Orthopedic Surgeons
14 years of experience
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Anne Arundel Orthopaedic Surgeons
2003 Medical Pkwy
Ste 400
Annapolis, MD 21401
410-573-2530
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Education ?

Medical School Score Rankings
University of Maryland (1996)
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Awards  
Patients' Choice Award (2011)
Compassionate Doctor Recognition (2011 - 2013)
Associations
American Association of Hip and Knee Surgeons
American Board of Orthopaedic Surgery
American Society for Dermatologic Surgery

Affiliations ?

Dr. King is affiliated with 1 hospitals.

Hospital Affilations

Score

Rankings

  • Anne Arundel Medical Center
    Orthopaedic Surgery
    2001 Medical Pkwy, Annapolis, MD 21401
    • Currently 2 of 4 crosses
  • Publications & Research

    Dr. King has contributed to 60 publications.
    Title Large-scale Exfoliation of Inorganic Layered Compounds in Aqueous Surfactant Solutions.
    Date December 2011
    Journal Advanced Materials (deerfield Beach, Fla.)
    Title Design and Commissioning of a High Magnetic Field Muon Spin Relaxation Spectrometer at the Isis Pulsed Neutron and Muon Source.
    Date December 2011
    Journal The Review of Scientific Instruments
    Excerpt

    The high magnetic field (HiFi) muon instrument at the ISIS pulsed neutron and muon source is a state-of-the-art spectrometer designed to provide applied magnetic fields up to 5 T for muon studies of condensed matter and molecular systems. The spectrometer is optimised for time-differential muon spin relaxation studies at a pulsed muon source. We describe the challenges involved in its design and construction, detailing, in particular, the magnet and detector performance. Commissioning experiments have been conducted and the results are presented to demonstrate the scientific capabilities of the new instrument.

    Title Two-dimensional Nanosheets Produced by Liquid Exfoliation of Layered Materials.
    Date February 2011
    Journal Science (new York, N.y.)
    Excerpt

    If they could be easily exfoliated, layered materials would become a diverse source of two-dimensional crystals whose properties would be useful in applications ranging from electronics to energy storage. We show that layered compounds such as MoS(2), WS(2), MoSe(2), MoTe(2), TaSe(2), NbSe(2), NiTe(2), BN, and Bi(2)Te(3) can be efficiently dispersed in common solvents and can be deposited as individual flakes or formed into films. Electron microscopy strongly suggests that the material is exfoliated into individual layers. By blending this material with suspensions of other nanomaterials or polymer solutions, we can prepare hybrid dispersions or composites, which can be cast into films. We show that WS(2) and MoS(2) effectively reinforce polymers, whereas WS(2)/carbon nanotube hybrid films have high conductivity, leading to promising thermoelectric properties.

    Title Improvement of Transparent Conducting Nanotube Films by Addition of Small Quantities of Graphene.
    Date December 2010
    Journal Acs Nano
    Excerpt

    We demonstrate a water-based method to prepare transparent, conducting graphene/single-walled nanotube hybrid films. While the transmittance decreases slightly with increasing graphene content, the DC conductivity, sigma(DC), and sheet resistance scale non-monotonically with film composition. We observe an optimum composition of approximately 3 wt % graphene, which results in a peak in the DC conductivity. We have calculated the figure of merit, the DC to optical conductivity ratio, sigmaDC/sigmaOp, which also shows a peak at this composition. We find that this effect is only present for small graphene flakes. In addition, acid treatment increases both the sigmaDC and sigmaDC/sigmaOp by x2.5. Interestingly, acid treatment is more effective for films close to the optimum composition. This has the effect of sharpening the peaks in both sigmaDC and sigmaDC/sigmaOp. For acid-treated films, addition of 3 wt % graphene results in a 40% increase in sigmaDC/sigmaOp compared to the nanotube-only film, from 12.5 to 18. Optimized, acid-treated films display transmittance of 80% coupled with a sheet resistance of 100 Omega/[square].

    Title High-concentration, Surfactant-stabilized Graphene Dispersions.
    Date October 2010
    Journal Acs Nano
    Excerpt

    A method is presented to produce graphene dispersions, stabilized in water by the surfactant sodium cholate, at concentrations up to 0.3 mg/mL. The process uses low power sonication for long times (up to 400 h) followed by centrifugation to yield stable dispersions. The dispersed concentration increases with sonication time while the best quality dispersions are obtained for centrifugation rates between 500 and 2000 rpm. Detailed TEM analysis shows the flakes to consist of 1-10 stacked monolayers with up to 20% of flakes containing just one layer. The average flake consists of approximately 4 stacked monolayers and has length and width of approximately 1 mum and approximately 400 nm, respectively. These dimensions are surprisingly stable under prolonged sonication. However, the mean flake length falls from approximately 1 mum to approximately 500 nm as the centrifugation rate is increased from 500 to 5000 rpm. Raman spectroscopy shows the flake bodies to be relatively defect-free for centrifugation rates below 2000 rpm. The dispersions can be easily cast into high-quality, free-standing films. The method extends the scope for scalable liquid-phase processing of graphene for a wide range of applications.

    Title Statistically Significant or Significant?
    Date June 2010
    Journal Canadian Medical Association Journal
    Title Partition Instability in Water-immersed Granular Systems.
    Date October 2009
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    It is well known that a system of grains, vibrated vertically in a cell divided into linked columns, may spontaneously move into just one of the columns due to the inelastic nature of their collisions. Here we study the behavior of a water-immersed system of spherical barium titanate particles in a rectangular cell which is divided into two columns, linked by two connecting holes, one at the top and one at the bottom of the cell. Under vibration the grains spontaneously move into just one of the columns via a gradual transfer of grains through the connecting hole at the base of the cell. We have developed numerical simulations that are able to reproduce this behavior and provide detailed information on the instability mechanism. We use this knowledge to propose a simple analytical model for this fluid-driven partition instability based on two coupled granular beds vibrated within an incompressible fluid.

    Title Chain Formation of Spheres in Oscillatory Fluid Flows.
    Date September 2009
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    A collection of spherical particles subjected to horizontal oscillatory fluid flow is known to form chains perpendicular to the direction of the oscillation. We have developed computer simulations to model such a system and have validated them against experiments carried out in a small fluid-filled cell. In both experiment and simulation we find that the particles go through the same stages of evolution from a dispersed initial configuration to an ordered chain structure. We then use our computer simulations to investigate in detail the interactions responsible for chain formation and the interaction between fully formed chains.

    Title Characterization of the Angiotensin (at1b) Receptor Promoter and Its Regulation by Glucocorticoids.
    Date September 2009
    Journal Journal of Molecular Endocrinology
    Excerpt

    Angiotensin II acts through two pharmacologically distinct receptors known as AT1 and AT2. Duplication of the AT1 receptor in rodents into At1a and b subtypes allows tissue-specific expression of the AT1b in adrenal and pituitary tissue. Adrenal expression of this receptor is increased in the offspring of rat mothers exposed to a low-protein diet and this is associated with the undermethylation of its promoter. This phenomenon is blocked by the inhibition of maternal glucocorticoid synthesis by metyrapone. We have mapped the transcriptional start site of the promoter and demonstrated that a 1.2 kbp fragment upsteam of this site is effective in driving luciferase expression in mouse Y1 cells. A combination of bioinformatic analysis, electrophoretic mobility shift analysis (EMSA), and mutagenesis studies demonstrates: i) the presence of a putative TATA box and CAAT box; ii) the presence of three Sp1 response elements, capable of binding SP1; mutation of any pair of these sites effectively disables this promoter; iii) the presence of four potential glucocorticoid response elements which each bind glucocorticoid receptor in EMSA, although only two confer dexamethasone inhibition on the promoter; iv) the presence of two AP1 sites. Mutagenesis of the distal AP1 site greatly diminishes promoter function but this is also associated with the loss of dexamethasone inhibition. These studies will facilitate an understanding of the mechanisms by which fetal programming leads to long term alterations in gene expression and the development of adult disease.

    Title Liquid Phase Production of Graphene by Exfoliation of Graphite in Surfactant/water Solutions.
    Date June 2009
    Journal Journal of the American Chemical Society
    Excerpt

    We have demonstrated a method to disperse and exfoliate graphite to give graphene suspended in water-surfactant solutions. Optical characterization of these suspensions allowed the partial optimization of the dispersion process. Transmission electron microscopy showed the dispersed phase to consist of small graphitic flakes. More than 40% of these flakes had <5 layers with approximately 3% of flakes consisting of monolayers. Atomic resolution transmission electron microscopy shows the monolayers to be generally free of defects. The dispersed graphitic flakes are stabilized against reaggregation by Coulomb repulsion due to the adsorbed surfactant. We use DLVO and Hamaker theory to describe this stabilization. However, the larger flakes tend to sediment out over approximately 6 weeks, leaving only small flakes dispersed. It is possible to form thin films by vacuum filtration of these dispersions. Raman and IR spectroscopic analysis of these films suggests the flakes to be largely free of defects and oxides, although X-ray photoelectron spectroscopy shows evidence of a small oxide population. Individual graphene flakes can be deposited onto mica by spray coating, allowing statistical analysis of flake size and thickness. Vacuum filtered films are reasonably conductive and are semitransparent. Further improvements may result in the development of cheap transparent conductors.

    Title The Majority of Adrenocorticotropin Receptor (melanocortin 2 Receptor) Mutations Found in Familial Glucocorticoid Deficiency Type 1 Lead to Defective Trafficking of the Receptor to the Cell Surface.
    Date January 2009
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    There are at least 24 missense, nonconservative mutations found in the ACTH receptor [melanocortin 2 receptor (MC2R)] that have been associated with the autosomal recessive disease familial glucocorticoid deficiency (FGD) type 1. The characterization of these mutations has been hindered by difficulties in establishing a functional heterologous cell transfection system for MC2R. Recently, the melanocortin 2 receptor accessory protein (MRAP) was identified as essential for the trafficking of MC2R to the cell surface; therefore, a functional characterization of MC2R mutations is now possible.

    Title Influence of Magnetic Cohesion on the Stability of Granular Slopes.
    Date December 2008
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    We use a molecular dynamics model to simulate the formation and evolution of a granular pile in two dimensions in order to gain a better understanding of the role of magnetic interactions in avalanche dynamics. We find that the angle of repose increases only slowly with magnetic field; the increase in angle is small even for intergrain cohesive forces many times stronger than gravity. The magnetic forces within the bulk of the pile partially cancel as a result of the anisotropic nature of the dipole-dipole interaction between grains. However, we show that this cancellation effect is not sufficiently strong to explain the discrepancy between the angle of repose in wet systems and magnetically cohesive systems. In our simulations we observe shearing deep within the pile, and we argue that it is this motion that prevents the angle of repose from increasing dramatically. We also investigate different implementations of friction with the front and back walls of the container, and conclude that the nature of the friction dramatically affects the influence of magnetic cohesion on the angle of repose.

    Title Migration of an Asymmetric Dimer in Oscillatory Fluid Flow.
    Date November 2008
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    We describe the motion of an asymmetric dimer across a horizontal surface when exposed to an oscillatory fluid flow. The dimer consists of two spheres of distinct sizes, rigidly attached to each other. The dimer is found to move in a direction perpendicular to the fluid flow, with the smaller sphere foremost. We have determined how the speed depends upon the vibratory conditions, on the fluid viscosity, and on the dimer size and aspect ratio. Computer simulations are used to give an insight into the mechanism responsible for the motion. We use a scaling argument based on the asymmetry of the streaming flow to predict the approximate dependence of the migration speed on the system parameters.

    Title Dynamics and Reactivity of Positively Charged Muonium in Heavily Doped Si:b and Comparisons with Hydrogen.
    Date August 2008
    Journal Physical Review Letters
    Excerpt

    The detailed dynamics of the positively charged muonium (Mu+) in heavily doped p-type Si:B is reported. Below 200 K, Mu+ is static and isolated, and is located in a stretched Si-Si bond. Above approximately 200 K, Mu+ diffuses incoherently. At temperatures higher than 300 K, the Mu+-B- complex is formed while above 520 K, it starts to dissociate. There is significant enhancement of the diffusion of Mu+ in Si compared to H+ and D+-this is attributed to its smaller mass.

    Title Interaction Between Intruders in Vibrated Granular Beds.
    Date June 2008
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    Two neutrally buoyant intruder particles in a granular bed fluidized by vertical, sinusoidal vibration are known to interact with each other over a range of about five intruder diameters. Using molecular dynamics simulations, we investigate in detail the spatial and temporal nature of this interaction. We show that the force of attraction between intruders can be calculated from the local density and kinetic energy using a simple equation of state. Moreover, the interaction can be changed from attractive to repulsive by reducing the coefficient of restitution between the intruders and host particles, one of the key results of this work.

    Title Interaction of Spheres in Oscillatory Fluid Flows.
    Date June 2008
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    Rigid spherical particles in oscillating fluid flows form interesting structures as a result of fluid mediated interactions. Here we show that spheres under horizontal vibration align themselves at right angles to the oscillation and sit with a gap between them. The details of this behavior have been investigated through experiments and simulations. We have carried out experiments in which a pair of stainless steel spheres is shaken horizontally in a cell filled with glycerol-water fluid mixtures of three different viscosities, at various frequencies and amplitudes of oscillation. There is an equilibrium gap between the particles resulting from a long-range attraction and a short-range repulsion. The size of the gap was found to depend on the fluid viscosity and the vibratory parameters, and we have identified two distinct scaling regimes for the dependence of the gap on the system parameters. Using a Navier-Stokes solver the same system was simulated. The interaction force between the spheres was measured and the streaming flows induced by the motion were determined.

    Title Mechanisms of Adrenocorticotropin-induced Activation of Extracellularly Regulated Kinase 1/2 Mitogen-activated Protein Kinase in the Human H295r Adrenal Cell Line.
    Date May 2008
    Journal Endocrinology
    Excerpt

    The role of ACTH in stimulating or inhibiting growth of adrenal cells has been a subject of some controversy. Reports that ACTH may stimulate ERK/MAPK in Y1 cells have suggested a role for cAMP in this process. In attempting to extend this work, the ACTH responses in the human H295R cell line have been studied. This cell line makes only a very modest cAMP response to ACTH, yet the ERK1/2 response is highly reproducible and immediate but not prolonged. It is minimally reduced by the protein kinase A inhibitor, H89, but unaffected by protein kinase C and calcium inhibitors. Inhibition of epidermal growth factor receptor or other tyrosine kinase receptor transactivation was without effect, as was inhibition of c-Src activity or c-Src phosphorylation. The most effective inhibitor of this pathway was dansylcadaverine, an inhibitor of receptor internalization. These findings imply that ACTH-induced ERK1/2 activation in H295R cells is dependent on a mechanism distinct from that by which most G protein-coupled receptors activate ERK1/2 but that nevertheless seems to depend on receptor internalization.

    Title Magneto-vibratory Separation of Glass and Bronze Granular Mixtures Immersed in a Paramagnetic Liquid.
    Date February 2008
    Journal The European Physical Journal. E, Soft Matter
    Excerpt

    A fluid-immersed granular mixture may spontaneously separate when subjected to vertical vibration, separation occurring when the ratio of particle inertia to fluid drag is sufficiently different between the component species of the mixture. Here, we describe how fluid-driven separation is influenced by magneto-Archimedes buoyancy, the additional buoyancy force experienced by a body immersed in a paramagnetic fluid when a strong inhomogeneous magnetic field is applied. In our experiments glass and bronze mixtures immersed in paramagnetic aqueous solutions of MnCl2 have been subjected to sinusoidal vertical vibration. In the absence of a magnetic field the separation is similar to that observed when the interstitial fluid is water. However, at modest applied magnetic fields, magneto-Archimedes buoyancy may balance the inertia/fluid-drag separation mechanism, or it may dominate the separation process. We identify the vibratory and magnetic conditions for four granular configurations, each having distinctive granular convection. Abrupt transitions between these states occur at well-defined values of the magnetic and vibrational parameters. In order to gain insight into the dynamics of the separation process we use computer simulations based on solutions of the Navier-Stokes' equations. The simulations reproduce the experimental results revealing the important role of convection and gap formation in the stability of the different states.

    Title Interaction of the Melanocortin 2 Receptor with Nucleoporin 50: Evidence for a Novel Pathway Between a G-protein-coupled Receptor and the Nucleus.
    Date December 2007
    Journal The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology
    Excerpt

    The adrenocorticotropin (ACTH) receptor (melanocortin 2 receptor, or MC2R) is the smallest G-protein-coupled receptor that, when activated by the peptide hormone ACTH, stimulates cAMP production and adrenal steroidogenesis. Receptor expression is dependent on a specific membrane trafficking process involving an accessory protein (melanocortin 2 receptor accessory protein, or MRAP) and other unidentified components. In an attempt to discover novel receptor interacting proteins, the C-terminal tail of the MC2R was used to screen a mouse adrenal Y6 cell cDNA library using the bacterial two-hybrid system. This identified the nucleoporin Nup 50 (Npap60) as the major full-length interacting protein. Interaction was confirmed by a GST pulldown assay and by coimmunoprecipitation in human H295R cells (which express both proteins endogenously). Deletion analysis identified the region between residues 143 and 466 in Nup50 as being required for interaction with the MC2R. Stimulation of H295R cells with ACTH (10(-6) M) was followed by a gradual translocation of the Nup50-MC2R complex from the membrane to the nucleus after 30 min. This time course is most consistent with MC2R internalization dynamics and may suggest a novel role for Nup50.

    Title Intruder Clustering in Three-dimensional Granular Beds.
    Date October 2007
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    We present results of computer simulations for neutrally buoyant intruders in a vertically vibrated three-dimensional granular bed of smaller host particles. Under sinusoidal excitation, pairs of intruders interact over a distance of several intruder diameters; a group of intruders forms a cluster. The strength of the interaction grows as the number of intruders is increased. We show that the tendency to cluster may be manipulated through the use of nonsinusoidal excitation, which allows partial mixing. Finally, we investigate the effects of walls on the clustering of intruders.

    Title Velocity Statistics in Dissipative, Dense Granular Media.
    Date September 2007
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    We use a two-dimensional random-force model to investigate the velocity distributions in driven granular media. In general, the shape of the distribution is found to depend on the degree of dissipation and the packing fraction but, in highly dissipative systems, the velocity distributions have tails close to exponential. We show that these arise from the dynamics of single particles traveling in dilute regions and influenced predominantly by the random force. A self-consistent kinetic theory is developed to describe this behavior.

    Title Stochastic Dynamics of a Rod Bouncing Upon a Vibrating Surface.
    Date July 2007
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    We describe the behavior of a rod bouncing upon a horizontal surface which is undergoing sinusoidal vertical vibration. The predictions of computer simulations are compared with experiments in which a stainless-steel rod bounces upon a metal-coated glass surface. We find that, as the dimensionless acceleration parameter Gamma is increased appreciably above unity, the motion of a long rod passes from periodic or near-periodic motion into stochastic dynamics. Within this stochastic regime the statistics of the times between impacts follow distributions with tails of approximately Gaussian form while the probability distributions of the angles at impact have tails that are close to exponential. We determine the dependence of each distribution upon the length of the rod, upon frequency, and on Gamma. The statistics of the total energy and of the translational and rotational components each approximately follow a Boltzmann distribution in their tails, the translational and rotational energy components being strongly correlated. The time-averaged mean vertical translational energy is significantly larger than the mean rotational energy, and both are considerably larger than the energy associated with horizontal motion.

    Title Instabilities in Vertically Vibrated Fluid-grain Systems.
    Date June 2007
    Journal The European Physical Journal. E, Soft Matter
    Excerpt

    When a bed of fluid-immersed fine grains is exposed to vertical vibration a wealth of phenomena may be observed. At low frequencies a horizontal bed geometry is generally unstable and the bed breaks spatial symmetry, acquiring a tilt. At the same time it undergoes asymmetric granular convection. Fine binary mixtures may separate completely into layers or patterns of stripes. The separated regions may exhibit instabilities in which they undergo wave-like motion or exhibit quasi-periodic oscillations. We briefly review these and a number of related behaviours, identifying the physical mechanisms behind each. Finally, we discuss the magneto-vibratory separation of binary mixtures which results from exposing each component to a different effective gravity and describe the influence of a background fluid on this process.

    Title Epigenetic Modification of the Renin-angiotensin System in the Fetal Programming of Hypertension.
    Date March 2007
    Journal Circulation Research
    Excerpt

    Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (eg, salt intake, obesity, alcohol) and genetic factors clearly contribute to the development of hypertension, but it has also been established that stress in utero may program the later development of the disease. This phenomenon, known as fetal programming can be modeled in a range of experimental animal models. In maternal low protein diet rat models of programming, administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists in early life can prevent development of hypertension, thus implicating the renin-angiotensin system in this process. Here we show that in this model, expression of the AT(1b) angiotensin receptor gene in the adrenal gland is upregulated by the first week of life resulting in increased receptor protein expression consistent with the increased adrenal angiotensin responsiveness observed by others. Furthermore, we show that the proximal promoter of the AT(1b) gene in the adrenal is significantly undermethylated, and that in vitro, AT(1b) gene expression is highly dependent on promoter methylation. These data suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life leading ultimately to the development of hypertension. It seems highly probable that similar influences may be involved in the development of human hypertension.

    Title Identification of a Novel Melanocortin 2 Receptor Splice Variant in Murine Adipocytes: Implications for Post-transcriptional Control of Expression During Adipogenesis.
    Date January 2007
    Journal Journal of Molecular Endocrinology
    Excerpt

    The ACTH receptor melanocortin 2 receptor (MC2-R) is a G-protein-coupled receptor principally expressed in the adrenal cortex and the adipocyte, where it stimulates steroidogenesis and lipolysis respectively. The coding region of the murine gene is encoded by a single exon, although three upstream non-coding exons have been documented, one of which is incorporated by alternative splicing in adrenal cells. We have detected a novel transcript in adipocytes, which includes a previously unidentified 86 bp exon upstream of the coding region. This transcript appears with slower kinetics during a time course of differentiation of 3T3-L1 cells and is much more highly expressed in these cells and murine adipose tissues than in the Y1 murine adrenocortical cell line, also it is undetectable in murine foetal testes. Inclusion of this exon extends the 5' UTR to 468 bp and introduces three upstream open reading frames. These are typical features of mRNAs under translational control and imply that the MC2-R gene is regulated both transcriptionally and post-transcriptionally during adipogenesis.

    Title A Ccaat/enhancer-binding Protein Site at -87 is Required for the Activation of a Novel Murine Melanocortin 2-receptor Promoter at Late Stages During Adipogenesis.
    Date January 2007
    Journal Endocrinology
    Excerpt

    The peptide hormone ACTH stimulates lipolysis and suppresses leptin production in adipocytes via the G protein-coupled receptor, melanocortin 2 receptor (MC2-R). We have shown previously that peroxisome proliferator-activated receptor-gamma2 is the primary factor responsible for transactivation of the already identified murine MC2-R promoter in the differentiating 3T3-L1 adipocyte cell line. In this study we show that despite the activity of this promoter being transient during differentiation, MC2-R message remains elevated at later time points during adipogenesis. Analysis of the late transcripts reveals that they initiate from a transcriptional start site in the first intron of the murine MC2-R. The genomic sequence upstream of this start site acts as an adipocyte-specific promoter whose activation is delayed in differentiation, compared with the upstream promoter. A CCAAT/enhancer-binding protein binding site, 87 bp upstream of the transcriptional initiation site, is necessary for the activity of this promoter, and protein binding analyses reveal that this site is bound by CCAAT/enhancer-binding protein factors. Real-time PCR analysis of mRNA initiating from the two start sites shows that there is a switch in promoter usage from the 5' to the 3' promoter around d 5, indicating the complex regulation of the murine MC2-R during adipogenesis.

    Title Anti-human Immunodeficiency Virus Activity of 3,4,5-tricaffeoylquinic Acid in Cultured Cells of Lettuce Leaves.
    Date June 2006
    Journal Molecular Nutrition & Food Research
    Excerpt

    3,4,5-Tricaffeoylquinic acid (TCQA) that is not found in intact plant of lettuce leaves was isolated from the cultured cells. The intact plant produced chicoric acid (dicaffeoyl tartaric acid: L-CCA) as well as chlorogenic acid (3-caffeoylquinic acid: 3-CQA) as the major metabolites. After subculturing of the cells for 40 days, the amount of 3,4,5-TCQA reached to 0.14 mg/g fresh weight. The inhibitory effect of 3,4,5-TCQA for human immunodeficiency virus (HIV) Type 1 integrase was assayed. Anti-HIV activity using HIV and MT-2 cells was 1.15 microM and IC(50) against HIV integrase was 0.063 microM whereas cell toxicity of this chemical was expressed as 5% death of all living cells to be 18.4 microM. The HIV inhibitory effect of 3,4,5-TCQA was the highest in values among L-CCA, and other dicaffeoylquinic acids. This data will provide a new possibility for creating a new drug design for HIV.

    Title Arthroscopically-assisted Removal of Retrograde Intramedullary Femoral Nails.
    Date May 2006
    Journal Journal of Orthopaedic Trauma
    Excerpt

    Retrograde nailing of femoral shaft fractures has become more prevalent as a result of its growing acceptance and familiarity to orthopaedic surgeons. Nail removal is occasionally indicated, which may require a formal arthrotomy. We describe an arthroscopic removal technique that has several advantages. The percutaneous technique imparts less morbidity than a more extensive arthrotomy. More importantly, additional intra-articular pathology can be thoroughly assessed and treated, such as meniscal tears and chondral injury, which may have occurred at the time of injury. These are potential causes of knee pain, which usually cannot be properly diagnosed without arthroscopy. Our findings also support the existence of a stable fibrous cap, which forms over the entry portal of a well-seated retrograde femoral nail as well as no evidence of intra-articular metallosis.

    Title Traveling Waves in a Water-immersed Binary Granular System Vibrated Within an Annular Cell.
    Date August 2005
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    It has been known since the time of Faraday that vertically vibrated fine grains may spontaneously form piles through their interaction with a fluid. More recently, it has been observed that a fine binary mixture may separate under vertical vibration through the differential influence of the fluid on the two granular components. Here, we report a detailed study of a system of water-immersed bronze and glass grains held between two coaxial cylinders. Under vertical vibration, the bronze separates to form a layer above the glass, which itself breaks symmetry to form a pile. Symmetry is broken a second time by the bronze forming layers of different thicknesses upon the two slopes of the glass pile. The pile then travels as a wave with the thicker bronze layer upon its leading surface. We examine the conditions for these traveling waves and determine how their speed varies with particle size, frequency, and amplitude of vibration. A model is developed which provides a semiquantitative account of the wave motion.

    Title Separation of Binary Granular Mixtures Under Vibration and Differential Magnetic Levitation Force.
    Date May 2005
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    The application of both a strong magnetic field and a magnetic field gradient to a diamagnetic or paramagnetic material can produce a vertical force that acts in concert with the force of gravity. We consider a binary granular mixture in which the two components have different magnetic susceptibilities and therefore experience different effective forces of gravity when subjected to an inhomogeneous magnetic field. Under vertical vibration, such a mixture may rapidly separate into regions almost pure in the two components. We investigate the conditions for this behavior, studying the speed and completeness of separation as a function of differential effective gravity and the frequency and amplitude of vibration. The influence of the cohesive magnetic dipole-dipole interactions on the separation process is also investigated. In our studies insight is gained through the use of a molecular dynamics simulation model.

    Title Faraday Tilting of Water-immersed Granular Beds.
    Date May 2005
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    Under low-frequency vertical vibration, a system of fine grains within a fluid is observed to tilt or to form piles, an effect studied by Faraday for grains in air. Here, we investigate the physical mechanisms behind Faraday tilting in a bed of vertically vibrated bronze spheres fully immersed in water. Experimental observations of surface tilting and bulk convection are compared with the results of molecular dynamics simulations in which the water is treated as an incompressible fluid. Our simulations reproduce the main features observed experimentally. Most tilt construction is shown to be due to horizontal fluid flow within the bed, principally occurring when the gap between the bed and the supporting platform is close to a maximum. Tilt destruction occurs by granular surface flow and in the bulk of the bed at times during each vibratory cycle close to and just later than bed impact. Destruction becomes more important for higher values of frequency and vibration amplitude, leading to lower tilt angles, partial tilting, or the symmetric domed geometry of Muchowski flow.

    Title Are Brazil Nuts Attractive?
    Date January 2005
    Journal Physical Review Letters
    Excerpt

    We present event-driven simulation results for single and multiple intruders in a vertically vibrated granular bed. Under our vibratory conditions, the mean vertical position of a single intruder is governed primarily by a buoyancylike effect. Multiple intruders also exhibit buoyancy governed behavior; however, multiple neutrally buoyant intruders cluster spontaneously and undergo horizontal segregation. These effects can be understood by considering the dynamics of two neutrally buoyant intruders. We have measured an attractive force between such intruders which has a range of five intruder diameters, and we provide a mechanistic explanation for the origins of this force.

    Title Stripe Formation in Granular Mixtures Due to the Differential Influence of Drag.
    Date December 2004
    Journal Physical Review Letters
    Excerpt

    We describe an investigation of fluid-immersed granular mixtures subjected to horizontal vibration. For sufficiently large amplitudes of vibration, a mixture of equal-sized glass and bronze particles in water is found to separate into a striped pattern. Numerical simulations based on soft-sphere molecular dynamics coupled to the interstitial fluid are able to capture many of the features observed experimentally. We propose a general pattern-formation mechanism based on the differential influence of drag on the components of the mixture. An expression for the number of stripes as a function of the system parameters is derived and shown to be in good agreement with experiments.

    Title L-chicoric Acid Inhibits Human Immunodeficiency Virus Type 1 Integration in Vivo and is a Noncompetitive but Reversible Inhibitor of Hiv-1 Integrase in Vitro.
    Date September 2004
    Journal Virology
    Excerpt

    The human immunodeficiency virus (HIV) integrase (IN) must covalently join the viral cDNA into a host chromosome for productive HIV infection. l-Chicoric acid (l-CA) enters cells poorly but is a potent inhibitor of IN in vitro. Using quantitative real-time polymerase chain reaction (PCR), l-CA inhibits integration at concentrations from 500 nM to 10 microM but also inhibits entry at concentrations above 1 microM. Using recombinant HIV IN, steady-state kinetic analyses with l-CA were consistent with a noncompetitive or irreversible mechanism of inhibition. IN, in the presence or absence of l-CA, was successively washed. Inhibition of IN diminished, demonstrating that l-CA was reversibly bound to the protein. These data demonstrate that l-CA is a noncompetitive but reversible inhibitor of IN in vitro and of HIV integration in vivo. Thus, l-CA likely interacts with amino acids other than those which bind substrate.

    Title A Peroxisome Proliferator-response Element in the Murine Mc2-r Promoter Regulates Its Transcriptional Activation During Differentiation of 3t3-l1 Adipocytes.
    Date July 2004
    Journal The Journal of Biological Chemistry
    Excerpt

    Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin expression in murine adipocytes. These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis. In this study, we have characterized the mc2-r promoter in the murine adipocyte, one of the few extra-adrenal sites of expression and a cell type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is required for mc2-r expression in adrenal cells. Transcriptional regulation of the mc2-r in the absence of SF-1 was investigated by 5' deletion analysis of the murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells. The results revealed the presence of a 59-base pair regulatory region within the promoter containing an adipocyte-specific enhancer. The ability of this region to confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator-response element (PPRE)-like sequence that bound to peroxisome proliferator-activated receptor gamma (PPARgamma) and its heterodimeric partner retinoid X receptor alpha (RXRalpha) in adipocyte nuclear extracts. Co-transfection of PPARgamma2/RXRalpha with the pMC2-R(-112/+105)GL3 reporter resulted in transcriptional activation in preadipocytes, and this response required an intact PPRE. Mutation of the PPRE to prevent PPARgamma/RXRalpha binding resulted in a complete abrogation of the pMC2-R(-112/+105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte. These data highlight a novel mechanism for mc2-r transcription, which may have significance in both adrenal and extra-adrenal sites of expression.

    Title The Fate of Patients Not Returning for Follow-up Five Years After Total Knee Arthroplasty.
    Date June 2004
    Journal The Journal of Bone and Joint Surgery. American Volume
    Excerpt

    BACKGROUND: Patients who do not return for follow-up after total knee arthroplasty are often assumed to have had a worse outcome. We postulated that the Internet may be useful for locating patients who do not return for follow-up. The purpose of this study was to compare outcomes between patients who attended prescribed postoperative appointments and those who did not. METHODS: We retrospectively reviewed the outcomes for 161 patients (200 knees) at a minimum of five years after a total knee replacement. All patients who had had no contact of any type with their surgeon in any manner beyond six months following the date of the surgery were classified as not having returned for follow-up. When patients could not be located with use of all available information in their chart, a standardized Internet search algorithm was employed with use of readily available and free search engines. RESULTS: Thirty patients with thirty-five treated knees met the definition of not returning for follow-up. Thirteen patients could not be located with use of the contact information given at their last visit. All were located with use of the Internet. None of the patients had had knee surgery elsewhere. The reasons for not adhering to the prescribed postoperative regimen were identified. The group had improved Knee Society pain and function scores compared with the preoperative values, and the patients were not significantly different from those who did return for follow-up. CONCLUSIONS: The patients who did not attend follow-up appointments in this series had not had any additional surgery and did not have any significant differences in measured outcome variables when compared with patients who had complied with a follow-up protocol. The Internet proved to be a valuable tool for locating patients who had not returned for follow-up postoperatively.

    Title Constitutive Activation of the Human Acth Receptor Resulting from a Synergistic Interaction Between Two Naturally Occurring Missense Mutations in the Mc2r Gene.
    Date June 2004
    Journal Molecular and Cellular Endocrinology
    Excerpt

    Two mutations in the same allele of the ACTH receptor (melanocortin 2 receptor, MC2R) associated with clinical hypersensitivity to ACTH have been described in a single case report. Using a stable Y6 cell expression system, we demonstrate that either the C21R or S247G mutations alone produce an inactive receptor with loss of ligand binding and responsiveness. However, the presence of both mutations in the same molecule leads to a receptor with a highly significant elevation in constitutive activity (basal cAMP accumulation for wild type expressing cells 199 +/- 11 pmol/mg protein; double mutant: 374 +/- 29 pmol/mg protein, P < 0.005. The co-expression of the normal MC2R allele results in the retention of a normal dose response to ACTH despite the presence of constitutive activity.

    Title Numerical Simulations of Air-driven Granular Separation.
    Date June 2004
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    Recently it has been shown that binary mixtures of equal-sized fine granular materials exhibit spontaneous separation under vertical vibration in the presence of air [Science 295, 1877 (2002)]. Here we describe a model of this behavior based on soft-sphere molecular dynamics coupled to the motion of the surrounding air. It exhibits many of the features observed experimentally including almost complete separation of the components into well defined regions with extremely sharp boundaries. The basic separation mechanism is robust and insensitive to many of the model parameters. Our results show that the forced flow of air through the bed, induced by vibration of the container, is responsible for this form of separation.

    Title Air-driven Brazil Nut Effect.
    Date May 2004
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    A large heavy object may rise to the top of a bed of smaller particles under the influence of vertical vibration, the "Brazil nut effect." Recently it has been noted that interstitial air can influence the Brazil nut rise time. Here we report that the air movement induced by vertical vibration produces a very strong Brazil nut effect for fine granular beds. We use a porous-bottomed box to investigate the mechanism responsible for this effect and to demonstrate that it is related to the piling of fine beds, first reported by Chladni and studied by Faraday. Both effects are due to the strong interaction of the fine particles with the air, as it is forced through the bed by the vibration.

    Title Expression, Desensitization, and Internalization of the Acth Receptor (mc2r).
    Date August 2003
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Research into the functions and mechanisms of action of the melanocortin 2 receptor (MC2R) has been severely hampered by difficulties in expressing this gene in heterologous cells. This probably arises because of the need for a cofactor for cell surface expression. Using either the Y1 cell line that expresses endogenous MC2R or the Y6 cell line that expresses this putative expression factor, we have explored the mechanisms of desensitization and internalization after agonist stimulation. Protein kinase A dependence of desensitization has been demonstrated, although internalization is apparently independent of this kinase and dependent on a G protein receptor kinase. Possible underlying reasons for this paradox are discussed.

    Title Agonist Activated Adrenocorticotropin Receptor Internalizes Via a Clathrin-mediated G Protein Receptor Kinase Dependent Mechanism.
    Date July 2003
    Journal Endocrine Research
    Excerpt

    The physiological effects of the pituitary hormone, adrenocorticotropic hormone (ACTH) on the adrenal are mediated by the melanocortin 2 receptor (MC2R), a G protein coupled receptor (GPCR) that signals via adenylate cyclase to elevate intracellular cyclic AMP (cAMP) levels. The function and expression of the receptor is likely to be a major determinant of the response to ACTH. Following repeated stimulation, the cAMP signal is diminished or desensitized. Prolonged desensitization may involve internalization of the receptor. Internalization may occur by at least two mechanisms--receptor mediated endocytosis via clathrin-coated pits and by caveolae mediated internalization. The mode of internalization for the endogenous MC2R in Y1 cells was determined using radiolabelled ACTH. Treatment of Y1 cells with hypertonic sucrose or with concanavalin A, which inhibit clathrin-mediated endocytosis, blocked internalization. Filipin and nystatin, which inhibit caveolae formation, did not influence internalization. A dominant negative GRK2 inhibited internalization whilst the protein kinase A (PKA) consensus site mutant MC2R (S208A) internalized normally. However, dominant negative V53D beta-arrestin-1 did not inhibit ACTH internalization in Y1 cells. In conclusion, it appears that the MC2R in Y1 cells internalizes by a G protein coupled receptor kinase (GRK) dependent clathrin-coated pit mechanism.

    Title Impaired Desensitization of a Mutant Adrenocorticotropin Receptor Associated with Apparent Constitutive Activity.
    Date June 2003
    Journal Molecular Endocrinology (baltimore, Md.)
    Excerpt

    A naturally occurring ACTH receptor [melanocortin 2 receptor (MC2R)] mutation (F278C) has been identified in a subject with ACTH-independent Cushing's syndrome. Functional characterization of this mutant receptor reveals that it is associated with elevated basal cAMP accumulation when compared with wild-type receptor-expressing cell lines. Dose responsiveness is similar between wild-type and mutant receptors in cell lines expressing similar numbers of binding sites. In view of the location of this mutation in the C-terminal tail of the MC2R, desensitization and internalization were investigated and found to be impaired. Inhibition of protein kinase A by H89 blocks wild-type MC2R desensitization and also results in increased basal activity, as does alanine substitution of Ser 280 in the C-terminal tail. Alanine substitution of Ser 208, the consensus protein kinase A phosphorylation target in the third cytoplasmic loop also results in a reduction in desensitization without significant change in basal activity or internalization. These findings suggest a novel mechanism is involved in the apparently constitutive activation of the MC2R in which failure of desensitization appears to be associated with enhanced basal receptor activity.

    Title Human Immunodeficiency Virus Type-1 Integrase Containing a Glycine to Serine Mutation at Position 140 is Attenuated for Catalysis and Resistant to Integrase Inhibitors.
    Date April 2003
    Journal Virology
    Excerpt

    L-chicoric acid (L-CA) is a potent inhibitor of HIV integrase (IN) in vitro. In this report, the effects of a glycine to serine mutation at position 140 (G140S) on HIV IN and its effects on IN inhibitor resistance are described. HIV containing the G140S mutation showed a delay in replication. Using real-time polymerase chain reaction, the delay was secondary to a failure in integration. The mutant protein (IN(G140S)) was attenuated approximately four-fold for catalysis under equilibrium conditions compared to wild-type IN (IN(WT)) and attenuated five-fold in steady-state kinetic analysis of disintegration. Fifty percent inhibitory concentration assays were performed with IN inhibitors against both IN proteins in disintegration and strand transfer reactions. IN(G140S) was resistant to both L-CA and L-731,988, a diketoacid. HIV containing the mutation was resistant to both inhibitors as well. The G140S mutation attenuates IN activity and confers resistance to IN inhibitors, suggesting that diketoacids and L-CA interact with a similar binding site on HIV IN.

    Title Autologous Chondrocyte Implantation for Chondral Defects of the Knee: Indications and Technique.
    Date January 2003
    Journal The Journal of Knee Surgery
    Title Failed Export of the Adrenocorticotrophin Receptor from the Endoplasmic Reticulum in Non-adrenal Cells: Evidence in Support of a Requirement for a Specific Adrenal Accessory Factor.
    Date September 2002
    Journal The Journal of Endocrinology
    Excerpt

    Difficulty in expressing the adrenocorticotrophin (ACTH) receptor (melanocortin 2 receptor; MC2R) after transfection of various MC2R expression vectors has been experienced by many researchers. Reproducible evidence for expression has been obtained only in the Y6/OS3 corticoadrenal cell lines or in cells expressing endogenous melanocortin receptors. In order to determine the cause of this failure of expression we have undertaken the following studies. An MC2R expression plasmid was constructed in which the green fluorescent protein (GFP) coding region had been added to the C-terminus of the mature protein. Transfection of this plasmid into Y6 cells with a cAMP-responsive reporter plasmid demonstrated normal function of this receptor. Imaging of CHO cells expressing MC2R-GFP revealed perinuclear expression, although a cholecystokinin receptor (CCKR)-GFP construct was efficiently expressed at the cell surface. Y6 cells, in contrast, showed cell surface fluorescence after transfection with MC2R-GFP. Several other cell types showed a similar pattern of GFP distribution characteristic of retention in the endoplasmic reticulum. Counterstaining with an anti-KDEL antibody confirmed this location. Co-expression of the MC2R and the CCKR-GFP did not impair CCKR trafficking to the cell surface, implying a receptor-specific impairment to trafficking in the CHO cell which was absent in the Y6 cell.

    Title Dicaffeoyltartaric Acid Analogues Inhibit Human Immunodeficiency Virus Type 1 (hiv-1) Integrase and Hiv-1 Replication at Nontoxic Concentrations.
    Date September 2002
    Journal Journal of Medicinal Chemistry
    Excerpt

    The human immunodeficiency virus type 1 (HIV-1) is a major health problem worldwide. In this study, 17 analogues of L-chicoric acid, a potent inhibitor of HIV integrase, were studied. Of these analogues, five submicromolar inhibitors of integrase were discovered and 13 compounds with activity against integrase at less than 10 microM were identified. Six demonstrated greater than 10-fold selectivity for HIV replication over cellular toxicity. Ten analogues inhibited HIV replication at nontoxic concentrations. Alteration of the linkages between the two bis-catechol rings, including the use of amides, mixed amide esters, cholate, and alkyl bridges, was explored. Amides were as active as esters but were more toxic in tissue culture. Alkyl and cholate bridges were significantly less potent against HIV-1 integrase in vitro and were inactive against HIV-1 replication. Two amino acid derivates and one digalloylderivative of L-chicoric acid (L-CA) showed improved selectivity over L-CA against integration in cell culture. These data suggest that in addition to the bis-catechols and free carboxylic acid groups reported previously, polar linkages are important constituents for optimal activity against HIV-1 integrase and that new derivatives can be developed with increased specificity for integration over HIV entry in vivo.

    Title Spontaneous Air-driven Separation in Vertically Vibrated Fine Granular Mixtures.
    Date April 2002
    Journal Science (new York, N.y.)
    Excerpt

    We report the observation of the spontaneous separation of vertically vibrated mixtures of fine bronze and glass spheres of similar diameters. At low frequencies and at sufficient vibrational amplitudes, a sharp boundary forms between a lower region of glass and an upper region of the heavier bronze. The boundary undergoes various oscillations, including periodic tilting motion, but remains extremely sharp. At higher frequencies, the bronze separates as a mid-height layer between upper and lower glass regions, and the oscillations are largely absent. The mechanism responsible for the separation can be traced to the effect of air on the granular motion.

    Title Knee Pain in a 16-year-old Girl.
    Date December 2001
    Journal Clinical Orthopaedics and Related Research
    Title Exterior Carpi Radialis Longus Tendinoplasty for Thumb Basal Joint Arthritis.
    Date July 2001
    Journal American Journal of Orthopedics (belle Mead, N.j.)
    Excerpt

    Thumb carpometacarpal arthritis has been successfully treated with a combination of trapezium excision, ligament reconstruction, and tendon interposition (most commonly with the flexor carpi radialis [FCR] tendon). We describe a technique using the extensor carpi radialis longus (ECRL) tendon and show, through dissection of 36 cadaver hands, the close relationship between this tendon and the intermetacarpal ligament. Of 16 patients (19 hands) managed with this technique, 95% were satisfied at a mean follow-up of 42 months. We conclude that ligament reconstruction and ECRL tendon interposition constitute a viable treatment option for carpometacarpal joint arthritis, especially when the FCR tendon is unavailable or its use is undesirable.

    Title Experimental Confirmation of the Predicted Shallow Donor Hydrogen State in Zinc Oxide.
    Date June 2001
    Journal Physical Review Letters
    Excerpt

    We confirm the recent prediction that interstitial protium may act as a shallow donor in zinc oxide, by direct spectroscopic observation of its muonium counterpart. On implantation into ZnO, positive muons--chemically analogous to protons in this context--form paramagnetic centers below about 40 K. The muon-electron contact hyperfine interaction, as well as the temperature and activation energy for ionization, imply a shallow level. Similar results for the cadmium chalcogenides suggest that such shallow donor states are generic to the II-VI compounds. The donor level depths should serve as a guide for the electrical activity of interstitial hydrogen.

    Title Structure-activity Relationships: Analogues of the Dicaffeoylquinic and Dicaffeoyltartaric Acids As Potent Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and Replication.
    Date March 1999
    Journal Journal of Medicinal Chemistry
    Excerpt

    The dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase. They also inhibit HIV-1 replication at nontoxic concentrations. Since integrase is an excellent target for anti-HIV therapy, structure-activity relationships were employed to synthesize compounds with: (1) improved potency against HIV-1 integrase, (2) improved anti-HIV effect in tissue culture, and (3) increased selectivity as indicated by low cellular toxicity. Thirty-four analogues of the DCTAs and DCQAs were synthesized and tested for cell toxicity, anti-HIV activity, and inhibition of HIV-1 integrase. Seventeen of the 34 analogues had potent activity against HIV-1 integrase ranging from 0. 07 to >10 microM. Seventeen analogues that were synthesized or purchased had no inhibitory activity against integrase at concentrations of 25 microM. Of the biologically active analogues, 7 of the 17 inhibited HIV replication at nontoxic concentrations. The most potent compounds were D-chicoric acid, meso-chicoric acid, bis(3,4-dihydroxydihydrocinnamoyl)-L-tartaric acid, digalloyl-L-tartaric acid, bis(3,4-dihydroxybenzoyl)-L-tartaric acid, dicaffeoylglyceric acid, and bis(3, 4-dihydroxyphenylacetyl)-L-tartaric acid. Anti-HIV activity of the active compounds in tissue culture ranged from 35 to 0.66 microM. Structure-activity relationships demonstrated that biscatechol moieties were absolutely required for inhibition of integrase, while at least one free carboxyl group was required for anti-HIV activity. These data demonstrate that analogues of the DCTAs and the DCQAs can be synthesized which have improved activity against HIV integrase.

    Title Resistance to the Anti-human Immunodeficiency Virus Type 1 Compound L-chicoric Acid Results from a Single Mutation at Amino Acid 140 of Integrase.
    Date October 1998
    Journal Journal of Virology
    Excerpt

    L-Chicoric acid is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase in vitro and of HIV-1 replication in tissue culture. Following 3 months of selection in the presence of increasing concentrations of L-chicoric acid, HIV-1 was completely resistant to the compound. Introduction of the mutant integrase containing a single glycine-to-serine amino acid change at position 140 into the native, L-chicoric acid-sensitive virus demonstrated that this change was sufficient to confer resistance to L-chicoric acid. These results confirm through natural selection previous biochemical studies showing that L-chicoric acid inhibits integrase and that the drug is likely to interact at residues near the catalytic triad in the integrase active site.

    Title Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase.
    Date February 1998
    Journal Antimicrobial Agents and Chemotherapy
    Excerpt

    Current pharmacological agents for human immunodeficiency virus (HIV) infection include drugs targeted against HIV reverse transcriptase and HIV protease. An understudied therapeutic target is HIV integrase, an essential enzyme that mediates integration of the HIV genome into the host chromosome. The dicaffeoylquinic acids (DCQAs) and the dicaffeoyltartaric acids (DCTAs) have potent activity against HIV integrase in vitro and prevent HIV replication in tissue culture. However, their specificity against HIV integrase in cell culture has been questioned. Thus, the ability of the DCQAs and DCTAs to inhibit binding of HIV type 1 (HIV-1) gp120 to CD4 and their activities against HIV-1 reverse transcriptase and HIV RNase H were studied. The DCQAs and DCTAs inhibited HIV-1 integrase at concentrations between 150 and 840 nM. They inhibited HIV replication at concentrations between 2 and 12 microM. Their activity against reverse transcriptase ranged from 7 microM to greater than 100 microM. Concentrations that inhibited gp120 binding to CD4 exceeded 80 microM. None of the compounds blocked HIV-1 RNase H by 50% at concentrations exceeding 80 microM. Furthermore, when the effects of the DCTAs on reverse transcription in acutely infected cells were measured, they were found to have no activity. Therefore, the DCQAs and DCTAs exhibit > 10- to > 100-fold specificity for HIV integrase, and their activity against integrase in biochemical assays is consistent with their observed anti-HIV activity in tissue culture. Thus, the DCQAs and DCTAs are a potentially important class of HIV inhibitors that act at a site distinct from that of current HIV therapeutic agents.

    Title Interleukin-1 Beta, Prostaglandin E2, and Immunoglobulin G Subclasses in Gingival Crevicular Fluid in Patients Undergoing Periodontal Therapy.
    Date January 1997
    Journal Journal of Periodontology
    Excerpt

    Determination of the presence of inflammatory products found in gingival crevicular fluid (GCF) may be of value in evaluating both periodontal disease status and the outcome of therapy. Immunoglobulin G subclasses 1 through 4 (IgGs), interleukin 1-beta (IL-1 beta), and prostaglandin E2 (PGE2) have all been shown to be present in GCF. This study monitored IgGs, IL-1 beta, and PGE2 in GCF of 18 adult patients as they progressed through periodontal treatment toward maintenance therapy. Sites were selected from the most severely affected sextant as determined by probeable crevice depth (PD) at initial examination (IE). GCF was collected on four occasions: initial examination; 4 weeks after completion of initial therapy (oral hygiene counseling, and scaling and root planing); 3 months after completion of surgery; and 7 to 9 months later at a maintenance visit. All variables were reduced to binary form (positive or negative), and break points chosen to separate the approximately symmetrical bell-shaped areas (negatives) from the skewed tails (positives). Repeated measures analyses of variance were performed to detect significant changes in all variables across time. Significant improvements were observed for all the clinical variables measured: PD, attachment level, and bleeding on probing. However, significant reductions for the GCF components only occurred in the concentrations of IL-1 beta and PGE2, but were not evident until the maintenance sampling. Surprisingly, GCF:serum ratios of IgG subclasses did not change significantly over the course of the investigation. The robustness of the levels of these components may be due to inflammation associated with the healing process, or to a further plaque induced response.

    Title The Relative Sensitivities of the Axillary and Accessory Nerves in the Diagnosis of Myasthenia Gravis.
    Date May 1994
    Journal Muscle & Nerve
    Title Cervical Magnetic Stimulation.
    Date December 1990
    Journal Neurology
    Excerpt

    We stimulated the cervical region with a 9-cm-diameter magnetic coil on centered on the spinous processes in 21 normal subjects. We obtained maximal amplitudes with clockwise coil current in right-sided upper extremity muscles and counterclockwise coil current in left-sided upper extremity muscles. Optimal stimulation sites for biceps, triceps, and abductor digiti minimi were C-3 or C-4, C-4 or C-5, and C-4, C-5, or C-6, respectively. The latencies of the muscle responses varied little in the same subject in spite of marked amplitude changes due to suboptimal position of the coil or submaximal stimulator output. In abductor digiti minimi, the amplitude of the muscle response on cervical magnetic stimulation was 9 to 100% of the supramaximal amplitude on wrist electrical stimulation. We established normal values for latency, amplitude, and interside differences for the above 3 upper extremity muscles. The findings were reproducible, and the latencies obtained with large coils from different manufacturers in the same subjects were comparable. We found no advantage in bipolar recording over tendon-belly montage. Comparison of magnetic and electrical needle root stimulation in the same subjects showed that the magnetic stimulus was more proximal in biceps and triceps, and that the site of excitation was approximately the same in abductor digiti minimi. Indirect assessment of the longitudinal site of excitation based on F-wave minimal latency indicated that excitation occurred within millimeters of the emergence of axon of the peripheral motor neuron.

    Title Pattern Erg: Effects of Reference Electrode Site, Stimulus Mode and Check Size.
    Date February 1989
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    We studied monocular pattern ERG (PERG) in 10 normal subjects and a patient with optic neuritis. No clinically significant PERG could be recorded from the occluded eye with any reference (ipsilateral ear or temple, or midfrontal), indicating that cross-contamination is not present with binocular testing. Ipsilateral temple reference minimized VEP (P100/N100) contribution to the PERG N95 which occurred with ipsilateral ear or midfrontal reference. The conclusions were confirmed by results from the patient, who had marked monocular delay of a normal amplitude P100. Twenty-four subjects were tested with monocular and binocular stimulation using an ipsilateral temple reference. There were differences in PERG latencies and amplitudes although the interside amplitude ratio showed smaller differences with binocular stimulation. Increasing check size (17, 35 and 70 min) decreased P50 and N95 latencies and increased P50 amplitude.

    Title Evoked Potentials in Motor System Diseases.
    Date February 1988
    Journal Neurology
    Excerpt

    We studied pattern-shift visual (PSVEP), brainstem auditory (BAEP), and somatosensory (SEP) evoked potentials in 38 unselected patients with motor system diseases (MSD) (28 sporadic, 10 familial). PSVEPs were normal in all patients, and BAEPs were normal in all except one with clinical hearing loss who had absent waves I and III and prolonged wave V latencies. Median and tibial SEPs revealed definite CNS conduction abnormalities in only 1 of 30 and 1 of 18 patients, respectively. In addition, four patients had peripheral and four had peripheral or central delays on tibial nerve testing. There were no or only small group differences in central conduction SEP, BAEP, and PSVEP values in patients with normal studies compared with controls. This study suggests that central conduction SEP, BAEP, or PSVEP abnormalities can rarely be attributed to MSD and that their presence in patients suspected of having this disorder should prompt a search for an alternative diagnosis.

    Title Surface Stability of Granular Systems Under Horizontal and Vertical Vibration: the Applicability of a Coefficient of Friction
    Date
    Journal Physical Review. E, Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics
    Excerpt

    We investigate the conditions under which the surface of a granular pile becomes unstable to vibrations. Three stability boundaries are identified, which depend upon the relative phase of the driving forces and the angle of the prepared slope. The experimental findings can be interpreted within the context of a Coulomb friction model and used to define an effective coefficient of friction. For up-hill motion we find that the coefficient of friction depends strongly on the slope angle and that, in general, it requires less vibration to transport grains uphill than would be otherwise expected.

    Title Size Effects and the Problem with Percolation in Nanostructured Transparent Conductors.
    Date
    Journal Acs Nano
    Excerpt

    Much research is underway at present to develop nanostructured transparent conductors for use as electrodes. Transparent electrodes typically require high visible transmittances, T > 90%, and so must be very thin. We show that for most nanostructured films thin enough to display T > 90%, the conduction can be described by percolation theory. This means DC conductivities are lower than in bulk, giving correspondingly higher sheet resistances, R(s). To improve our understanding of the consequences of this, we develop a model which relates T to R(s) in the percolation regime. We define a percolative figure of merit, Π, for which high values result in high T and low R(s). High values of Π are achieved for high DC conductivity and low optical conductivity. In addition, the film thickness, t(min), where the DC conductivity first deviates from its bulk value and the percolation exponent, n, must both be as low as possible. We find that this model fits extremely well to much of the data in the literature. We demonstrate that t(min) scales linearly with the smallest dimension of the nanostructure in question (i.e., diameter for wires or thickness for flakes). This clearly confirms that low diameter nanowires or thin platelets are best for transparent conducting applications. We predict the properties of silver nanowire networks to improve as wire diameter is decreased. Networks of wires with D < 20 nm should display properties superior to the best ITO. We demonstrate the deficiencies of standard bulk theory and the importance of understanding percolation by measuring R(s) and T for networks of silver flakes. We measure the bulk ratio of DC to optical conductivity to be ∼35, suggesting R(s) = 100 Ω/◻ and T = 90% are attainable. However, the large flake thickness results in high t(min) and so low Π, resulting in actual values of T = 26% for R(s) = 100 Ω/◻. This makes this material completely unsuitable for transparent conductor applications.


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