized for nutrient concentrations. These include SRM 1544 Fatty Acids and Cholesterol in a Frozen Diet Composite, SRM 1546 Meat Homogenate, SRM 1548a Typical Diet, SRM 1566b Oyster Tissue, SRM 1846 Infant Formula, SRM 1946 Lake Superior Fish Tissue, SRM 1947 Lake Michigan Fish Tissue, SRM 2383 Baby Food Composite, SRM 2384 Baking Chocolate, SRM 2385 Slurried Spinach, and SRM 2387 Peanut Butter. With the enactment of the Dietary Supplement Health and Education Act of 1994, NIST has been working to develop suites of dietary supplement SRMs characterized for active and marker compounds and for toxic elements and pesticides, where appropriate. An updated SRM 1588b Organics in Cod Liver Oil, a suite of ephedra-containing materials (SRMs 3240-3245), a carrot extract in oil (SRM 3276), and a suite of ginkgo-containing materials (SRMs 3246-3248) are available. Several other materials are currently in preparation. Dietary supplements are sometimes provided in forms that are food-like; for these, values may also be assigned for nutrients, for example SRM 3244 Ephedra-Containing Protein Powder. Both the food-matrix and dietary supplement reference materials are intended primarily for validation of analytical methods. They may also be used as "primary control materials" in assignment of values to in-house (secondary) control materials to confirm accuracy and to establish measurement traceability to NIST.

Title 40ar Retention in the Terrestrial Planets.
Date October 2007
Journal Nature
Excerpt

The solid Earth is widely believed to have lost its original gases through a combination of early catastrophic release and regulated output over geologic time. In principle, the abundance of 40Ar in the atmosphere represents the time-integrated loss of gases from the interior, thought to occur through partial melting in the mantle followed by melt ascent to the surface and gas exsolution. Here we present data that reveal two major difficulties with this simple magmatic degassing scenario--argon seems to be compatible in the major phases of the terrestrial planets, and argon diffusion in these phases is slow at upper-mantle conditions. These results challenge the common belief that the upper mantle is nearly degassed of 40Ar, and they call into question the suitability of 40Ar as a monitor of planetary degassing. An alternative to magmatism is needed to release argon to the atmosphere, with one possibility being hydration of oceanic lithosphere consisting of relatively argon-rich olivine and orthopyroxene.

Title A Sensory Feedback Circuit Coordinates Muscle Activity in Drosophila.
Date August 2007
Journal Molecular and Cellular Neurosciences
Excerpt

Drosophila larval crawling is a simple behavior that allows us to dissect the functions of specific neurons in the intact animal and explore the roles of genes in the specification of those neurons. By inhibiting subsets of neurons in the PNS, we have found that two classes of multidendritic neurons play a major role in larval crawling. The bipolar dendrites and class I mds send a feedback signal to the CNS that keeps the contraction wave progressing quickly, allowing smooth forward movement. Genetic manipulation of the sensory neurons suggests that this feedback depends on proper dendritic morphology and axon pathfinding to appropriate synaptic target areas in the CNS. Our data suggest that coordination of muscle activity in larval crawling requires feedback from neurons acting as proprioceptors, sending a "mission accomplished" signal in response to segment contraction, and resulting in rapid relaxation of the segment and propagation of the wave.

Title Paramedic Perceptions of Challenges in Out-of-hospital Endotracheal Intubation.
Date June 2007
Journal Prehospital Emergency Care : Official Journal of the National Association of Ems Physicians and the National Association of State Ems Directors
Excerpt

Paramedics often perform endotracheal intubation (ETI), insertion of a breathing tube, on critically ill out-of-hospital patients. Recent studies highlight important paramedic ETI shortcomings including adverse events, errors, and poor outcomes resulting from this procedure. Little is known about workforce perceptions of these events. We sought to identify paramedic and physician perceptions regarding the challenges and pitfalls of out-of-hospital ETI.

Title Preparation and Characterization of a Suite of Ephedra-containing Standard Reference Materials.
Date February 2007
Journal Journal of Aoac International
Excerpt

The National Institute of Standards and Technology, the U.S. Food and Drug Administration, Center for Drug Evaluation and Research and Center for Food Safety and Applied Nutrition, and the National Institutes of Health, Office of Dietary Supplements, are collaborating to produce a series of Standard Reference Materials (SRMs) for dietary supplements. A suite of ephedra materials is the first in the series, and this paper describes the acquisition, preparation, and value assignment of these materials: SRMs 3240 Ephedra sinica Stapf Aerial Parts, 3241 E. sinica Stapf Native Extract, 3242 E. sinica Stapf Commercial Extract, 3243 Ephedra-Containing Solid Oral Dosage Form, and 3244 Ephedra-Containing Protein Powder. Values are assigned for ephedrine alkaloids and toxic elements in all 5 materials. Values are assigned for other analytes (e.g., caffeine, nutrient elements, proximates, etc.) in some of the materials, as appropriate. Materials in this suite of SRMs are intended for use as primary control materials when values are assigned to in-house (secondary) control materials and for validation of analytical methods for the measurement of alkaloids, toxic elements, and, in the case of SRM 3244, nutrients in similar materials.

Title Highly Potent and Selective Phenylmorphan-based Inverse Agonists of the Opioid Delta Receptor.
Date October 2006
Journal Journal of Medicinal Chemistry
Excerpt

We recently reported the discovery of (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-5] as a novel chemotype possessing potent antagonist activity at the delta opioid receptor. Additional SAR studies involving changes to both the 2-amino and 7-amido N-substituents using this same (+)-morphan scaffold have revealed compounds with improved potency and selectivity for the delta opioid receptor. The highly potent and selective 2,2-dimethylphenylacetamide analogue (+)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2-phenylpropanamide (13d, delmorphan-A) showed picomolar inhibitory potency (Ke = 0.1 nM) in the [35S]GTPgammaS functional assay with delta opioid receptor selectivity ratios of 103- and 132-fold versus the mu and kappa opioid receptors, respectively. The compounds showed no agonist activity at any of the three opioid receptors; however, measurements of delta inverse agonist activity within this series illustrated a broad range of negative efficacy and IC50 values 650-fold more potent than the prototypical delta opioid receptor inverse agonist ICI 174,864 (22).

Title Effects of Ageing on the Biomechanical Properties of Rat Articular Cartilage.
Date July 2006
Journal Proceedings of the Institution of Mechanical Engineers. Part H, Journal of Engineering in Medicine
Excerpt

Previous studies have demonstrated that male Sprague Dawley (SD) rats experience age-related bone loss with the same characteristics as that in ageing men. As articular cartilage, like bone, is a critical component of the health and function of the musculoskeletal system, the authors hypothesized that articular cartilage in the untreated male SD rats could be a suitable model for studying the age-related deterioration of articular cartilage in men. To test this hypothesis, male SD rats were killed at between 6 and 27 months. The right femur of each rat was removed. The effects of ageing on the structural integrity of the distal femoral articular cartilage were studied by biomechanical testing with a creep indentation apparatus. The aggregate modulus, Poisson's ratio, permeability, thickness, and percentage recovery of articular cartilage were determined using finite element/non-linear optimization modelling. No significant differences were observed in these biomechanical properties of the distal femoral articular cartilage as a function of age. Therefore, untreated male SD rats appear to be unsuitable for studying the age-related changes of articular cartilage as they occur in men. However, and more intriguingly, it is also possible that ageing does not affect the biomechanical properties of articular cartilage in the absence of cartilage pathology.

Title Drosophila Eph Receptor Guides Specific Axon Branches of Mushroom Body Neurons.
Date June 2006
Journal Development (cambridge, England)
Excerpt

The conserved Eph receptors and their Ephrin ligands regulate a number of developmental processes, including axon guidance. In contrast to the large vertebrate Eph/Ephrin family, Drosophila has a single Eph receptor and a single Ephrin ligand, both of which are expressed within the developing nervous system. Here, we show that Eph and Ephrin can act as a functional receptor-ligand pair in vivo. Surprisingly, and in contrast to previous results using RNA-interference techniques, embryos completely lacking Eph function show no obvious axon guidance defects. However, Eph/Ephrin signaling is required for proper development of the mushroom body. In wild type, mushroom body neurons bifurcate and extend distinct branches to different target areas. In Eph mutants, these neurons bifurcate normally, but in many cases the dorsal branch fails to project to its appropriate target area. Thus, Eph/Ephrin signaling acts to guide a subset of mushroom body branches to their correct synaptic targets.

Title The Impact of Social Status on the Erythrocyte Beta-adrenergic Response in Rainbow Trout, Oncorhynchus Mykiss.
Date May 2006
Journal Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
Excerpt

The objective of the present investigation was to determine whether chronic increases in circulating cortisol concentrations, resulting from the occupation of subordinate status in rainbow trout social hierarchies, resulted in an enhancement of the erythrocyte adrenergic response. Rainbow trout (Oncorhynchus mykiss) were confined in fork length matched pairs for 6 h, 18 h, 48 h or 5-7 days, and social status was assigned through observations of behaviour. Erythrocyte adrenergic responsiveness, determined in vitro as changes in water content following incubation with the beta-adrenoreceptor agonist isoproterenol, was significantly greater in subordinate than dominant fish at 48 h of social interactions but not after 5-7 days, nor when assessed as changes in extracellular pH (pHe). However, the activity of the Na+/H+ exchanger (beta-NHE), assessed in vitro as the pHe change following incubation with the permeable cyclic AMP analogue 8-bromo-cyclic AMP, was significantly lower in subordinate fish. The number of erythrocyte membrane-bound adrenergic receptors (Bmax) was significantly higher in subordinate than dominant fish at 48 h, but had decreased by 5-7 days to a value that was not significantly different from that for dominant fish. The apparent dissociation constant (KD) of these receptors was not significantly impacted by either social status or interaction time. Finally, the relative expressions of beta-3b adrenergic receptor (AR) and beta-NHE mRNA were determined using real-time PCR and were found to be minimally affected by social rank. Relative to a control group, beta-3b AR mRNA was significantly up-regulated in both dominant and subordinate trout at all time periods, whereas the expression of beta-NHE was in general significantly down-regulated. Unlike the situation in rainbow trout treated with exogenous cortisol, elevations in circulating cortisol resulting from low social status did not "pre-adapt" the erythrocyte adrenergic response, but rather may have served to offset the potentially adverse effects elicited by plasma catecholamines, which were elevated during social hierarchy formation.

Title N-substituted 4beta-methyl-5-(3-hydroxyphenyl)-7alpha-amidomorphans Are Potent, Selective Kappa Opioid Receptor Antagonists.
Date April 2006
Journal Journal of Medicinal Chemistry
Excerpt

In a previous study, we identified (-)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl)propanamide (5a, KAA-1) as the first potent and selective kappa opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues 5b-r where the morphan N-substituent and 7alpha-amido group were varied. Most of the analogues showed sub-nanomolar potency for the kappa opioid receptor and were highly selective relative to the mu and delta opioid receptors. (-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-[2-(2-methylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and selective as nor-BNI as a kappa opioid receptor antagonist in the [35S]GTP-gamma-S in vitro functional test.

Title Variation in the Carotid Bifurcation Geometry of Young Versus Older Adults: Implications for Geometric Risk of Atherosclerosis.
Date February 2006
Journal Stroke; a Journal of Cerebral Circulation
Excerpt

Retrospective analysis of clinical data has demonstrated major variations in carotid bifurcation geometry, in support of the notion that an individual's vascular anatomy or local hemodynamics may influence the development of atherosclerosis. On the other hand, anecdotal evidence suggests that vessel geometry is more homogenous in youth, which would tend to undermine this geometric risk hypothesis. The purpose of our study was to test whether the latter is indeed the case.

Title N-substituted Cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists.
Date January 2006
Journal Journal of Medicinal Chemistry
Excerpt

N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has lower potential energy relative to that of the axial conformation. Evaluation of 6a-g in the [(35)S]GTP-gamma-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a K(e) of 0.27 nM at the kappa opioid receptor with 154- and 46-fold selectivity relative to those of the micro and delta receptors, respectively, possessed the best combination of kappa potency and selectivity.

Title Wnt Signaling in Neural Circuit Development.
Date January 2006
Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Title The Homeobox Transcription Factor Even-skipped Regulates Netrin-receptor Expression to Control Dorsal Motor-axon Projections in Drosophila.
Date January 2006
Journal Current Biology : Cb
Excerpt

Homeobox transcription-factor codes control motor-neuron subtype identity and dorsal versus ventral axon guidance in both vertebrate and invertebrate nervous systems; however, the specific axon guidance-receptors that are regulated by these transcription factors to control pathfinding are poorly defined. In Drosophila, the Even-skipped (Eve) transcription factor specifies dorsal motor-axon projection through the regulation of unidentified guidance molecules. The Netrins and their attractive and repulsive receptors DCC and Unc-5, respectively, define important conserved cue and receptor families that control growth-cone guidance. In Drosophila, the Netrins and frazzled (the fly homolog of DCC) contribute to motor-axon guidance. Here, using genetics and single-cell mRNA-expression analysis, we show that expression and requirement of different Netrin receptor combinations correlate with distinct dorsal and ventral motor-axon projections in Drosophila. Mis-expression of eve dorsalizes ventral axons in part through the upregulation of Unc-5, whereas loss of eve function in two dorsally projecting motor neurons results in aberrant axon projections and a failure to express Unc-5. Our results support a functional link between the expression of distinct Netrin receptor combinations and the transcriptional control of dorsal motor-axon guidance.

Title Synthesis of Long-chain Amide Analogs of the Cannabinoid Cb1 Receptor Antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1h-pyrazole-3-carboxamide (sr141716) with Unique Binding Selectivities and Pharmacological Activities.
Date October 2005
Journal Bioorganic & Medicinal Chemistry
Excerpt

An extended series of alkyl carboxamide analogs of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 1H-pyrazole-3-carboxamide (SR141716; 5) was synthesized. Each compound was tested for its ability to displace the prototypical cannabinoid ligands ([3H]CP-55,940, [3H]2; [3H]SR141716, [3H]5; and [3H]WIN55212-2, [3H]3), and selected compounds were further characterized by determining their ability to affect guanosine 5'-triphosphate (GTP)-gamma-[35S] binding and their effects in the mouse vas deferens assay. This systematic evaluation has resulted in the discovery of novel compounds with unique binding properties at the central cannabinoid receptor (CB1) and distinctive pharmacological activities in CB1 receptor tissue preparations. Specifically, compounds with nanomolar affinity which are able to fully displace [3H]5 and [3H]2, but unable to displace [3H]3 at similar concentrations, have been synthesized. This selectivity in ligand displacement is unprecedented, in that previously, compounds in every structural class of cannabinoid ligands had always been shown to displace each of these radioligands in a competitive fashion. Furthermore, the selectivity of these compounds appears to impart unique pharmacological properties when tested in a mouse vas deferens assay for CB1 receptor antagonism.

Title Anthropometric Data for Magnetic Resonance Imaging of the Carotid Bifurcation.
Date September 2005
Journal Journal of Magnetic Resonance Imaging : Jmri
Excerpt

To provide anthropometric data applicable to the design of protocols for high-resolution magnetic resonance imaging (MRI) of the carotid bifurcation, particularly those aimed at elucidating the role of local factors in carotid atherogenesis.

Title Addison's Disease Presenting in Four Adolescents with Type 1 Diabetes.
Date May 2005
Journal Pediatric Diabetes
Excerpt

Primary adrenocortical insufficiency (Addison's disease) is a potentially fatal condition that often develops insidiously and can be easily overlooked. Although rare in the general population, it is more common in patients with type 1 diabetes mellitus (T1DM). The combination of Addison's disease with T1DM and/or autoimmune thyroid disease is known as autoimmune polyendocrine syndrome type-2 (APS-2). T1DM commonly precedes the development of adrenocortical insufficiency in most patients with APS-2. We, in this study, present four cases of Addison's disease developing in adolescents with pre-existing T1DM. Risk factors for Addison's disease in this population include a history of other organ-specific autoimmunity, particularly thyroid, and a positive family history. In addition to the 'classic' Addisonian features, the development of unexplained recurrent hypoglycemia, reduction in total insulin requirement, improvement in glycemic control, or abnormal pigmentation should arouse suspicion of adrenocortical insufficiency. Adrenal antibodies have been proposed as a screening tool for Addison's disease in the T1DM population, but doubts remain about their specificity and sensitivity. The addition of specific HLA DRB1 subtyping has been proposed to improve predictive value.

Title Pharmacological Properties of Jdtic: a Novel Kappa-opioid Receptor Antagonist.
Date March 2005
Journal European Journal of Pharmacology
Excerpt

Biological studies were conducted on (3R)-7-Hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist.

Title Correlation of Cartilage Stiffness to Thickness and Level of Degeneration Using a Handheld Indentation Probe.
Date October 2004
Journal Annals of Biomedical Engineering
Excerpt

The in vivo assessment of the quality of cartilage is a critical tool to determine how to clinically treat damaged cartilage. Utilizing nondestructive indentation, a hand-held instrument (ACTAEON Probe) was used to rapidly measure the stiffness of articular cartilage, which can then be correlated to cartilage condition. An integrated series of tests were performed to determine whether the Probe is sensitive enough to detect early degenerative changes in articular cartilage and to examine if it is dependent on the thickness of the cartilage being tested. Results demonstrated that there is no effect of thickness on the Probe measurements for clinically relevant human cartilage samples, that the Probe is sensitive enough to detect different levels of cartilage degeneration, and that Probe data correlate well with traditional creep indentation testing. This study demonstrates the utility of the Probe for detecting degenerative changes in animal and human joints.

Title Twenty-one Cases of Aortoenteric Fistula: Lessons for the General Surgeon.
Date August 2004
Journal The American Surgeon
Excerpt

We retrospectively reviewed our experience from 1984 to 2001 with 21 cases of aortoenteric fistula (AEF) in 19 patients. The majority of cases were in men (13 of 19, 68%). One AEF was spontaneous, the other 20 developed after prior vascular reconstruction (95%). The majority of AEF were duodenal (48%) followed by small bowel (38%), colon (10%), and esophageal AEF (5%). The proximal anastomosis of the prior vascular repair was the site of AEF origin in 62 per cent of cases, the distal anastomosis accounted for 19 per cent, and the body of the graft for 14 per cent. The intestinal repair was chosen on a case-by-case basis by the general surgeon and consisted of a simple primary repair in 48 per cent, resection with primary anastomosis in 38 per cent, and patching with pleura or omentum in individual cases. Colostomies were created in the two cases with colonic AEF. The duodenum was excluded in one of 10 duodenal AEF. Six patients (32%) died in the 90 days following surgery. The biggest risk of postoperative death was presentation with sepsis (P = 0.069); interestingly, women were more likely to present with sepsis (P = 0.019) and experienced a disproportionate rate of postoperative death (male 23%, female 50%, P = 0.24). The method used to repair the bowel was linked to a higher rate of postoperative death, and patients that required bowel resection died more frequently (66%) than those who had a simple repair (10%, P = 0.07). Overall mortality with AEF remains high despite routine SICU care. The biggest risk for death is preoperative sepsis. Women presented with sepsis more frequently than men. The method of bowel repair appears to be related to overall survival and along with sepsis is, perhaps, a surrogate for the degree of erosion present at the site of the AEF. Simple bowel repairs were sufficient when technically possible. Duodenal exclusion is not an obligatory adjunct to duodenal repairs.

Title Determination of Caffeine, Theobromine, and Theophylline in Standard Reference Material 2384, Baking Chocolate, Using Reversed-phase Liquid Chromatography.
Date July 2004
Journal Journal of Agricultural and Food Chemistry
Excerpt

A rapid and selective isocratic reversed-phase liquid chromatographic method has been developed at the National Institute of Standards and Technology to simultaneously measure caffeine, theobromine, and theophylline in a food-matrix standard reference material (SRM) 2384, Baking Chocolate. The method uses isocratic elution with a mobile phase composition (volume fractions) of 10% acetronitrile/90% water (pH adjusted to 2.5 using acetic acid) at a flow rate of 1.5 mL/min with ultraviolet absorbance detection (274 nm). Total elution time for these analytes is less than 15 min. Concentration levels of caffeine, theobromine, and theophylline were measured in single 1-g samples taken from each of eight bars of chocolate over an eight-day period. Samples were defatted with hexane, and beta-hydroxyethyltheophylline was added as the internal standard. The repeatability for the caffeine, theobromine, and theophylline measurements was 5.1, 2.3, and 1.9%, respectively. The limit of quantitation for all analytes was <100 ng/mL. The measurements from this method were used in the value-assignment of caffeine, theobromine, and theophylline in SRM 2384.

Title Biomechanical Tissue Characterization of the Superior Joint Space of the Porcine Temporomandibular Joint.
Date April 2004
Journal Annals of Biomedical Engineering
Excerpt

The objective of this study was to characterize the biomechanical properties of articular cartilage in the superior joint space of the porcine temporomadibular joint (TMJ). These properties and thickness of the disk and fossa cartilage were obtained from eight joints using creep indentation. Five sites per surface were tested to obtain the aggregate modulus, Poisson's ratio, permeability, creep, recovery percentage, and cartilage thickness. Histology was also performed to characterize the orientation of the collagen fibers and the proteoglycan content. It was found that the temporal fossa cartilage was 57% thinner and 50% stiffer than the disk. The aggregate modulus of the porcine TMJ disk and fossa was much smaller, but the permeability of the TMJ disk and fossa was much higher than those of articular cartilage in other joints. It was also noted that the TMJ disk did not fully recover following indentation testing unlike the articular cartilage in other joints. The biomechanical properties of the TMJ disk and temporal fossa obtained in this study are significantly different from those of cartilage present in other diarthrodial joints. This suggests that the function of the fibrocartilage in the superior TMJ space is substantially different from that of hyaline cartilage in other joints.

Title Secreted Cell Signaling Molecules in Axon Guidance.
Date April 2004
Journal Current Opinion in Neurobiology
Excerpt

The growth cones of developing neurons respond to specific guidance cues in their extracellular environment. Recent studies have shown that secreted signaling molecules from protein families that are best known for their roles as morphogens in specifying cell fate can function as axon guidance molecules. These signaling molecules seem to act directly on the growth cone and thus are likely to activate non-canonical signaling pathways that are coupled to the cytoskeleton.

Title Importance of Phenolic Address Groups in Opioid Kappa Receptor Selective Antagonists.
Date April 2004
Journal Journal of Medicinal Chemistry
Excerpt

In vitro characterization and comparison of JDTic, its dehydroxy analogue and nor-BNI, and its dehydroxy analogue demonstrates that the N-substituted 3,4-dimethyl-(3-hydroxyphenyl)piperidine-derived antagonist, JDTic, relies more heavily on its phenol address group for affinity and antagonist activity relative to the corresponding naltrexone derived antagonists, nor-BNI. The structural flexibility of the former class of compound relative to the latter is postulated to underlie the difference.

Title Discovery of the First N-substituted 4beta-methyl-5-(3-hydroxyphenyl)morphan to Possess Highly Potent and Selective Opioid Delta Receptor Antagonist Activity.
Date March 2004
Journal Journal of Medicinal Chemistry
Excerpt

A structurally novel opioid delta receptor selective antagonist has been identified. This compound, (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-4], showed a K(e) value of 0.15 nM in the [(35)S]GTPgammaS functional assay. (+)-KF4 is also a delta inverse agonist with an IC(50) value of 1.8 nM. To our knowledge, this is the first potent and selective delta opioid receptor antagonist from the 5-phenylmorphan class of opioids.

Title Neuroscience. The Ups and Downs of Wnt Signaling.
Date December 2003
Journal Science (new York, N.y.)
Title Reproducibility of Image-based Computational Fluid Dynamics Models of the Human Carotid Bifurcation.
Date September 2003
Journal Annals of Biomedical Engineering
Excerpt

Recent studies have demonstrated the ability of magnetic resonance imaging (MRI) to provide anatomically realistic boundary conditions for computational fluid dynamics (CFD) simulations of arterial hemodynamics. To date, however, little is known about the overall reproducibility of such image-based CFD techniques. Towards this end we used serial black blood and cine phase contrast MRI to reconstruct CFD models of the carotid bifurcations of three subjects with early atherosclerosis, each imaged three times at weekly intervals. The lumen geometry was found to be precise on average to within 0.15 mm or 5%, while measured flow and heart rates varied by less than 10%. Spatial patterns of a variety of wall shear stress (WSS) indices were largely preserved among the three repeat models. Time-averaged WSS was reproduced best, on average to within 5 dyn/cm2 or 37%, followed by WSS spatial gradients, angle gradients, and oscillatory shear index. The intrasubject flow rate variations were found to contribute little to the overall WSS variability. Instead, reproducibility was determined largely by the precision of the lumen boundary extraction from the individual MR images, itself shown to be a function of the image quality and proximity to the geometrically complex bifurcation region.

Title Identification of (3r)-7-hydroxy-n-((1s)-1-[[(3r,4r)-4-(3-hydroxyphenyl)- 3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro- 3-isoquinolinecarboxamide As a Novel Potent and Selective Opioid Kappa Receptor Antagonist.
Date August 2003
Journal Journal of Medicinal Chemistry
Excerpt

(3R)-7-Hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) was identified as a potent and selective kappa opioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R,4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroisoquinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its kappa potency and selectivity. The results suggest that, like other kappa opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective kappa antagonist activity in the [(35)S]GTPgammaS functional assay. However, unlike previously reported kappa antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective kappa antagonist properties of JDTic can be rationalized using the "message-address" concept wherein the (3R,4R)-3,4-dimethyl-4-(hydroxyphenyl)piperidinyl group represents the message, and the basic amino and phenol group in the N substituent constitutes the address. It is interesting to note the structural commonality (an amino and phenol groups) in both the message and address components of JDTic. The unique structural features of JDTic will make this compound highly useful in further characterization of the kappa receptor.

Title Ssdp Proteins Bind to Lim-interacting Co-factors and Regulate the Activity of Lim-homeodomain Protein Complexes in Vivo.
Date June 2003
Journal Development (cambridge, England)
Excerpt

LIM-homeodomain transcription factors control a variety of developmental processes, and are assembled into functional complexes with the LIM-binding co-factor Ldb1 (in mouse) or Chip (in Drosophila). We describe the identification and characterization of members of the Ssdp family of proteins, which we show to interact with Ldb1 and Chip. The N terminus of Ssdp is highly conserved among species and binds a highly conserved domain within Ldb1/Chip that is distinct from the domains required for LIM binding and self-dimerization. In Drosophila, Ssdp is expressed in the developing nervous system and imaginal tissues, and it is capable of modifying the in vivo activity of complexes comprised of Chip and the LIM-homeodomain protein Apterous. Null mutations of the ssdp gene are cell-lethal in clones of cells within the developing wing disc. However, clones mutant for a hypomorphic allele give rise to ectopic margins, wing outgrowth and cell identity defects similar to those produced by mutant clones of Chip or apterous. Ssdp and Ldb/Chip each show structural similarity to two Arabidopsis proteins that cooperate with one another to regulate gene expression during flower development, suggesting that the molecular interactions between Ssdp and Ldb/Chip proteins are evolutionarily ancient and supply a fundamental function in the regulated control of transcription.

Title Wnt-mediated Axon Guidance Via the Drosophila Derailed Receptor.
Date April 2003
Journal Nature
Excerpt

In nervous systems with bilateral symmetry, many neurons project axons across the midline to the opposite side. In each segment of the Drosophila embryonic nervous system, axons that display this projection pattern choose one of two distinct tracts: the anterior or posterior commissure. Commissure choice is controlled by Derailed, an atypical receptor tyrosine kinase expressed on axons projecting in the anterior commissure. Here we show that Derailed keeps these axons out of the posterior commissure by acting as a receptor for Wnt5, a member of the Wnt family of secreted signalling molecules. Our results reveal an unexpected role in axon guidance for a Wnt family member, and show that the Derailed receptor is an essential component of Wnt signalling in these guidance events.

Title Motor Neuron Specification in Worms, Flies and Mice: Conserved and 'lost' Mechanisms.
Date March 2003
Journal Current Opinion in Genetics & Development
Excerpt

Motor neuron differentiation has been studied intensively in both invertebrates and vertebrates in recent years. These studies have led to the identification of several key regulatory genes acting to generate motor neurons and to specify their subclass identities. By comparing findings from Caenorhabditis elegans, Drosophila and vertebrate model systems, it is apparent that both evolutionarily conserved and non-conserved mechanisms are used.

Title On the Influence of Vessel Planarity on Local Hemodynamics at the Human Carotid Bifurcation.
Date October 2002
Journal Biorheology
Excerpt

The human carotid artery bifurcation is a complex, three-dimensional structure exhibiting non-planarity and both in- and out-of-plane curvature. The aim of this study was to determine the relative importance of vessel planarity, a potential geometric risk factor for atherogenesis, in determining the local hemodynamics. A combination of computational fluid dynamics and magnetic resonance imaging was used to reconstruct the subject-specific hemodynamics for three subjects. Planar models were then constructed by translating the centroids of the lumen contours onto a plane defined by the centroids of the vessel branches near the bifurcation apex. A novel "patching" technique was used to convert the continuous arterial surfaces into contiguous but discrete patches according to an objective scheme, making it possible to compare the original and planar models without the need for registration and warping. Results suggest that the planarity of the vessel has a relatively minor effect on the spatial distribution of mean and oscillatory wall shear stress. Out-of-plane curvature was, however, found to have a marked influence on the extent and magnitude of these hemodynamic variables. We conclude that vessel curvature - whether in- or out-of-plane - rather than planarity may deserve further scrutiny as a potential geometric risk for atherogenesis.

Title Discovery of an Opioid Kappa Receptor Selective Pure Antagonist from a Library of N-substituted 4beta-methyl-5-(3-hydroxyphenyl)morphans.
Date August 2002
Journal Journal of Medicinal Chemistry
Excerpt

A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous solution phase synthetic methodology. From this library, N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)-7alpha-[3-(1-piperidinyl)propanamido]morphan [(-)-3b] was identified as the first potent and selective kappa opioid receptor antagonist from the 5-phenylmorphan class of opioids.

Title Enzymic Degradation of Plasma Arginine Using Arginine Deiminase Inhibits Nitric Oxide Production and Protects Mice from the Lethal Effects of Tumour Necrosis Factor Alpha and Endotoxin.
Date June 2002
Journal The Biochemical Journal
Excerpt

Septic shock is mediated in part by nitric oxide (NO) and tumour necrosis factor alpha (TNFalpha). NO is synthesized primarily from extracellular arginine. We tested the ability of an arginine-degrading enzyme to inhibit NO production in mice and to protect mice from the hypotension and lethality that occur after the administration of TNFalpha or endotoxin. Treatment of BALB/c mice with arginine deiminase (ADI) formulated with succinimidyl succinimide polyethylene glycol of M(r) 20000 (ADI-SS PEG(20000)) eliminated all measurable plasma arginine (from normal levels of approximately 155 microM arginine to 2 microM). In addition, ADI-SS PEG(20000) also inhibited the production of NO, as quantified by plasma nitrate+nitrite. Treatment of mice with TNFalpha or endotoxin resulted in a dose-dependent increase in NO production and lethality. Pretreatment of mice with ADI-SS PEG(20000) resulted in increased resistance to the lethal effects of TNFalpha and endotoxin. These observations are consistent with NO production resulting, to some extent, from the metabolism of extracellular arginine. The toxic effects of TNFalpha and endotoxin may be partially inhibited by enzymic degradation of plasma arginine by ADI-SS PEG(20000). Interestingly, pretreatment with ADI-SS PEG(20000) did not inhibit the anti-tumour activity of TNFalpha in vitro or in vivo. This treatment may allow greater amounts of TNFalpha, as well as other cytokines, to be administered while abrogating side effects such as hypotension and death.

Title Expression and Function of the Lim Homeodomain Protein Apterous During Embryonic Brain Development of Drosophila.
Date May 2002
Journal Development Genes and Evolution
Excerpt

We analyzed the expression and function of the LIM-homeodomain transcription factor Apterous (Ap ) in embryonic brain development of Drosophila. Expression of Ap in the embryonic brain begins at early stage 12 and is subsequently found in approximately 200 protocerebral neurons and in 4 deutocerebral neurons. Brain glia do not express Ap. Most of the Ap-expressing neurons are interneurons and project their axons across the midline to the contralateral hemisphere; a smaller subset projects their axons into the ventral nerve cord. A few Ap-expressing neurons project to the ring gland, suggesting that they are neurosecretory cells. In ap loss-of-function mutants, some of the protocerebral and deutocerebral interneurons that express Ap in the wild type show axon pathfinding errors and fasciculation defects in the brain, notably in the fascicles of the brain commissure. In contrast, the interneurons that project to the ring gland do not appear to be affected in ap mutants. Thus, in brain development, Ap is required for correct axon guidance and fasciculation of interneurons, and Ap-expressing cells may also be involved in the brain neuroendocrine system.

Title Reconstruction of Carotid Bifurcation Hemodynamics and Wall Thickness Using Computational Fluid Dynamics and Mri.
Date February 2002
Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
Excerpt

A thorough understanding of the relationship between local hemodynamics and plaque progression has been hindered by an inability to prospectively monitor these factors in vivo in humans. In this study a novel approach for noninvasively reconstructing artery wall thickness and local hemodynamics at the human carotid bifurcation is presented. Three-dimensional (3D) models of the lumen and wall boundaries, from which wall thickness can be measured, were reconstructed from black-blood magnetic resonance imaging (MRI). Along with time-varying inlet/outlet flow rates measured via phase contrast (PC) MRI, the lumen boundary was used as input for computational fluid dynamic (CFD) simulation of the subject-specific flow patterns and wall shear stresses (WSSs). Results from a 59-year-old subject with early, asymptomatic carotid artery disease show good agreement between simulated and measured velocities, and demonstrate a correspondence between wall thickening and low and oscillating shear at the carotid bulb. High shear at the distal internal carotid artery (ICA) was also colocalized with higher WSS; however, a quantitative general relationship between WSS and wall thickness was not found. Similar results were obtained from a 23-year-old normal subject. These findings represent the first direct comparison of hemodynamic variables and wall thickness at the carotid bifurcation of human subjects. The noninvasive nature of this image-based modeling approach makes it ideal for carrying out future prospective studies of hemodynamics and plaque development or progression in otherwise healthy subjects.

Title Mutation of Drosophila Homer Disrupts Control of Locomotor Activity and Behavioral Plasticity.
Date January 2002
Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Excerpt

Homer proteins have been proposed to play a role in synaptogenesis, synapse function, receptor trafficking, and axon pathfinding. Here we report the isolation and characterization of the Drosophila gene homer, the single Homer-related gene in fly. Using anti-Homer antibody we show that Homer is expressed in a broad range of tissues but is highly enriched in the CNS. Similarly to its mammalian counterpart, the Drosophila Homer localizes to the dendrites and the endoplasmic reticulum (ER). This subcellular distribution is dependent on an intact Enabled/Vasp homology 1 domain, suggesting that Homer must bind to one or more of its partners for proper localization. We have created a mutation of homer and show that flies homozygous for this mutation are viable and show coordinated locomotion, suggesting that Homer is not essential for basic neurotransmission. However, we found that homer mutants display defects in behavioral plasticity and the control of locomotor activity. Our results argue that in the CNS, Homer-related proteins operate in the ER and in dendrites to regulate the development and function of neural networks underlying locomotor control and behavioral plasticity.

Title A Semi-automatic Technique for Measurement of Arterial Wall from Black Blood Mri.
Date December 2001
Journal Medical Physics
Excerpt

Black blood magnetic resonance imaging (MRI) has become a popular technique for imaging the artery wall in vivo. Its noninvasiveness and high resolution make it ideal for studying the progression of early atherosclerosis in normal volunteers or asymptomatic patients with mild disease. However, the operator variability inherent in the manual measurement of vessel wall area from MR images hinders the reliable detection of relatively small changes in the artery wall over time. In this paper we present a semi-automatic method for segmenting the inner and outer boundary of the artery wall, and evaluate its operator variability using analysis of variance (ANOVA). In our approach, a discrete dynamic contour is approximately initialized by an operator, deformed to the inner boundary, dilated, and then deformed to the outer boundary. A group of four operators performed repeated measurements on 12 images from normal human subjects using both our semiautomatic technique and a manual approach. Results from the ANOVA indicate that the inter-operator standard error of measurement (SEM) of total wall area decreased from 3.254 mm2 (manual) to 1.293 mm2 (semi-automatic), and the intra-operator SEM decreased from 3.005 mm2 to 0.958 mm2. Operator reliability coefficients increased from less than 69% to more than 91% (inter-operator) and 95% (intra-operator). The minimum detectable change in wall area improved from more than 8.32 mm2 (intra-operator, manual) to less than 3.59 mm2 (inter-operator, semi-automatic), suggesting that it is better to have multiple operators measure wall area with our semi-automatic technique than to have a single operator make repeated measurements manually. Similar improvements in wall thickness and lumen radius measurements were also recorded. Since the semi-automatic technique has effectively ruled out the effect of the operator on these measurements, it may be possible to use such techniques to expand prospective studies of atherogenesis to multiple centers so as to increase access to real patient data without sacrificing reliability.

Title Use of Contrast Echocardiography in the Diagnosis of Subacute Myocardial Rupture After Myocardial Infarction.
Date December 2001
Journal Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography
Excerpt

Myocardial rupture is an uncommon and catastrophic complication after acute myocardial infarction. It can present in an acute form or in a subacute form, with slower hemorrhage and thrombus formation at the site of rupture. These patients can survive several hours or days before the diagnosis is confirmed and the myocardial ruptured repaired. Two-dimensional Doppler echocardiography is very useful in the diagnosis of this complication, but the number of false-positive diagnoses is high, even in the presence of a large amount of pericardial effusion. In these patients, administration of a contrast agent can be useful to demonstrate active bleeding into the pericardium. We report a case of subacute myocardial rupture for which contrast echocardiography was useful in demonstrating the presence of persistent hemorrhage into the pericardium. To reduce the number of false-positive diagnoses, contrast echocardiography should be considered in patients with possible subacute myocardial rupture.

Title Selenium Status of Cats in Four Regions of the World and Comparison with Reported Incidence of Hyperthyroidism in Cats in Those Regions.
Date October 2001
Journal American Journal of Veterinary Research
Excerpt

To assess selenium (Se) status of cats in 4 regions of the world and to compare results for Se status with reported incidence of hyperthyroidism in cats in those regions.

Title Effect of Black Blood Mr Image Quality on Vessel Wall Segmentation.
Date October 2001
Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
Excerpt

Black blood MRI has become a popular technique for measuring arterial wall area as an indicator of plaque size. Computer-assisted techniques for segmenting vessel boundaries have been developed to increase measurement precision. In this study, the carotid arteries of four normal subjects were imaged at seven different fields of view (FOVs), keeping all other imaging parameters fixed, to determine whether spatial resolution could be increased at the expense of image quality without sacrificing precision. Wall areas were measured via computer-assisted segmentation of the vessel boundaries performed repeatedly by two operators. Analysis of variance (ANOVA) demonstrated that the variability of wall area measurements was below 1.5 mm(2) for in-plane spatial resolutions between 0.22 mm and 0.37 mm. An inverse relationship between operator variability and the signal difference-to-noise ratio (SDNR) demonstrated that semi-automatic segmentation of the wall boundaries was robust for SDNR >3, defining a criterion above which subjective image quality can be degraded without an appreciable loss of information content. Our study also suggested that spatial resolutions higher than 0.3 mm may be required to quantify normal wall areas to within 10% accuracy, but that the reduced SNR associated with the higher resolution may be tolerated by semi-automated wall segmentation without an appreciable loss of precision.

Title Effects of Conjugated Linoleic Acids and Docosahexaenoic Acid on Rat Liver and Reproductive Tissue Fatty Acids, Prostaglandins and Matrix Metalloproteinase Production.
Date October 2001
Journal Prostaglandins, Leukotrienes, and Essential Fatty Acids
Excerpt

Long chain n-6 and n-3 fatty acids play important roles in labor and delivery. These effects may be mediated by prostaglandin (PG) synthesis and by regulation of matrix metalloproteinases (MMPs), both of which play roles in uterine contraction, cervical ripening and rupture of fetal membranes. The effects of altering dietary n-6:n-3 long chain fatty acid ratios, and the addition of dietary conjugated linoleic acids (CLA) and docosahexaenoic acid (DHA) on fatty acid composition of reproductive tissues, PG synthesis in liver and reproductive tissue and serum MMP levels were examined in pregnant rats. Modified AIN-96G diets with n-6:n-3 ratios of 7:1 and 34:1 with and without added 1.1% (by weight) conjugated linoleic acid (CLA) and/or 0.3% (by weight) DHA were fed through day 20 of gestation. Reproductive tissues readily incorporated both DHA and CLA. CLA significantly (P<0.05) depressed PGF(2 alpha)synthesis in placenta, uterus and liver by 50% when the n-6:n-3 ratio was 7:1 and by 66% at 34:1 ratio. Significant differences (P<0.05) in PGE(2)synthesis in uterus and liver were seen only between groups fed the high ratio of n-6:n-3 without CLA, and the low ratio with CLA. Addition of CLA to DHA containing diets depressed PGF(2alpha) by one-third in uterus and liver (P<0.05). Serum MMP-9 and active MMP-2 were suppressed (P<0.05) by addition of either CLA or DHA.

Title Agonist-, Antagonist-, and Inverse Agonist-regulated Trafficking of the Delta-opioid Receptor Correlates With, but Does Not Require, G Protein Activation.
Date September 2001
Journal The Journal of Pharmacology and Experimental Therapeutics
Excerpt

In this study, we explored the relationship between ligand-induced regulation of surface delta opioid receptors and G protein activation. G protein activation was assessed with [(35)S]guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) binding assays conducted at both 37 and 0 degrees C. Ligand-independent (constitutive) activity of the delta-receptor was readily observed when the [(35)S]GTP gamma S binding assay was performed at 37 degrees C. We identified a new class of alkaloid inverse agonists (RTI-5989-1, RTI-5989-23, RTI-5989-25), which are more potent than the previously described peptide inverse agonist ICI-174864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu). Treatment with these inverse agonists for 18 h caused up-regulation of surface receptors. Eighteen-hour treatment with etorphine resulted in approximately 90% loss of surface receptor, whereas fentanyl, diprenorphine, and morphine caused between 20 and 50% loss. The abilities of ligands to modulate [(35)S]GTP gamma S binding at 37 degrees C showed a strong correlation with their abilities to regulate surface receptor number (r(2) = 0.86). Interestingly, the ability of fentanyl to activate G proteins was markedly temperature sensitive. Fentanyl showed no stimulation of [(35)S]GTP gamma S binding at 0 degrees C but was as efficacious as etorphine, morphine, and diprenorphine at 37 degrees C. Neither the ligand-induced receptor increases nor decreases were perturbed by pertussis toxin pretreatment, suggesting that functional G proteins are not required for ligand-regulated delta-opioid receptor trafficking.

Title Identification of the First Trans-(3r,4r)- Dimethyl-4-(3-hydroxyphenyl)piperidine Derivative to Possess Highly Potent and Selective Opioid Kappa Receptor Antagonist Activity.
Date September 2001
Journal Journal of Medicinal Chemistry
Excerpt

A structurally novel opioid kappa receptor selective ligand has been identified. This compound, (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 10) demonstrated high affinity for the kappa receptor in the binding assay (kappa K(i) = 0.3 nM) and highly potent and selective kappa antagonism in the [(35)S]GTP-gamma-S assay using cloned opioid receptors (kappa K(i) = 0.006 nM, mu/kappa ratio = 570, delta/kappa ratio > 16600).

Title Opioid Peptide Receptor Studies. 15. Relative Efficacy of 4-[(n-allyl-3-methyl-4-piperidinyl)phenylamino]-n,n-diethylbenzamide and Related Compounds at the Cloned Human Delta-opioid Receptor.
Date July 2001
Journal Synapse (new York, N.y.)
Excerpt

Previous data obtained from both binding and functional assays demonstrated that (-)-4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide [(-)-RTI5989-54] displays selective binding and full agonist activity relative to (+/-)-RTI5989-54 for the delta opioid receptor. The present study was conducted to evaluate the activities of structurally diverse opioid receptor delta ligands in the [(35)S]GTP-gamma-S binding assay, comparing the relationship between receptor binding, activation, efficacy, and intrinsic efficacy. The data, obtained with cloned human delta receptors, demonstrated that (-)-RTI5989-54 behaves like the highly selective delta agonist SNC80. Addition of the hydroxyl group to RTI5989-54 (RTI5989-61) or replacement of the allyl group with the trans-crotyl group on the piperidine nitrogen of RTI-5989-61 (RTI5989-62) increased binding affinity, produced full agonist activity, and decreased intrinsic efficacy at the delta opioid receptor. The order of potency for the EC(50) (GTP-gamma-S) was RTI5989-62 (0.20 nM) > RTI5989-61 (0.43 nM) > SNC80 (1.92 nM) > DPDPE (3.50 nM) > (-)-RTI5989-54 (17.6 nM) > (+/-)-RTI5989-54 (65.6 nM) > (+)-RTI5989-54 (483 nM). RTI5989-61 and RTI5989-62 were fully efficacious, but had intrinsic efficacy values that were 2.2-3.1 times lower than that of DPDPE and SNC80. Comparison of the binding K(i) in competitively inhibiting [(125)I]IOXY binding to the functional K(i) for delta antagonists [Ki (IOXY)/Ki (GTP-gamma-S)] shows that antagonists might antagonize agonist-evoked neurochemical effects with equal magnitude while occupying different proportions of target receptors.

Title Factors Influencing Agonist Potency and Selectivity for the Opioid Delta Receptor Are Revealed in Structure-activity Relationship Studies of the 4-[(n-substituted-4-piperidinyl)arylamino]-n,n-diethylbenzamides.
Date May 2001
Journal Journal of Medicinal Chemistry
Excerpt

A study of the effect of transposition of the internal nitrogen atom for the adjacent benzylic carbon atom in delta-selective agonists such as BW373U86 (1) and SNC-80 (2) has been undertaken. It was shown that high-affinity, fully efficacious, and delta opioid receptor-selective compounds can be obtained from this transposition. In addition to the N,N-diethylamido group needed as the delta address, the structural features identified to promote delta receptor affinity in the set of compounds studied included a cis relative stereochemistry between the 3- and 4-substituents in the piperidine ring, a trans-crotyl or allyl substituent on the basic nitrogen, the lack of a 2-methyl group in the piperidine ring, and either no substitution or hydroxyl substitution in the aryl ring not substituted with the N,N-diethylamido group. Structural features found to be important for mu affinity include hydroxyl substitution in the aryl ring, the presence of a 2-methyl group in a cis relative relationship to the 4-amino group as well as N-substituents such as cyclopropylmethyl. It was also determined that mu receptor affinity could be increased while maintaining delta receptor affinity, especially when hydroxyl-substituted compounds are considered. Additionally, it was discovered that the somewhat lower mu/delta selectivities observed for the piperidine compounds relative to the piperazine-based ligands appear to arise as a consequence of the carbon-nitrogen transposition which imparts an overall lower delta and higher mu affinity to the piperidine-based ligands. This higher affinity for the mu receptor, apparently intrinsic to the piperidine-based compounds, suggests that ligands of this class will more easily be converted to mu/delta combination agonists compared to the piperazine ligands such as 1. This is particularly important since analogues of 1, which show both mu- and delta-type activity, are now recognized as important for their strong analgesia and cross-canceling of many of the side effects found in agonists operating exclusively from either the delta or mu opioid receptor.

Title Drosophila Wing Development in the Absence of Dorsal Identity.
Date April 2001
Journal Development (cambridge, England)
Excerpt

The developing wing disc of Drosophila is divided into distinct lineage-restricted compartments along both the anterior/posterior (A/P) and dorsal/ventral (D/V) axes. At compartment boundaries, morphogenic signals pattern the disc epithelium and direct appropriate outgrowth and differentiation of adult wing structures. The mechanisms by which affinity boundaries are established and maintained, however, are not completely understood. Compartment-specific adhesive differences and inter-compartment signaling have both been implicated in this process. The selector gene apterous (ap) is expressed in dorsal cells of the wing disc and is essential for D/V compartmentalization, wing margin formation, wing outgrowth and dorsal-specific wing structures. To better understand the mechanisms of Ap function and compartment formation, we have rescued aspects of the ap mutant phenotype with genes known to be downstream of Ap. We show that Fringe (Fng), a secreted protein involved in modulation of Notch signaling, is sufficient to rescue D/V compartmentalization, margin formation and wing outgrowth when appropriately expressed in an ap mutant background. When Fng and alphaPS1, a dorsally expressed integrin subunit, are co-expressed, a nearly normal-looking wing is generated. However, these wings are entirely of ventral identity. Our results demonstrate that a number of wing development features, including D/V compartmentalization and wing vein formation, can occur independently of dorsal identity and that inter-compartmental signaling, refined by Fng, plays the crucial role in maintaining the D/V affinity boundary. In addition, it is clear that key functions of the ap selector gene are mediated by only a small number of downstream effectors.

Title The Derailed Guidance Receptor Does Not Require Kinase Activity in Vivo.
Date February 2001
Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Excerpt

The Drosophila Derailed (DRL) receptor tyrosine kinase (RTK) controls key guidance events in the developing nervous system and mesoderm. Like other members of the "related to tyrosine kinases" (RYK) subfamily of RTKs, DRL has several highly unusual amino acid substitutions within the catalytic domain, raising the possibility that members of this subfamily are catalytically inactive. To test the role of DRL kinase activity in vivo, we mutated the invariant lysine required for catalytic activity of known kinases and examined the ability of this mutant to function in two assays: a dominant gain-of-function axon switch assay in the nervous system and phenotypic rescue of muscle attachment in drl mutants. We show that this predicted kinase-deficient DRL mutant is capable of functioning in both assays. Our results indicate that DRL does not require kinase activity in vivo and suggest that members of the RYK subfamily of RTKs transduce signals unconventionally.

Title Opioid Peptide Receptor Studies. 14. Stereochemistry Determines Agonist Efficacy and Intrinsic Efficacy in the [(35)s]gtp-gamma-s Functional Binding Assay.
Date January 2001
Journal Synapse (new York, N.y.)
Excerpt

Previous data obtained with the cloned rat mu opioid receptor demonstrated that stereochemistry affects the four parameters of the ligand-receptor interaction: potency (ED(50)), efficacy (maximal stimulation), intrinsic efficacy (effect as a function of receptor occupation), and binding affinity. This study evaluated the activities of structurally diverse opioid receptor ligands in the [(35)S]GTP-gamma-S binding assay, comparing the relationship between receptor binding, activation, efficacy, and intrinsic efficacy. The data, obtained with cloned rat mu receptors, demonstrated that an analgetic, (-)-5-m-hydroxyphenyl-2-methylmorphan (NIH8508), and its (+)-isomer (NIH8509), behave as partial agonists, but had different intrinsic efficacy in the [(35)S]GTP-gamma-S binding assay. Replacement of the methyl group with the phenethyl group on the piperidine nitrogen of NIH8508 and NIH8509 [(1R,5S)-AH019 and (1S, 5R)-AH019] increased affinity for the mu receptor and eliminated any agonist effect, supporting the hypothesis that certain structural features make these compounds antagonists. These study also show that all of the fully efficacious mu agonists studied here had high levels of intrinsic efficacy, producing a 50% response at about 10% receptor occupancy. Comparison of the binding K(i) in competitively inhibiting [(125)I]IOXY binding to the functional K(i) for opioid antagonists [K(i)(IOXY)/K(i)(GTP-gamma-S)] provides more detailed evidence that the [(35)S]GTP-gamma-S binding assay can be used to reliably determine apparent functional antagonist K(i) values in addition to agonist ED(50), efficacy and intrinsic efficacy.

Title The Evaluation of Subatmospheric Pressure and Hyperbaric Oxygen in Ischemic Full-thickness Wound Healing.
Date January 2001
Journal The American Surgeon
Excerpt

We evaluated the efficacy of subatmospheric pressure and hyperbaric oxygen (HBO) as adjuncts in the treatment of hypoxic full-thickness wounds in a rabbit model. We hypothesized that subatmospheric pressure and HBO independently are effective in improving wound healing in the ischemic wound model and that when they are used in combination there is an increased positive effect on wound healing. Using a standard ischemic wound model four full-thickness wounds were created on each ear of 41 male New Zealand white rabbits (N = 82 ears). On each rabbit one ear was dressed with the vacuum-assisted closure (VAC) device and connected to suction; the other was dressed identically without the suction and suction tubing. Twenty rabbits were treated with HBO daily for 10 days at 2.0 atmospheres absolute for 90 minutes plus descent and ascent times. Necropsy on all rabbits was performed on postoperative day 10. Four ischemic wound treatment groups were evaluated: Group 1 (N = 21) VAC dressing alone; Group 2 (N = 20) VAC dressing plus HBO; Group 3 (N = 21) VAC dressing to suction alone; and Group 4 (N = 20) VAC dressing to suction and HBO. Using light microscopy a veterinary pathologist blinded to treatment groups quantified peak granulation tissue, granulation tissue gap, and epithelialization tissue gap. Data were analyzed by analysis of variance with significance indicated by P < 0.05. Statistical significance was found in a comparison of VAC dressing to suction and VAC dressing alone for peak granulation tissue and granulation tissue gap both with and without use of HBO. VAC device use appears to increase the rate of healing in a rabbit ischemic wound model. HBO therapy did not significantly affect the rate of healing in this model.

Title 4-[(8-alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-n,n-diethylbenzamides: High Affinity, Selective Ligands for the Delta Opioid Receptor Illustrate Factors Important to Antagonist Activity.
Date November 2000
Journal Bioorganic & Medicinal Chemistry Letters
Excerpt

The tropane derived compounds, 4-[(8-alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-d iethylbenzamides (5a-d), were synthesized and found to have high affinity and selectivity for the delta receptor. Compounds 5a-d are structurally similar to the full agonist (-)-RTI-5989-54 (3); yet, efficacy studies for compounds in this series (5a-d) reveal greatly diminished agonist activity as well as antagonism not found in piperidine-based compounds like 3.

Title Determination of Vitamins in Food-matrix Standard Reference Materials.
Date November 2000
Journal Journal of Chromatography. A
Excerpt

In recent years, the National Institute of Standards and Technology (NIST) has developed several food-matrix Standard Reference Materials (SRMs) characterized for vitamins and other organic nutrients. NIST uses several "modes" for assignment of analyte concentrations in SRMs, one of which includes the use of data provided by collaborating laboratories. Certification modes and liquid chromatographic methods that were used by NIST for value assignment of vitamin concentrations in recently introduced food-matrix SRMs are described in this paper. These materials and methods include vitamins D and E in coconut oil (SRM 1563) by gravimetry and multi-dimensional liquid chromatography (LC); vitamins A, E, and several B vitamins by reversed-phase LC and vitamin C by ion-exchange chromatography in infant formula (SRM 1846); and carotenoids and vitamins A and E by reversed-phase liquid chromatography in a baby food composite (SRM 2383).

Title Nist Micronutrients Measurement Quality Assurance Program: Characterizing Individual Participant Measurement Performance over Time.
Date November 2000
Journal Analytical Chemistry
Excerpt

The mission of the Micronutrients Measurement Quality Assurance Program (M2QAP) at the National Institute of Standards and Technology is enhanced interlaboratory measurement comparability for fat-soluble vitamin-related measurands in human serum. We recently described improved tools for evaluating individual participant measurement performance in single interlaboratory comparison exercises; we here apply and extend these tools to the evaluation of participant performance over the entire 15-year history of the M2QAP. We describe and illustrate a set of interconnected graphical reporting tools for identifying long-term trends and single-exercise events. We document and discuss recurrent patterns we observe in the measurement performance characteristics for M2QAP participants. The graphical analysis techniques utilized may be applicable to other interlaboratory comparison programs.

Title Nist Micronutrients Measurement Quality Assurance Program: Characterizing the Measurement Community's Performance over Time.
Date October 2000
Journal Analytical Chemistry
Excerpt

The Micronutrients Measurement Quality Assurance Program (M2QAP) at the National Institute of Standards and Technology was created in 1984 with the goal of improving among-participant measurement comparability for fat-soluble vitamin-related compounds in human serum. We recently described improved tools for evaluating comparison exercise data; we here extend and apply these tools to the evaluation of the measurement community's performance over the entire 15-year history of the M2QAP. We here display measurement performance characteristics for the 14 measurands most commonly reported by the M2QAP community. We confirm that among-participant comparability for total beta-carotene cannot be much improved without improving average long-term within-participant measurement stability. We demonstrate that improved measurand definition and/or identification of interferences may help participants improve comparability for many of the M2QAP's other commonly reported measurands. The reported measurement performance characteristics may be of interest to clinical, nutritional, and epidemiological studies involving any of these measurands. The data analysis techniques utilized may be applicable to other programs.

Title Chip is an Essential Cofactor for Apterous in the Regulation of Axon Guidance in Drosophila.
Date June 2000
Journal Development (cambridge, England)
Excerpt

LIM-homeodomain transcription factors are expressed in subsets of neurons and are required for correct axon guidance and neurotransmitter identity. The LIM-homeodomain family member Apterous requires the LIM-binding protein Chip to execute patterned outgrowth of the Drosophila wing. To determine whether Chip is a general cofactor for diverse LIM-homeodomain functions in vivo, we studied its role in the embryonic nervous system. Loss-of-function Chip mutations cause defects in neurotransmitter production that mimic apterous and islet mutants. Chip is also required cell-autonomously by Apterous-expressing neurons for proper axon guidance, and requires both a homodimerization domain and a LIM interaction domain to function appropriately. Using a Chip/Apterous chimeric molecule lacking domains normally required for their interaction, we reconstituted the complex and rescued the axon guidance defects of apterous mutants, of Chip mutants and of embryos doubly mutant for both apterous and Chip. Our results indicate that Chip participates in a range of developmental programs controlled by LIM-homeodomain proteins and that a tetrameric complex comprising two Apterous molecules bridged by a Chip homodimer is the functional unit through which Apterous acts during neuronal differentiation.

Title Transcriptional Mechanisms in the Development of Motor Control.
Date March 2000
Journal Current Opinion in Neurobiology
Excerpt

Considerable progress has been made in understanding how combinatorially expressed transcription factors control the development of neuronal subtypes in the fly and vertebrate central nervous systems. The mode of action of many of these factors has been conserved from invertebrates to vertebrates throughout evolution, such as the formation and regulation of specific transcriptional complexes, the utilization of repressors for maintaining specificity, and the use of phosphorylation as an important means for transiently altering transcriptional activity.

Title The Lim Homeodomain Protein Dlim1 Defines a Subclass of Neurons Within the Embryonic Ventral Nerve Cord of Drosophila.
Date January 2000
Journal Mechanisms of Development
Excerpt

Members of the LIM homeodomain family of transcription factors have been implicated in specifying cell identity in a range of species. In Drosophila three LIM homeobox genes, apterous, lim3 and isl, have been shown to control axon pathfinding of subsets of neurons within the embryo. Here we describe the isolation and characterization of another LIM homeobox gene in Drosophila termed dlim1, a homolog of the vertebrate Lim-1 gene. The sequence and expression of dLim1 is highly related to its vertebrate homologs. Within the Drosophila embryo, dLim1 is expressed in the head primordia, the brain lobes, and in distinct sets of motorneurons and interneurons within the ventral nerve cord. Comparatively in vertebrates, Lim-1 (Lhx1) along with Lim-3 (Lhx3), Gsh-4 (Lhx4), Isl-1 and Isl-2 are expressed in developing motorneurons along the spinal column, where their overlapping expression suggests a role for these genes in the establishment of specific motorneuron subtypes. dLim1 is absent from all cells expressing Isl, Lim3, and Apterous, indicating that these proteins function independently within the Drosophila embryo. To investigate the function of dlim1, we generated loss-of-function mutations within the locus. Our findings show that dlim1 is an essential gene that when mutated results in lethality near the larval-pupal boundary. In contrast to vertebrate Lim-1, dlim1 has no apparent role in anterior patterning of the Drosophila embryo. Our analysis shows that dlim1 has been evolutionarily conserved, however the Drosophila lim1 gene exhibits unique properties that distinguishes it from its vertebrate homologs.

Title Optically Pure (-)-4-[(n-allyl-3-methyl-4-piperidinyl)phenyl-amino]-n,n-diethylbenzami De Displays Selective Binding and Full Agonist Activity for the Delta Opioid Receptor.
Date January 2000
Journal Bioorganic & Medicinal Chemistry Letters
Excerpt

The optical isomers of 4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide+ ++ (3) have been prepared and tested in both binding and functional assays. The data show that (-)-3 is responsible for the delta opioid activity demonstrated by the racemic material. This compound displays a binding affinity of 5.5 nM for the delta opioid receptor as well as a 470-fold delta versus mu selectivity. Importantly, (-)-3 is a full agonist at the delta receptor in comparison with SNC-80 (2). Taken together, the data suggest that (-)-3 behaves more like the prototypical delta agonists, BW373U86 or SNC-80, and less like the peptidomimetic compound SL-3111 (5).

Title Vascular Reconstruction Utilizing Artery from an Amputated Extremity: A Case Report.
Date January 2000
Journal Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
Excerpt

Although infrainguinal arterial reconstruction is best performed with autologous tissue, reconstruction with vein in an infected field has been associated with vein graft disruption and hemorrhage. H.P., a 61-year-old man with peripheral vascular disease, was initially seen with an infected prosthetic right femoral-tibioperoneal artery bypass graft. Because of the presence of purulent drainage from the proximal and distal anastomotic regions and his comorbidities, a right through-knee guillotine amputation was performed, followed by graft excision and groin débridement. Right hip and thigh perfusion was preserved via arterial reconstruction by using a segment of endarterectomized popliteal artery, harvested from the amputated extremity. Arterial reconstruction with autologous tissue from an amputated extremity allowed us to balance our patient's overall risks with life and tissue preservation. This technique may be applied in the settings of lower extremity ischemia, trauma, or malignancy requiring concomitant arterial or venous reconstruction.

Title (+/-)-4-[(n-allyl-cis-3-methyl-4-piperidinyl)phenylamino]-n,n-diethylbenzamide Displays Selective Binding for the Delta Opioid Receptor.
Date December 1999
Journal Bioorganic & Medicinal Chemistry Letters
Excerpt

Racemic 4-[(N-allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzam ide (3a) was synthesized and found to have good affinity and selectivity for the delta receptor. These compounds can be viewed as an analog of BW373U86 and SNC-80 where an internal piperazine nitrogen has been transposed with a benzylic carbon. Functionally, 3a behaves as an agonist at the delta receptor with no measurable stimulation of either the mu or kappa receptor subtypes and was found to be devoid of any measurable amount of antagonist activity for any opioid receptor. A comparison of 3a to SNC-80 and DPDPE in the [35S]GTPgammaS functional assay suggests that 3a may be more like the peptide DPDPE.

Title Axon Routing Across the Midline Controlled by the Drosophila Derailed Receptor.
Date December 1999
Journal Nature
Excerpt

In nervous systems with symmetry about the midline, many neurons project axons from one side to the other. Although several of the components controlling midline crossing have been identified, little is known about how axons choose the appropriate pathway when crossing. For example, in the Drosophila embryo axons cross the midline in one of two distinct tracts, the anterior or posterior commissure (AC or PC, respec tively). Here we show that the Derailed (Drl) receptor tyrosine kinase is expressed by neurons that project in the AC, and that in the absence of Drl such neurons often project abnormally into the PC. Conversely, misexpression of Drl in PC neurons forces them to cross in the AC. The behaviour of Drl-misexpressing neurons and the in vivo binding pattern of a soluble Drl receptor probe indicate that Drl acts as a guidance receptor for a repellent ligand present in the PC. Our results show that Drl is a novel component in the control of midline crossing.

Title Chip and Apterous Physically Interact to Form a Functional Complex During Drosophila Development.
Date October 1999
Journal Molecular Cell
Excerpt

LIM homeodomain (LIM-HD) proteins play key roles in a variety of developmental processes throughout the animal kingdom. Here we show that the LIM-binding protein Chip acts as a cofactor for the Drosophila LIM-HD family member Apterous (Ap) in wing development. We define the domains of Chip required for LIM-HD binding and for homodimerization and show that mutant proteins deleted for these domains act in a dominant-negative fashion to disrupt Ap function. Our results support a model for multimeric complexes containing Chip and Ap in transcriptional regulation. This model is confirmed by the activity of a chimeric fusion between Chip and Ap that reconstitutes the complex and rescues the ap mutant phenotype.

Title Cell-type Specific Modular Regulation of Derailed in the Drosophila Nervous System.
Date August 1999
Journal Mechanisms of Development
Excerpt

The derailed (drl) gene encodes a receptor tyrosine kinase (RTK) that governs aspects of axon guidance and muscle-epidermal interactions in the Drosophila embryo. To determine the types of neurons that express drl, we have examined a series of drl promoter fusions to axon-targeted reporters. We have identified enhancers that drive reporter expression in four distinct subtypes of embryonic neurons, all of which project axons in the anterior commissure of the developing nervous system. We also identified enhancers driving expression in the drl-expressing muscles and epidermal attachment cells. These enhancers define the classes of neurons projecting in the anterior commissure and can be used to precisely define axon pathfinding errors in drl and other mutants.

Title Isolation and Characterization of Dek, a Drosophila Eph Receptor Protein Tyrosine Kinase.
Date June 1999
Journal Molecular and Cellular Neurosciences
Excerpt

We have isolated a Drosophila receptor protein tyrosine kinase (RTK) of the Eph subfamily. Dek, for Drosophila Eph kinase, possesses all the domains characteristic of the Eph subfamily of RTKs and is equally similar in sequence to both the EphA and the EphB subclasses. Antibody staining and promoter fusions to axon-targeted reporters reveal that Dek is expressed by a large subset of developing embryonic interneurons and is targeted to their axons and growth cones at the time of axon pathfinding. Dek is also expressed by photoreceptor cells of third-instar larvae as they project axons into the optic brain lobe. Misexpression and overexpression of full-length Dek or kinase-inactive Dek do not grossly affect axon pathfinding.

Title Micronutrients Measurement Quality Assurance Program: Helping Participants Use Interlaboratory Comparison Exercise Results to Improve Their Long-term Measurement Performance.
Date June 1999
Journal Analytical Chemistry
Excerpt

Over the past decade, the Micronutrients Measurement Quality Assurance Program (M2QAP) at the National Institute of Standards and Technology (NIST) has administered nearly 40 interlaboratory comparison exercises devoted to fat-soluble vitamin-related analytes in human serum. While M2QAP studies have been used to help certify reference materials and to document the performance of analytical systems, the primary focus of the M2QAP has been, and remains, the improvement of among-participant measurement comparability for target analytes. Recent analysis of historical measurement performance indicated the most efficient mechanism for further improving measurement comparability among participants is the improvement of long-term (months to years) comparability within each laboratory. The summary reports for the M2QAP studies are being redesigned to provide more chemist-friendly analyses of participant performance, dissecting systematic and random components of measurement incomparability as functions of analyte level and time. This report documents the semantic and graphical tools developed to help interlaboratory-comparison-exercise participants interpret their own measurement performance.

Title Value Assignment of Retinol, Retinyl Palmitate, Tocopherol, and Carotenoid Concentrations in Standard Reference Material 2383 (baby Food Composite).
Date April 1999
Journal Journal of Aoac International
Excerpt

In 1997, the National Institute of Standards and Technology (NIST) released Standard Reference Material (SRM) 2383 Baby Food Composite. This SRM can be used as a control material when assigning values to in-house control materials and when validating analytical methods for the measurement of proximates, vitamins, minerals, and trace elements in baby foods and similar matrixes. The Certificate of Analysis for SRM 2383 provides certified and reference values for concentrations of lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, delta-tocopherol, gamma-tocopherol, alpha-tocopherol, retinol, and retinyl palmitate for 2 types of sample preparation--extraction and saponification. The assigned values were based on the agreement of measurements made by NIST and collaborating laboratories. The Certificate of Analysis also provides reference and information values for concentrations of proximates, minerals, and additional vitamins; assignment of these values is discussed in a companion paper (this issue, page 276).

Title Cell Type-specific Regulation of the Drosophila Fmrf-nh2 Neuropeptide Gene by Apterous, a Lim Homeodomain Transcription Factor.
Date March 1999
Journal Development (cambridge, England)
Excerpt

We describe the direct and cell-specific regulation of the Drosophila FMRFa neuropeptide gene by Apterous, a LIM homeodomain transcription factor. dFMRFa and Apterous are expressed in partially overlapping subsets of neurons, including two of the seventeen dFMRFa cell types, the Tv neuroendocrine cells and the SP2 interneurons. Apterous contributes to the initiation of dFMRFa expression in Tv neurons, but not in those dFMRFa neurons that do not express Apterous. Apterous is not required for Tv neuron survival or morphological differentiation. Apterous contributes to the maintenance of dFMRFa expression by postembryonic Tv neurons, although the strength of its regulation is diminished. Apterous regulation of dFMRFa expression includes direct mechanisms, although ectopic Apterous does not induce ectopic dFMRFa. These findings show that, for a subset of neurons that share a common neurotransmitter phenotype, the Apterous LIM homeoprotein helps define neurotransmitter expression with very limited effects on other aspects of differentiation.

Title Embryonic Expression and Activity of Doughnut, a Second Ryk Homolog in Drosophila.
Date March 1999
Journal Mechanisms of Development
Excerpt

In the Drosophila embryo, a subset of muscles require expression and function of the RYK subfamily RTK gene derailed (drl) for correct attachment. We have isolated a second RYK homolog, doughnut (dnt), from Drosophila. The DNT protein exhibits 60% amino acid identity to DRL, and is structurally as similar to the mammalian RYK proteins as is DRL, indicating an ancient duplication event. dnt is expressed in dynamic patterns in the embryonic epidermis, being found at high level in epithelia adjacent to cells that are invaginating into the interior of the embryo, including ventral furrow, cephalic furrow, fore- and hindgut, optic lobe and tracheal pits. dnt is capable of a partial rescue of the muscle attachment defect of drl-/- embryos, indicating that it encodes a receptor with a related and significantly overlapping biochemical function.

Title A Lim-homeodomain Combinatorial Code for Motor-neuron Pathway Selection.
Date January 1999
Journal Nature
Excerpt

Different classes of vertebrate motor neuron that innervate distinct muscle targets express unique combinations of LIM-homeodomain transcription factors, suggesting that a combinatorial code of LIM-homeodomain proteins may underlie the control of motor-neuron pathway selection. Studies of LIM-homeodomain genes in mouse, Drosophila melanogaster and Caenorhabditis elegans have revealed functions of these genes in neuronal survival, axon guidance, neurotransmitter expression and neuronal function, but, to our knowledge, none of these studies have addressed the issue of a functional code. Here we study two members of this gene family in Drosophila, namely lim3, the homologue of the vertebrate Lhx3 and Lhx4 genes, and islet, the homologue of the vertebrate Isl1 and Is12 genes. We show that Drosophila lim3 is expressed by a specific subset of islet-expressing motor neurons and that mutating or misexpressing lim3 switches motor-neuron projections predictably. Our results provide evidence that lim3 and islet constitute a combinatorial code that generates distinct motor-neuron identities.

Title N-substituted Octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines Are Opioid Receptor Pure Antagonists.
Date January 1999
Journal Bioorganic & Medicinal Chemistry Letters
Excerpt

N-Methyl- and N-phenylethyl-(+/-)-1,2,3,4,4a,5,10,10a- octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines (4 and 5, respectively) were found to be pure opioid antagonists. These compounds were shown to share many of the characteristics identified with the N-methyl- and N-phenylethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1 and 2, respectively) including N-substituent mediated potency and a lack of N-substituent mediated antagonism. These data suggest that compounds 4 and 5 and the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (1 and 2) may interact with opioid receptors similarly.

Title Identification of an Opioid Kappa Receptor Subtype-selective N-substituent for (+)-(3r,4r)-dimethyl-4-(3-hydroxyphenyl)piperidine.
Date January 1999
Journal Journal of Medicinal Chemistry
Excerpt

A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-¿(2'S)-[3-(4-hydroxyphenyl)propanamido]-3'-methylbutyl¿-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [35S]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor.

Title Tracing Axons.
Date January 1999
Journal Current Opinion in Neurobiology
Excerpt

For more than a century, neuroscientists have gained insight into brain function by examining its complex patterns of connectivity. To achieve this, a wide variety of axon-tracing techniques have been employed to chart the projections of neurons. New, experimentally flexible, reporter-based tracers, many of which are fusion proteins designed to target axons and dendrites, are being developed and are assisting the molecular characterization of the nervous system.

Title Function and Specificity of Lim Domains in Drosophila Nervous System and Wing Development.
Date November 1998
Journal Development (cambridge, England)
Excerpt

LIM domains are found in a variety of proteins, including cytoplasmic and nuclear LIM-only proteins, LIM-homeodomain (LIM-HD) transcription factors and LIM-kinases. Although the ability of LIM domains to interact with other proteins has been clearly established in vitro and in cultured cells, their in vivo function is unknown. Here we use Drosophila to test the roles of the LIM domains of the LIM-HD family member Apterous (Ap) in wing and nervous system development. Using a rescuing assay of the ap mutant phenotype, we have found that the LIM domains are essential for Ap function. Furthermore, expression of LIM domains alone can act in a dominant-negative fashion to disrupt Ap function. The Ap LIM domains can be replaced by those of another family member to generate normal wing structure, but LIM domains are not interchangeable during axon pathfinding of the Ap neurons. This suggests that the Ap LIM domains mediate different protein interactions in different developmental processes, and that LIM domains can participate in conferring specificity of target gene selection.

Title Genome Analysis of Thinopyrum Intermedium and Thinopyrum Ponticum Using Genomic in Situ Hybridization.
Date November 1998
Journal Genome / National Research Council Canada = Génome / Conseil National De Recherches Canada
Excerpt

Genomic in situ hybridization (GISH) using genomic DNA probes from Thinopyrum elongatum (Host) D.R. Dewey (genome E, 2n = 14), Thinopyrum bessarabicum (Savul. & Rayss) A. Löve (genome J, 2n = 14), and Pseudoroegneria strigosa (M. Bieb.) A. Löve (genome S, 2n = 14), was used to examine the genomic constitution of Thinopyrum intermedium (Host) Barkworth & D.R. Dewey (2n = 6x = 42) and Thinopyrum ponticum (Podp.) Barkworth & D.R. Dewey (2n = 10x = 70). Evidence from GISH indicated that hexaploid Th, intermedium contained the J, Js, and S genomes, in which the J genome was related to the E genome of Th. elongatum and the J genome of Th. bessarabicum. The S genome was homologous to the S genome of Ps. strigosa, while the Js genome referred to modified J- or E-type chromosomes distinguished by the presence of S genome specific sequences close to the centromere. Decaploid Th. ponticum had only the two basic genomes J and Js. The Js genome present in Th. intermedium and Th. ponticum was homologous with E or J genomes, but was quite distinct at centromeric regions, which can strongly hybridize with the S genome DNA probe. Based on GISH results, the genomic formula of Th. intermedium was redesignated JJsS and that of Th. ponticum was redesignated JJJJsJs. The finding of a close relationship among S, J, and Js genomes provides valuable markers for molecular cytogenetic analyses using S genome DNA probes to monitor the transfer of useful traits from Th. intermedium and Th. ponticum to wheat.

Title N-substituted 9beta-methyl-5-(3-hydroxyphenyl)morphans Are Opioid Receptor Pure Antagonists.
Date November 1998
Journal Journal of Medicinal Chemistry
Excerpt

The inhibition of radioligand binding and [35S]GTPgammaS functional assay data for N-methyl- and N-phenethyl-9beta-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) show that these compounds are pure antagonists at the micro, delta, and kappa opioid receptors. Since 5b and 5c have the 5-(3-hydroxyphenyl) group locked in a conformation comparable to an equatorial group of a piperidine chair conformation, this information provides very strong evidence that opioid antagonists can interact with opioid receptors in this conformation. In addition, it suggests that the trans-3, 4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist operates via a phenyl equatorial piperidine chair conformation. Importantly, the close relationship between the 4-(3-hydroxyphenyl)piperidines and 5-(3-hydroxyphenyl)morphan antagonists shows that the latter class of compound provides a rigid platform on which to build a novel series of opioid antagonists.

Title Investigation of the N-substituent Conformation Governing Potency and Mu Receptor Subtype-selectivity in (+)-(3r, 4r)-dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonists.
Date June 1998
Journal Journal of Medicinal Chemistry
Excerpt

A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [35S]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.

Title Axon Guidance: Crossing the Midline.
Date April 1998
Journal Current Biology : Cb
Excerpt

Neurons that connect the two sides of the nervous system project their axons across the midline. New studies provide evidence for a conserved gatekeeping mechanism that controls this midline crossing.

Title Selection of Column and Gradient Elution System for the Separation of Catechins in Green Tea Using High-performance Liquid Chromatography.
Date March 1998
Journal Journal of Chromatography. A
Excerpt

A study of a variety of stationary phases and elution conditions for the liquid chromatographic (LC) determination of six biologically active green tea catechins has resulted in the development of two well-defined, reproducible systems for such analyses which overcome limitations of previously described methods. Comparison of six reversed-phase columns indicates that deactivated stationary phases, which utilize ultrapure silica and maximize coverage of the silica support, provide significantly improved separation and chromatographic efficiencies for catechin analyses using LC, compared to conventional monomeric or polymeric C18 columns. Evaluation of elution conditions used for the separations reveals that the presence of acid in the mobile phase (0.05% trifluoroacetic acid) is essential for both the complete resolution of the catechins present in tea and the efficient chromatography of these compounds. The efficacy of one of the developed systems was demonstrated by the quantitative measurement of the six biologically active catechins in aqueous infusions of green tea (Camellia sinensis). Overall precision values for the analyses were within the range 0.3-1% (relative standard deviation).

Title Capillary Liquid Chromatography/electrospray Mass Spectrometry for the Separation and Detection of Catechins in Green Tea and Human Plasma.
Date January 1998
Journal Rapid Communications in Mass Spectrometry : Rcm
Excerpt

The separation and detection of biologically active green tea catechins has been accomplished using capillary liquid chromatography/electrospray mass spectrometry (cLC/ESI-MS). Microscale determination (approximately 20 ng) of all six catechins in a green tea infusion, and the most extensively studied catechin, (-)epigallocatechin gallate (EGCG), in human plasma is demonstrated by cLC/ESI-MS with selected ion monitoring of protonated molecular ions. The overall quality of the analysis is shown to be dependent on the use of a capillary column with a deactivated, monomeric C18 stationary phase. The high chromatographic separation efficiency of this packed-capillary column, combined with the high sensitivity and selectivity afforded by the mass spectrometer as detector, provide a reliable approach to the analysis of picomolar quantities of these interesting compounds in complex matrices.

Title Inter-hemispheric Conflict Theory of Mind for Schizophrenia.
Date August 1997
Journal Schizophrenia Research
Title Certification of Nutrients in Standard Reference Material 1846: Infant Formula.
Date July 1997
Journal Journal of Aoac International
Excerpt

In 1996, the National Institute of Standards and Technology (NIST) released Standard Reference Material 1846 (Infant Formula), which can be used as a control material for assigning values to in-house control materials and for validating analytical methods for measurement of proximates, vitamins, and minerals in infant formula and similar matrixes. The SRM was manufactured by preparing a spray-dried formula base containing fat, protein, carbohydrates, and minerals and then combining that formula base with a dry-blend vitamin premix that supplied the vitamins. The Certificate of Analysis for SRM 1846 provides assigned values for concentrations of proximates (fat, protein, etc.), vitamins, and minerals for which product labeling is required by the Infant Formula Act of 1980 and by the Nutrition Labeling and Education Act of 1990. These assigned values were based on agreement of measurements by NIST and/or collaborating laboratories. Certified values are provided for vitamins A (trans), E, C, B2, and B6 and niacin. Noncertified values are provided for solids, ash, fat, nitrogen, protein, carbohydrate, calories, vitamin D, delta-tocopherol, gamma-tocopherol, vitamin B1, vitamin B12, folic acid, pantothenic acid, biotin, choline, inositol, calcium, phosphorus, magnesium, iron, zinc, copper, sodium, potassium, and chloride. Information values are provided for iodine, manganese, selenium, and vitamin K.

Title Nist/nci Micronutrients Measurement Quality Assurance Program: Measurement Repeatabilities and Reproducibilities for Fat-soluble Vitamin-related Compounds in Human Sera.
Date May 1997
Journal Analytical Chemistry
Excerpt

The NIST/NCI Micronutrient Measurement Quality Assurance Program has conducted 33 interlaboratory comparison exercises for fat-soluble vitamin-related compounds in human sera over the past 12 years. Periodic reanalysis of lyophilized serum samples prepared from more than 70 different sera has enabled estimation of the short- and long-term measurement characteristics. Median- and interquartile-range-based statistics adequately estimate the distribution of results from laboratories that are in analytical control from total distributions that include a significant minority of outlier data. Short-term interlaboratory reproducibility standard deviations (SDs) are predictable functions of analyte concentration, with an asymptotic limit at low analyte concentration and a linear relationship at high concentrations. Long-term trends in the interlaboratory reproducibility can be estimated by standardizing the short-term SD at the observed analyte concentration to an expected SD at a given physiologically significant analyte concentration. The "average" laboratory's same-day analytical repeatability SD is about one-third of the estimated interlaboratory reproducibility; repeatability for longer periods between analyses is, on average, on better than the reproducibility. While a few exceptional laboratories have maintained excellent repeatability over the entire decade, long-term study measurements generated within a single laboratory are not generally more internally consistent than results from multiple laboratories. Enhanced and more consistently implemented intralaboratory quality control and quality assurance methods are required to further improve and maintain interlaboratory measurement comparability.

Title The Drosophila Islet Gene Governs Axon Pathfinding and Neurotransmitter Identity.
Date April 1997
Journal Neuron
Excerpt

We have isolated the Drosophila homolog of the vertebrate islet-1 and islet-2 genes, two members of the LIM homeodomain family implicated in the transcriptional control of motor neuronal differentiation. Similar to vertebrates, Drosophila islet is expressed in a discrete subset of embryonic motor neurons and interneurons that includes the dopaminergic and serotonergic cells of the ventral nerve cord. In contrast to mouse where mutation of islet-1 leads to loss of neurons due to programmed cell death, Drosophila islet is not required for neuron survival. Instead, loss of islet function causes defects in axon pathfinding and targeting plus loss of dopamine and serotonin synthesis. Ectopic expression of islet induces both specific alterations in pathfinding and changes in neurotransmitter identity. These findings indicate that islet coordinately controls two distinct aspects of neuronal identity.

Title Ocular Neoplasms of Vascular Origin in the Horse.
Date April 1997
Journal Equine Veterinary Journal. Supplement
Title Liquid Chromatographic Determination of Carotenoids in Human Serum Using an Engineered C30 and a C18 Stationary Phase.
Date January 1997
Journal Journal of Chromatography. B, Biomedical Applications
Excerpt

A C30 stationary phase was specifically engineered for carotenoid separations, and carotenoid measurements using this column are compared with those obtained using a somewhat more conventional C18 column. Both methods were used to contribute measurements for the certification of carotenoids in Standard Reference Material 968b, Fat-Soluble Vitamins and Cholesterol in Human Serum. Analytes were extracted from the serum into hexane. Measurements on the C18 column were made using a gradient of acetonitrile, methanol, and ethyl acetate, which is described in detail elsewhere. Measurements on the C30 column were made using a gradient of water, methanol, and methyl tert.-butyl ether.

Title Derailed is Required for Muscle Attachment Site Selection in Drosophila.
Date November 1996
Journal Development (cambridge, England)
Excerpt

During development, muscles must form and attach at highly stereotyped positions to allow for coordinated movements. In Drosophila, muscles grow towards and attach to specifically positioned cells within the epidermis. At the molecular level, very little is known about how muscles recognize these attachment sites. The derailed gene encodes a receptor tyrosine kinase family member that is essential for the pathfinding ability of expressing neurons. Here we show that the Drl RTK is also expressed by a small subset of developing embryonic muscles and neighboring epidermal cells during muscle attachment site selection. In drl mutants, these muscles often fail to attach at appropriate locations although their epidermal attachment cells appear unaffected. These results show that, similar to its role in neuronal pathway recognition, the Drl RTK participates in a mechanism required for muscle attachment site selection. The data suggest that both neurons and muscles use common mechanisms to recognize their paths or targets, and that Drl plays an analogous role in both developing systems.

Title Control of Neuronal Pathway Selection by the Drosophila Lim Homeodomain Gene Apterous.
Date August 1995
Journal Development (cambridge, England)
Excerpt

The Drosophila apterous gene encodes a LIM homeodomain protein expressed embryonically in a small subset of differentiating neurons. To establish the identity of these neurons and to study the role of apterous in their development, we made apterous promoter fusions to an axon-targeted reporter gene. We found that all apterous-expressing neurons are interneurons that choose a single pathway within the developing central nervous system. In apterous mutants, these neurons choose incorrect pathways and fail to fasciculate with one another. Our results indicate that apterous functions to control neuronal pathway selection and suggest that other vertebrate and invertebrate members of the LIM homeodomain class of proteins may serve similar functions.

Title Control of Neuronal Pathway Selection by a Drosophila Receptor Protein-tyrosine Kinase Family Member.
Date August 1995
Journal Nature
Excerpt

During development, neurons are capable of selecting specific pathways that lead them to their appropriate target areas. A variety of molecular mechanisms are thought to be involved in pathway recognition, including cell adhesion, repulsion and chemotropism. However, apart from a few genes whose involvement has been shown genetically, the mechanisms underlying neuronal pathway selection are largely unknown. Here we report the isolation of the Drosophila derailed (drl) gene, which encodes a novel member of the receptor protein-tyrosine kinase family. Using a newly developed axon-targeted reporter gene we find that drl is expressed by a small subset of embryonic interneurons whose growth cones choose common pathways during development. In drl mutant embryos these neurons fail to make the correct pathway choices. Our results provide evidence for receptor protein-tyrosine kinase involvement in key aspects of neuronal pathway recognition.

Title The Role of Apterous in the Control of Dorsoventral Compartmentalization and Ps Integrin Gene Expression in the Developing Wing of Drosophila.
Date October 1994
Journal Development (cambridge, England)
Excerpt

During the development of Drosophila appendages from imaginal discs lineage restrictions appear that prevent dividing cells from crossing between regionally distinct compartments. These compartments correspond not only to regions of cell lineage restrictions but also to regions of specific gene expression. When compartments were first discovered, it was proposed that their formation relied on compartment-specific 'selector' gene activity; engrailed is thought to play such a role for the early-arising anterior-posterior restriction. Recent results suggest that the dorsally expressed transcription factor encoded by apterous may control dorsoventral identity in the wing. In this study we use mosaic analysis to show that apterous maintains the late-arising dorsoventral lineage restriction in a manner that strongly supports the selector gene hypothesis: loss of apterous function from dorsal cells after the formation of the boundary causes them to cross into the ventral compartment. Moreover, we show that apterous plays a role controlling patterns of gene expression in the developing wing disc. The PS1 and PS2 integrins are normally expressed in primarily dorsal-specific and ventral-specific patterns, respectively. We show that ectopic expression of apterous induces ectopic ventral expression of PS1 integrin and alpha PS1 mRNA, while loss of apterous can induce the ectopic dorsal expression of PS2 integrin. Thus, apterous plays a selector-like role both in terms of the control of lineage restrictions and the regulation of downstream gene expression.

Title Tau-beta-galactosidase, an Axon-targeted Fusion Protein.
Date July 1994
Journal Proceedings of the National Academy of Sciences of the United States of America
Excerpt

The most commonly used enzymatic reporter molecule, Escherichia coli beta-galactosidase (beta-gal; beta-D-galactoside galactohydrolase, EC 3.2.1.23), fails to readily diffuse into axons; consequently, the morphologies of beta-gal-labeled neurons cannot directly be determined. For analysis of neuronal pathfinding and synaptic connectivity, this information is essential. We have constructed an axon-targeted beta-gal reporter by fusing the cDNA encoding the bovine microtubule-binding protein, tau, to lacZ, the E. coli gene encoding beta-gal. This reporter labels cell bodies and axons when expressed by developing and adult Drosophila neurons. It also reveals the entire cellular extent of nonneuronal cells such as muscle fibers and glia. To generate neuronal markers for studies of Drosophila neural development, we constructed a tau-beta-gal enhancer-trap transposon. From 1500 independent lines generated by mobilization of this transposon, we have isolated a set of useful markers for specific subsets of neurons, glia, and muscles. Since the tau cDNA-lacZ reporter utilizes bovine tau, it may also effectively target beta-gal in vertebrate neurons and prove to be a useful reagent for the analysis of vertebrate nervous systems.

Title The Drosophila Bendless Gene Encodes a Neural Protein Related to Ubiquitin-conjugating Enzymes.
Date September 1993
Journal Neuron
Excerpt

The bendless (ben) mutation of Drosophila alters synaptic connectivity between a subset of CNS neurons. Here, we show that ben also causes morphological abnormalities within the visual system, suggesting that ben functions in a number of different developmental processes. We show that the ben gene encodes a protein which is closely related to ubiquitin-conjugating enzymes and that a missense mutation in the highly conserved active site region is associated with the ben mutation. High levels of ben expression are restricted to the nervous system during development. These results suggest a role for ubiquitin-mediated protein modification in nervous system development, including, but not exclusive to, the regulation of synaptic connectivity.

Title Single-minded Regulation of Genes in the Embryonic Midline of the Drosophila Central Nervous System.
Date July 1993
Journal Mechanisms of Development
Excerpt

Proper development of the midline cells within the Drosophila central nervous system is controlled by the single-minded (sim) gene. The sim protein defines a new subclass of bHLH transcription factors and as such, is predicted to function as a transcriptional regulator of other genes important for midline development. Here we identify two potential targets of sim regulation: the sim gene itself, and the 47F gene, which is expressed specifically in the sim-expressing midline cells. Using a transgene containing sim regulatory sequences fused to beta-galactosidase, we show that the sim gene uses two distinct promoters with overlapping temporal specificities, and that expression from the late promoter is autoregulated by sim itself. By expressing sim protein in salivary gland nuclei using the heat-shock inducible Hsp70 gene promoter, we show that sim protein associates with the sim late promoter on polytene chromosomes. In addition, sim protein binds to a small number of additional chromosomal sites, among which are the sites of the 47F gene, and two other genes, Tl and cdi, whose expression also depend on sim function.

Title Strategic Sensemaking and Organizational Performance: Linkages Among Scanning, Interpretation, Action, and Outcomes.
Date May 1993
Journal Academy of Management Journal. Academy of Management
Excerpt

This study investigated the strategic "sensemaking" processes of scanning, interpretation, and action and how those activities are linked to organizational performance. Using path analyses on data from 156 hospitals, we tested the direct and indirect effects among these sensemaking processes and performance outcomes and developed a model of their relationships. In a more general sense, the research represents an attempt to provide insight not only into relationships between cognition and action, but also into the links between those fundamental processes and organizational performance outcomes.

Title Apterous is a Drosophila Lim Domain Gene Required for the Development of a Subset of Embryonic Muscles.
Date October 1992
Journal Neuron
Excerpt

The recently discovered LIM motif is found in a set of homeodomain-containing proteins thought to mediate the generation of particular cell types. Of the four LIM domain family members described to date, mec-3 and lin-11 determine cell lineages in C. elegans. Isl-1 and Xlim-1 may play similar roles in vertebrates. We have identified a Drosophila member of this class, the product of the apterous (ap) gene. During embryogenesis, ap is expressed in a small subset of fusing mesodermal precursors that give rise to 6 muscles in each abdominal hemisegment and in 5 neurons within each corresponding CNS hemisegment. Lack of ap function results in loss of ap-expressing muscles, while misexpression of ap using a heterologous promoter produces ectopic muscles.

Title Cryptococcosis in Seven Horses.
Date August 1992
Journal Australian Veterinary Journal
Excerpt

The clinical, radiographic and post-mortem findings in 6 horses with cryptococcal pneumonia and one horse with an abdominal cryptococcal granuloma are described. In pulmonary cryptococcosis, the lesions were either diffuse and multiple, with bilateral lung involvement, or localised mainly to the dorsocaudal region of one lung. The cases of diffuse multiple cryptococcosis were thought to be associated with haematogenous spread of the fungus after gastrointestinal infection and dissemination from regional lymph nodes. The localised form of the disease was thought to have been associated with inhalation of cryptococci. In all cases of pulmonary cryptococcosis, encapsulated yeast-like organisms were demonstrated in Wright's-stained sediment of tracheal washes. In the horse with the abdominal granuloma, cryptococci were present in a fine needle aspirate sample. Isolates of Cryptococcus neoformans var gattii were recovered from 2 of the 5 horses in which cultures were attempted. In addition to a history of previous illness that may have predisposed to infection, most horses in this report had been in areas in which Eucalyptus camaldulensis, or the closely related E rudis, were growing. In humans, an epidemiological relationship between E camaldulensis and infection with C neoformans var gattii has been suggested. Cases of equine cryptococcosis carry a poor prognosis and treatment was not attempted in any of these cases.

Title Developing Interorganizational Relationships in the Health Sector: a Multicase Study.
Date July 1992
Journal Health Care Management Review
Excerpt

Because of the wide diversity among health care organizations, interorganizational relationships (IORs) among them are difficult to manage. This article describes three case studies that, taken together, suggest that IOR performance is related to IOR development processes. Specifically, IOR performance is related to the way managers process information to manage uncertainty and ambiguity.

Title Aligning Business and Information Technology Domains: Strategic Planning in Hospitals.
Date March 1992
Journal Hospital & Health Services Administration
Excerpt

This article develops a framework for strategic information technology (IT) management in hospitals, termed the Strategic Alignment Model. This model is defined in terms of four domains--business strategy, IT strategy, organizational infrastructure, and IT infrastructure--each with its constituent components. The concept of strategic alignment is developed using two fundamental dimensions--strategic fit and integration. Different perspectives that hospitals use for aligning the various domains are discussed, and a prescriptive model of strategic IT planning is proposed.

Title Experimental Copper and Heliotrope Intoxication in Sheep: Morphological Changes.
Date November 1991
Journal Journal of Comparative Pathology
Excerpt

Young Merino wethers were used to determine the effects of copper and heliotrope, fed together or separately, on the development of toxicity and the concentration of trace elements in the liver and kidney. In one experiment copper and heliotrope were given concurrently, in a second experiment heliotrope was fed for 12 weeks and copper administration commenced 8 weeks later. The 10 sheep fed heliotrope alone did not show signs of clinical illness but one died and was found to have severe liver damage. Eleven sheep were given copper alone and three developed the clinical signs and lesions of haemolysis. Fourteen sheep were given copper and heliotrope and 13 became ill. Of these, three developed haemolysis, eight became jaundiced and two became weak without developing jaundice. The concentrations of copper in the livers of control and heliotrope-treated sheep, were comparable. In the animals given copper alone, the concentration of copper in the liver was twice as high as that in controls and in those given heliotrope and copper, it was three times as high as in the liver of control sheep. Feeding heliotrope alone induced the histological changes of pyrrolizidine alkaloid toxicity in the liver, but this was not associated with an excessive accumulation of copper or the development of clinical illness. However, it did predispose the animals to the effects of a second toxin since giving heliotrope and copper concurrently, or giving copper subsequent to feeding heliotrope, markedly enhanced the toxicity of the two substances and caused an excessive accumulation of copper in the liver.

Title The Thinking Hospital.
Date October 1991
Journal Health Progress (saint Louis, Mo.)
Title Hospitals As Interpretation Systems.
Date March 1991
Journal Health Services Research
Excerpt

In this study of 162 hospitals, it was found that the chief executive officer's (CEO's) interpretation of strategic issues is related to the existing hospital strategy and the hospital's information processing structure. Strategy was related to interpretation in terms of the extent to which a given strategic issue was perceived as controllable or uncontrollable. Structure was related to the extent to which an issue was defined as positive or negative, was labeled as controllable or uncontrollable, and was perceived as leading to a gain or a loss. Together, strategy and structure accounted for a significant part of the variance in CEO interpretations of strategic events. The theoretical and managerial implications of these findings are discussed.

Title Immunohistochemical Demonstration of Canine Distemper Virus Antigen As an Aid in the Diagnosis of Canine Distemper Encephalomyelitis.
Date December 1990
Journal Research in Veterinary Science
Excerpt

Brain tissue from 33 dogs with non-suppurative encephalitis was examined for evidence of canine distemper virus (CDV) encephalitis. Sections were examined for lesions, inclusion bodies, syncytial cells and CDV antigen using a double bridge unlabelled antibody enzyme technique. Histopathological lesions considered to be typical of granulomatous meningoencephalomyelitis were found in seven dogs. They all lacked inclusion bodies, syncytial cells and CDV antigen. The remaining 26 dogs all had histopathological lesions typical of CDV encephalitis. Inclusion bodies were found in 24 dogs, four of which also had syncytial cells and CDV antigen was detected immunocytochemically in 25. One dog had no inclusion bodies or syncytial cells and was immunohistochemically negative. Syncytial cells have been found to be of limited diagnostic value for the diagnosis of CDV encephalitis. While inclusion bodies proved to be a good diagnostic criterion for the confirmation of CDV infection, the immunohistochemical demonstration of CDV antigen proved to be superior. CDV antigen was more prevalent than inclusion bodies in tissue sections and much more easily detectable.

Title Breaking Down Complex Problems: the Use of Decision Analysis.
Date October 1990
Journal Health Progress (saint Louis, Mo.)
Title Cholecalciferol Rodenticide Toxicity in a Domestic Cat.
Date September 1990
Journal Australian Veterinary Journal
Title Molecular Genetics of Neuronal Development in the Drosophila Embryo.
Date June 1990
Journal Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology
Excerpt

Making a functional nervous system involves the production of specific types of neurons in characteristic locations and their ability to find and synapse with appropriate target cells. By capitalizing on the advanced genetics and molecular biology of Drosophila, a rapidly growing number of genes have been identified that control these events. Studies of the expression and function of these genes in single, uniquely identified cells is possible because of the relative simplicity of the Drosophila embryonic nervous system. A class of neurogenic genes, including N, Dl, and E(spl), controls the emergence of the entire neuronal precursor population, whereas some of the segmentation genes, such as ftz and eve, control the fates of individual neurons. Later in development, genes encoding cell-surface molecules, called fasciclins, may be involved in the ability of growing neurons to recognize and elongate axons along specific pathways to reach their synaptic targets.

Title Generalised Protothecosis in a Collie Dog.
Date May 1990
Journal Australian Veterinary Journal
Excerpt

A case of generalised protothecosis in a Collie dog is discussed. A long-standing history of severe colitis was the major clinical sign. Dissemination to many organs was confirmed histologically. Possible pathogenesis is discussed along with a review of the literature. The possibility of a breed disposition in Collie dogs is discussed. The organisms are ubiquitous in the environment and generalised disease suggests the possibility of immune competence.

Title Advanced Cardiac Life Support (acls) Algorithms. A Powerful Decision Tree for Management of Cardiac Arrest Victims.
Date February 1990
Journal Canadian Critical Care Nursing Journal
Title Hereditary Cerebellar Abiotrophy in Australian Kelpie Dogs.
Date December 1989
Journal Australian Veterinary Journal
Title Malignant Fibrous Histiocytoma in a Dog.
Date November 1988
Journal Australian Veterinary Journal
Excerpt

A large tumour present on the proximal tibia of a Bull Mastiff dog was diagnosed on histological appearance as a Malignant Fibrous Histiocytoma. These tumours, rarely identified in domestic animals, but well recognised in humans, are typically pleomorphic sarcomas with histiocytic and fibroblastic differentiation. Less commonly, one cell type predominates. In this case there was prominent histiocytic differentiation.

Title Tumours of the Paranasal Sinuses in 16 Horses.
Date September 1988
Journal Australian Veterinary Journal
Title Molecular Genetics of the Single-minded Locus: a Gene Involved in the Development of the Drosophila Nervous System.
Date April 1988
Journal Cell
Excerpt

The embryonic neuroepithelium of Drosophila gives rise to the central nervous system. We have studied the mutant phenotype and expression of a gene, single-minded (sim), which is involved in generating a specific region of this neuroepithelium. In sim mutant embryos, a subset of neuronal and nonneuronal precursor cells lying along the midline fail to emerge with the rest of the neuroepithelium. We have identified the sim transcription unit and have shown by in situ hybridization to embryos that the sim gene is expressed specifically in the midline neuroepithelium. Both the mutant phenotype and the temporal and spatial expression of transcripts suggest that the sim gene plays a key role in the emergence of this subset of cells along the midline of the developing central nervous system.

Title The Drosophila Single-minded Gene Encodes a Nuclear Protein with Sequence Similarity to the Per Gene Product.
Date April 1988
Journal Cell
Excerpt

Mutations in the single-minded (sim) gene of Drosophila result in the loss of the precursor cells giving rise to the midline cells of the embryonic central nervous system. We have examined the structure of the sim product by sequencing a sim cDNA clone, and have also determined the subcellular localization of the protein and its developmental expression by staining embryos with an antiserum against a sim fusion protein. The results indicate that sim is a nuclear protein specifically expressed along the midline of the neuroepithelium, the same subset of cells that are missing in the mutant. No similarity is observed between sim and any known nuclear protein, but, surprisingly, it is similar to the Drosophila period (per) locus gene product, which controls the periodicity of biological rhythms.

Title The Use of Decision Analysis for Organizational Design: Reorganizing a Community Hospital.
Date January 1988
Journal The Journal of Applied Behavioral Science
Excerpt

Organizational design is presented as a decision process, with specific structures seen as providing alternative choices. To illustrate this, the authors present the case of a major metropolitan hospital that used the process to coordinate service delivery (nursing care versus patient care) and service focus (product oriented versus function oriented). Through interviews with more than 40 hospital administrators and staff, the authors created a list of 20 attributes, and used simple multi-attribute utility analysis to generate six design alternatives. The decision makers unanimously chose one alternative, even though potential for significant conflict existed because of differing values and objectives. The authors find decision analytic techniques useful for both the problem formulation and for generating and evaluating structural alternatives, and conclude that in this case consensus was facilitated by the decision process used.

Title Anorexia Nervosa.
Date February 1986
Journal Child: Care, Health and Development
Excerpt

This paper, following a brief historical note, reviews the literature on anorexia nervosa. It begins by describing the characteristics of the syndrome and then considers incidence, aetiology and treatment. The results of treatment are described and the paper concludes by attempting a prognosis for those who are diagnosed anorexic. The authors are eclectic in their literature survey and also present some experience collected in a hospital school. The paper is intended as a teaching synthesis for clinicians new to this area or for those seeking a brief introduction to the present 'state of the art' in theory and practice.

Title Cell Recognition During Neuronal Development.
Date October 1984
Journal Science (new York, N.y.)
Excerpt

Insect embryos, with their relatively simple nervous systems, provide a model system with which to study the cellular and molecular mechanisms underlying cell recognition during neuronal development. Such an approach can take advantage of the accessible cells of the grasshopper embryo and the accessible genes of Drosophila. The growth cones of identified neurons express selective affinities for specific axonal surfaces; such specificities give rise to the stereotyped patterns of selective fasciculation common to both species. These and other results suggest that early in development cell lineage and cell interactions lead to the differential expression of cell recognition molecules on the surfaces of small subsets of embryonic neurons whose axons selectively fasciculate with one another. Monoclonal antibodies reveal surface molecules in the Drosophila embryo whose expression correlates with this prediction. It should now be possible to isolate the genes encoding these potential cell recognition molecules and to test their function through the use of molecular genetic approaches in Drosophila.

Title From Grasshopper to Drosophila: a Common Plan for Neuronal Development.
Date September 1984
Journal Nature
Excerpt

Little is known about the mechanisms that generate neuronal specificity during development. Whereas the grasshopper embryo has been an ideal system for a cellular analysis of neuronal development, the Drosophila embryo has obvious attributes for a molecular genetic analysis. Here we show that the early Drosophila embryo is a miniature replica of the grasshopper embryo in terms of its identified neurones, their growth cones and their selective fasciculation choices, thus opening the way for a combined cellular and molecular genetic analysis of cell recognition during neuronal development in Drosophila.

Title What Genes Are Necessary to Make an Identified Synapse?
Date July 1984
Journal Cold Spring Harbor Symposia on Quantitative Biology
Title Duplicated Neural Structure in Bithorax Mutant Drosophila.
Date May 1984
Journal Developmental Biology
Excerpt

The bithorax complex (BX-C) of genes in Drosophila control the segmental identity of the thoracic and abdominal cuticle. In flies containing BX-C mutations causing meta- to mesothoracic transformation, the mesothoracic branching pattern of a well-studied identified neuron is faithfully duplicated in the metathoracic ganglion. Thus these mutations also cause the duplication of mesothoracic cues involved in this neuron's branching.

Title Mutations Altering Synaptic Connectivity Between Identified Neurons in Drosophila.
Date April 1984
Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Excerpt

By studying the effects of mutations on a simple circuit of identified neurons in Drosophila, we have found genes whose proper functioning is necessary to produce normal synaptic connections between the neurons. These neurons comprise the giant fiber (GF) system; the GFs are command neurons activated by a light-off stimulus and evoke a stereotyped pattern of activity in the thoracic muscles producing an escape jump. Each GF monosynaptically drives a motor neuron innervating the tergotrochanteral muscle (jump muscle, TTM). Each GF also disynaptically drives the motor neurons innervating the dorsal longitudinal flight muscle (DLM) via the peripherally synapsing interneuron (PSI) (King, D. G., and R. J. Wyman (1980) J. Neurocytol. 9: 753-770; M. A. Tanouye and R. J. Wyman (1980) J. Neurophysiol. 44: 405-421). A search was made for mutations affecting these identified synapses. Fifty thousand mutagenized flies were screened for nonjumping behavior to the light-off stimulus. Fifty-seven nonjumping mutant lines were established from individuals selected in the screen. Members of the lines were then tested for abnormal GF motor output to the TTM and DLM. From these lines, four X-linked mutations (representing three complementation groups) were isolated which affect the circuit. The mutations differentially disrupt specific synapses within the GF system. One mutation, bendless, disrupts synaptic transmission between the GF and the TTM motor neuron. Another, gfA, disrupts the synaptic connections of the PSI, and a third mutation, passover, disrupts transmission in both pathways.

Title The Mathematics of Mosaic Analysis. I: The Relationship Between Sturts and Distance.
Date December 1982
Journal Genetics
Excerpt

In mosaic fate mapping the fraction of mosaics in which two structures are of different genotype is calculated. This frequency of separation has been called a "distance" and the units of this distance are called "sturts". The fundamental assumption of fate mapping is that the frequency of separation increases continuously with the actual distance between the anlage for these structures on the blastoderm. This paper shows that the frequency of separation does not increase beyond a certain value. --For the current theory to work as proposed, each mosaic animal must be half mutant and half normal. This is rarely the case in collections of mosaics. It has been thought that if some flies are less than half mutant and others more than half, these two types would introduce compensating errors in mapping distance. We show that this is not true and describe the nature of the errors introduced. It is probable that these errors are the main reason that mapping distances reported from different sets of mosaics have not been reproducible. This paper presents methods for the proper handling of data from mosaics with different amounts of mutant tissue.--We prove here that for mosaics with an arbitrary fraction of mutant tissue (m), the largest frequency of separation that can occur is 2m. We prove that sturts underestimate actual distance on the blastoderm by a factor of r/m, where r is the radius of the mutant patch, and that sturts give no information on distances greater than 2r. This, and not double crossing over, is the reason for the nonadditivity of sturts and the shrinking of large distances in sturt measures. Sturtoids overestimate distances by a factor of 1/(2r) and also give no information on distances over 2r. This paper gives formulae for correctly estimating distance when using a collection of mosaics with varying amounts of mutant tissue. We also describe the nature of the errors introduced by convoluted or elongate mosaic boundaries and by multiple mosaic patches.

Title A Mutation in Drosophila Alters Normal Connectivity Between Two Identified Neurones.
Date September 1982
Journal Nature
Title The Morphology of the Cervical Giant Fiber Neuron of Drosophila.
Date December 1981
Journal Brain Research
Excerpt

The morphology of the cervical giant fiber (CGF) neuron of Drosophila melanogaster was studied by intracellular injection of Lucifer yellow dye. The CGF neuron is the command cell in a motor circuit causing visually driven escape behavior: a single action potential in a CGF axon produces patterned activity in jump and flight muscles. The present study identified the CGF cell body, a large soma located in the posterior part of the lower ipsilateral protocerebrum. The main process runs anteriorly from the cell body, extends three branches, and turns posteromedially while descending through the brain. The CGF axon courses through the cervical connective and ends within the mesothoracic neuromere of the thoracic ganglion. Thus, the CGF neuron is an interneuron, not a motoneuron as previously believed. We have been isolating mutants that affect CGF neuron-mediated behavior. Comparison of CGF neuron morphology in wildtype strains with that in these mutants will allow identification of genes that affect the development, structure, and connections of the CGF neuron.

Title Intramembranous Particles and Chlorophyll Complexes in Chloroplasts.
Date October 1977
Journal Biochimica Et Biophysica Acta
Excerpt

The size and population density of large and small particles from freeze-fractured chloroplasts of three wild-type algae and of normal spinach were determined. Computer analyses of low-temperature absorption spectra of chloroplast preparations from these species were performed, and a possible correlation between the occurrence of seven chlorophyll complexes and the aforementioned properties of the intramembranous particles was studies. It was found that only single-sized particles occur in a species containing neither chlorophyll b nor chlorophyll a-685 complexes. The three remaining species carry particles of two sizes, termed large and small particles. However, from quantitative considerations it is concluded that the chlorophyll content of none of the various pigment complexes is related to the size and the population density of the studied particles. If such a relationship exists, it seems likely to be due to the carrier moiety of the chorophyll b-chlorophyll a-685 complex.

Title Interactive Effects of Training Condition and Septal Lesions on Perseverative Responding in the Rat.
Date February 1976
Journal Journal of Comparative and Physiological Psychology
Excerpt

Rats that had received septal lesions either prior to acquisition of a position habit (Group SAR) or immediately after position habit acquisition (Group SR) were tested on two reversals of the task. Compared with control-operated rats, both groups of rats with septal lesions exhibited position-habit reversal deficits. The two groups with septal lesions could not be distinguished in terms of the total number of errors made during reversal learning, but could be distinguished on the basis of the type of error committed. Compared with Group SR, Group SAR made significantly more perservative errors on the first reversal and significantly fewer perserverative errors on the second reversal. Group SR made significantly more nonperservative errors than Group SAR on both reversals.

Title Vmh Lesions Facilitate Baitshyness in the Rat.
Date February 1976
Journal Physiology & Behavior
Excerpt

Normal rats and rats with lesions of the ventromedial hypothalamus were compared on the acquisition of a single trial, long CS-US interval, conditioning task (baitshyness). The rats with hypothalamic damage exhibited facilitated baitshyness when tested both shortly after surgery and several months after surgery. The magnitude of the suppression observed in these animals could not be related to either specific anatomical structures within the hypothalamus or to the amount of obesity exhibited following the lesions. Similarities and differences between the results of the present study and previous studies are discussed.

Title Septal Lesions Facilitate the Shift from Conditioned Escape to Conditioned Avoidance Behavior in the Rat.
Date November 1975
Journal Physiology & Behavior
Excerpt

Normal rats were given 1000 training trials in a discriminated lever-press avoidance task. Those animals which exhibited consistent escape behavior but minimal avoidance responding were subjected to either septal lesions or control operations. One week later they were retested in the avoidance apparatus for an additional 1000 trials. Rats with large septal lesions exhibited an immediate increase in avoidance performance relative to the control rats. This increase occurred without a concomitant increase in number of lever-press responses. The performance of 3 out of 4 rats with smaller more dorsal septal lesions was unaffected by the surgery.

Title Square-runway Avoidance Behavior and Septal Lesions in the Rat.
Date March 1975
Journal Physiology & Behavior
Title A Possible Effect of Heterochromatin on Chromosome Pairing.
Date November 1974
Journal Proceedings of the National Academy of Sciences of the United States of America
Excerpt

Rye chromosomes were selectively stained in the meiosis of triticale by means of heterochromatin banding techniques. Compared to wheat chromosomes, rye chromosomes showed reduced pairing at first meiotic metaphase. Within the rye genome this pairing failure was associated with the presence of large, terminal heterochromatic bands. Since these terminal bands of rye chromosomes are late replicating, the effect of heterochromatin could arise from an overlap between the processes of chromosome replication and chromosome pairing.

Title Further Data on the Identity of a Pigment Absorbing Around 640 Nm in Ulva Lactuca.
Date October 1974
Journal Biochimica Et Biophysica Acta
Title One-way Avoidance Behavior and Septal Lesions in the Rat.
Date July 1974
Journal Journal of Comparative and Physiological Psychology
Title Fornical Lesions and Aversievely-motivated Behavior in the Rat.
Date June 1974
Journal Physiology & Behavior
Title Cross-maze Avoidance Behavior and Septal Lesions in the Rat.
Date May 1974
Journal Physiology & Behavior
Title On the Identity of the 640-nm Component Observed in Chlorophyll B Absorption Spectra in Vivo.
Date November 1973
Journal Biochimica Et Biophysica Acta
Title Hyperirritability, Lever-press Avoidance, and Septal Lesions in the Albino Rat.
Date October 1973
Journal Physiology & Behavior
Title Some Behavioral Effects of Olfactory Bulb Damage in the Rat.
Date July 1973
Journal Journal of Comparative and Physiological Psychology
Title Running-wheel Avoidance Behavior Following Septal Area Lesions in Rats.
Date November 1972
Journal Journal of Comparative and Physiological Psychology
Title Non-appetitive Passive Avoidance in Rats with Septal Lesions.
Date November 1972
Journal Physiology & Behavior
Title Stimulus Perserveration and Choice Behavior in Rats with Septal Lesions.
Date September 1972
Journal Journal of Comparative and Physiological Psychology
Title New Approaches to Teaching Basic Interview Skills to Medical Students.
Date May 1971
Journal The American Journal of Psychiatry
Title [rabies in Dogs in the City of Cali].
Date December 1970
Journal Boletín De La Oficina Sanitaria Panamericana. Pan American Sanitary Bureau
Title A Study of Chlorophyll B in Vivo.
Date December 1970
Journal Biochimica Et Biophysica Acta
Title Fractionation of Spinach Chloroplasts with Sodium Deoxycholate.
Date May 1969
Journal Biochimica Et Biophysica Acta
Title Infracardiac Total Anomalous Pulmonary Venous Drainage.
Date September 1968
Journal British Medical Journal
Title Relative Stability of Chlorophyll Complexes in Vivo.
Date August 1968
Journal Biochimica Et Biophysica Acta
Title Dichroism in Spinach Chloroplasts.
Date December 1967
Journal Biochimica Et Biophysica Acta
Title Sinusule: Timed-release Therapy in Allergic Rhinitis, with Human In-vivo Release Rates and Clinical Statistics.
Date November 1967
Journal Current Therapeutic Research, Clinical and Experimental
Title Blindness, Biologic Rhythms, and Menarche.
Date November 1967
Journal Obstetrics and Gynecology
Title A Linguistic Approach to Medical Education.
Date December 1966
Journal Journal of Medical Education
Title Studies on the Red Absorption Band of Chlorophyll a in Vivo.
Date March 1966
Journal Biochimica Et Biophysica Acta
Title The Approximate Red Absorption Band of Chlorophyll B in Ulva Lactuca at 77 Degrees K.
Date
Journal Febs Letters
Title Certification of Fat-soluble Vitamins, Carotenoids, and Cholesterol in Human Serum: Standard Reference Material 968b.
Date
Journal Analytical and Bioanalytical Chemistry
Excerpt

In Standard Reference Material 968b, fat-soluble vitamins and cholesterol in human serum, certified values are provided for cholesterol, retinol, retinyl palmitate, alpha-tocopherol, trans-beta-carotene, total beta-carotene ( trans plus cis isomers), total alpha-carotene, and lutein. Non-certified values are also reported for gamma-tocopherol (includes beta-tocopherol), delta-tocopherol, zeaxanthin, beta-cryptoxanthin, trans-lycopene, trans-lycopene, trans-alpha-carotene, total lycopene, 9- cis-betacarotene, 13- plus 15- cis-beta-carotene, and 15- cis-beta-carotene. Both certified and non-certified values are based on the agreement among results from three different liquid chromatographic analytical procedures developed at NIST and from an interlaboratory comparison exercise among institutions that participate in a NIST-managed Micronutrients Measurement Quality Assurance Program. Cholesterol is certified in this material using the NIST isotope dilution/mass spectrometric definitive method.

Title Reaction of Alien Chromosome Substitution and Addition Lines of Hard Red Spring Wheat to Common Root Rot and Black Point.
Date
Journal Genome / National Research Council Canada = Génome / Conseil National De Recherches Canada
Excerpt

Resistance to common root rot and black point, caused by Cochliobolus sativus, was evaluated in alien chromosome substitution and addition lines of the cultivars 'Cadet' and 'Rescue'. Substitution of chromosome 5B in 'Rescue' with 5Ag from Agropyron elongatum decreased root rot susceptibility to a level intermediate between that in the susceptible 'Rescue' and the resistant 'Cadet'. The substitution of 'Rescue' chromosome 5A or 5D with 5Ag, or the addition of 5Ag to 'Rescue' complement had no consistent effect on root rot susceptibility. The root rot resistance of 'Cadet' was unaffected by substitution of chromosomes 5A, 5B, or 5D with 5Ag, or the addition of 5Ag. This indicates that the susceptible allele of the gene Crr is the primary determinant in the reaction of wheat to common root rot. Black point resistance in the susceptible cultivar 'Rescue' was significantly increased by substitution of chromosome 5B with 5Ag, or the addition of 5Ag. No corresponding effect was demonstrated for black point incidence in the moderately resistant cultivar 'Cadet' with substitution of chromosome 5Ag for 5B, or the addition of 5Ag. Chromosome 5Ag apparently carries one or more genes conferring resistance to black point. The identity of these lines was confirmed by restriction fragment length polymorphism analysis using group 5 chromosome arm specific probes. This extends the use of these molecular probes to the Agropyron genome.

Title Development of Saw Palmetto (serenoa Repens) Fruit and Extract Standard Reference Materials.
Date
Journal Analytical and Bioanalytical Chemistry
Excerpt

As part of a collaboration with the National Institutes of Health's Office of Dietary Supplements and the Food and Drug Administration's Center for Drug Evaluation and Research, the National Institute of Standards and Technology has developed two standard reference materials (SRMs) representing different forms of saw palmetto (Serenoa repens), SRM 3250 Serenoa repens fruit and SRM 3251 Serenoa repens extract. Both of these SRMs have been characterized for their fatty acid and phytosterol content. The fatty acid concentration values are based on results from gas chromatography with flame ionization detection (GC-FID) and mass spectrometry (GC/MS) analysis while the sterol concentration values are based on results from GC-FID and liquid chromatography with mass spectrometry analysis. In addition, SRM 3250 has been characterized for lead content, and SRM 3251 has been characterized for the content of beta-carotene and tocopherols. SRM 3250 (fruit) has certified concentration values for three phytosterols, 14 fatty acids as triglycerides, and lead along with reference concentration values for four fatty acids as triglycerides and 16 free fatty acids. SRM 3251 (extract) has certified concentration values for three phytosterols, 17 fatty acids as triglycerides, beta-carotene, and gamma-tocopherol along with reference concentration values for three fatty acids as triglycerides, 17 fatty acids as free fatty acids, beta-carotene isomers, and delta-tocopherol and information values for two phytosterols. These SRMs will complement other reference materials currently available with concentrations for similar analytes and are part of a series of SRMs being developed for dietary supplements.

Title Genetics and Mapping of Seedling Resistance to Ug99 Stem Rust in Canadian Wheat Cultivars 'peace' and 'ac Cadillac'.
Date
Journal Tag. Theoretical and Applied Genetics. Theoretische Und Angewandte Genetik
Excerpt

Stem rust (caused by Puccinia graminis Pers.:Pers. f. sp. tritici Eriks. & E. Henn.) has re-emerged as a threat to wheat production with the evolution of new pathogen races, namely TTKSK (Ug99) and its variants, in Africa. Deployment of resistant wheat cultivars has provided long-term control of stem rust. Identification of new resistance genes will contribute to future cultivars with broad resistance to stem rust. The related Canadian cultivars Peace and AC Cadillac show resistance to Ug99 at the seedling stage and in the field. The purpose of this study was to elucidate the inheritance and genetically map resistance to Ug99 in these two cultivars. Two populations were produced, an F(2:3) population from LMPG/AC Cadillac and a doubled haploid (DH) population from RL6071/Peace. Both populations showed segregation at the seedling stage for a single stem rust resistance (Sr) gene, temporarily named SrCad. SrCad was mapped to chromosome 6DS in both populations with microsatellite markers and a marker (FSD_RSA) that is tightly linked to the common bunt resistance gene Bt10. FSD_RSA was the closest marker to SrCad (≈ 1.6 cM). Evaluation of the RL6071/Peace DH population and a second DH population, AC Karma/87E03-S2B1, in Kenya showed that the combination of SrCad and leaf rust resistance gene Lr34 provided a high level of resistance to Ug99-type races in the field, whereas in the absence of Lr34 SrCad conferred moderate resistance. A survey confirmed that SrCad is the basis for all of the seedling resistance to Ug99 in Canadian wheat cultivars. While further study is needed to determine the relationship between SrCad and other Sr genes on chromosome 6DS, SrCad represents a valuable genetic resource for producing stem rust resistant wheat cultivars.

Title Subtype-selective Na(v)1.8 Sodium Channel Blockers: Identification of Potent, Orally Active Nicotinamide Derivatives.
Date
Journal Bioorganic & Medicinal Chemistry Letters
Excerpt

A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.

Title 1-substituted 4-(3-hydroxyphenyl)piperazines Are Pure Opioid Receptor Antagonists.
Date
Journal Acs Medicinal Chemistry Letters
Excerpt

This report describes the discovery that 1-substituted 4-(3-hydroxyphenyl)piperazines are pure opioid receptor antagonists. Compounds in this new series include N-phenylpropyl (3S)-3-methyl-4-(3-hydroxyphenyl)piperazine and (3R)-3-methyl-4-(3-hydroxyphenyl)piperazine, both of which diaplay low nanomolar potencies at μ, δ, and κ receptors and pure antagonist properties in a [(35)S]GTPγS assay.

Title Isotope Dilution Liquid Chromatography - Mass Spectrometry Methods for Fat- and Water-soluble Vitamins in Nutritional Formulations.
Date
Journal Analytical Chemistry
Excerpt

Vitamins are essential to human health, and dietary supplements containing vitamins are widely used by individuals hoping to ensure they have adequate intake of these important nutrients. Measurement of vitamins in nutritional formulations is necessary to monitor regulatory compliance and in studies examining the nutrient intake of specific populations. Liquid chromatographic methods, primarily with UV absorbance detection, are well established for both fat- and water-soluble measurements, but they do have limitations for certain analytes and may suffer from a lack of specificity in complex matrices. Liquid chromatography-mass spectrometry (LC-MS) provides both sensitivity and specificity for the determination of vitamins in these matrices, and simultaneous analysis of multiple vitamins in a single analysis is often possible. In this work, LC-MS methods were developed for both fat- and water-soluble vitamins and applied to the measurement of these analytes in two NIST Standard Reference Materials. When possible, stable isotope labeled internal standards were employed for quantification.

Title Certification of Vitamins and Carotenoids in Srm 3280 Multivitamin/multielement Tablets.
Date
Journal Analytical Chemistry
Excerpt

A new multivitamin/multielement dietary supplement Standard Reference Material (SRM) has been issued by the National Institute of Standards and Technology (NIST), with certified and reference concentration values for 13 vitamins, 24 elements, and 2 carotenoids. The constituents have been measured by multiple analytical methods with data contributed by NIST and by collaborating laboratories. This effort included the first use of isotope dilution mass spectrometry for value assignment of both fat-soluble vitamins (FSVs) and water-soluble vitamins (WSVs). Excellent agreement was obtained among the methods, with relative expanded uncertainties for the certified concentration values typically ranging from <2% to 15% for vitamins.

Title Physiological Causes and Consequences of Social Status in Salmonid Fish.
Date
Journal Integrative and Comparative Biology
Excerpt

Social interactions in small groups of juvenile rainbow trout (Oncorhynchus mykiss) lead to the formation of dominance hierarchies. Dominant fish hold better positions in the environment, gain a larger share of the available food and exhibit aggression towards fish lower in the hierarchy. By contrast, subordinate fish exhibit behavioural inhibition, including reduced activity and feeding. The behavioural characteristics associated with social status are likely the result of changes in brain monoamines resulting from social interactions. Whereas substantial physiological benefits, including higher growth rates and condition factor, are experienced by dominant trout, low social status appears to be a chronic stress, as indicated by sustained elevation of circulating cortisol concentrations in subordinate fish. High cortisol levels, in turn, may be responsible for many of the deleterious physiological consequences of low social status, including lower growth rates and condition factor, immunosuppression and increased mortality. Circulating cortisol levels may also be a factor in determining the outcome of social interactions in pairs of rainbow trout, and hence in determining social status. Rainbow trout treated with cortisol were significantly more likely to become subordinate in paired encounters with smaller untreated conspecifics.

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