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J R King

Publications and source records attributed to J R King.

At least 37 records · Page 2Linked to original sources
PubMed2000

Response characteristics of an identified, sexually dimorphic olfactory glomerulus.

Partitioning of synaptic neuropil into glomeruli is a common feature of primary olfactory centers in most animal species. The functional significance of glomeruli, however, is not yet well understood. The present study is part of our effort to test the hypothesis that each glomerulus is a functional unit dedicated to processing information about a particular odorant or attribute of odor molecules and that the glomerular array constitutes a map of "odor space." We investigated the physiological and morphological features of uniglomerular projection neurons (PNs) associated with an identified glomerulus in each antennal lobe of the female sphinx moth, Manduca sexta. This "lateral large female glomerulus" (latLFG) is sexually dimorphic and therefore may play a female-specific role, such as processing of information about one or more odorants important for orientation of a female to host plants for oviposition. Together with the medial LFG (medLFG), the latLFG resides outside the array of spheroidal ordinary glomeruli, near the entrance of the antennal (olfactory) nerve. Each LFG is innervated by four to five PNs. Using intracellular recording and staining, we examined the responses of latLFG-PNs to odorants that represent major classes of volatiles released by host plants of M. sexta. All latLFG-PNs were excited when the ipsilateral antenna was stimulated with low concentrations of the monoterpenoid linalool. Dose-response analysis showed that neither other monoterpenoids nor representatives of other classes of host plant volatiles were similarly stimulatory to latLFG-PNs. These findings are consistent with the idea that each glomerulus has a characteristic, limited molecular receptive range.

Action Potentials↗
PubMed1999

Mathematical modelling of avascular-tumour growth. II: Modelling growth saturation.

We build on our earlier mathematical model (Ward & King, 1997, IMA J. Appl. Math Appl. Med. Biol., 14, 39-69) by incorporating two necrotic depletion mechanisms, which results in a model that can predict all the main phases of avascular-tumour growth and heterogeneity. The model assumes a continuum of live cells which, depending on the concentration of a generic nutrient, may reproduce or die, generating local volume changes and thus producing movement described by a velocity field. The necrotic material is viewed as basic cellular material (i.e. as a generic mix of proteins, DNA, etc.) which is able to diffuse and is utilized by living cells as raw material to construct new cells during mitosis. Numerical solution of the resulting system of partial differential equations shows that growth ultimately tends either to a steady-state (growth saturation) or becomes linear. Both the travelling-wave and steady-state limits of the model are therefore derived and studied. The analysis demonstrates that, except in a very special case, passage of cellular material across the tumour surface is necessary for growth saturation to occur. Using numerical techniques, the domains of existence of the large-time solutions are explored in parameter space. For a particular limit, asymptotic analysis makes explicit the main phases of growth and gives the location of the bifurcation between the long-time outcomes.

Models, Biological↗
PubMed1998

Mathematical modelling of the release of drug from porous, nonswelling transdermal drug-delivery devices.

A general model is presented for the release of drug from porous nonswelling, transdermal drug-delivery devices and it is shown to reduce to previously proposed models in suitable limits. The processes which govern the release of drug are considered to be diffusion of dissolved drug and dissolution of dispersed drug, both in the body of the device and in the device pores, and transfer of drug between the two domains. In the classical limit of large dissolution rates, the problem reduces to one of the moving-boundary type, and solution of this problem in the case where the initial drug loading is much greater than the drug solubility in the device yields expressions for the flux of drug to a perfect sink (modelling in vitro conditions). It is shown that behaviour greatly differing from the classical first-order drug delivery (alpha t 1/2) may be exhibited, depending upon the parameter regime. In some situations the dissolution rates may not be so large and solutions of the general model are derived in the case where the dispersed drug is considered to be undepleted and the diffusivity in the solvent-filled pores is much larger than in the body of the delivery device. Numerical studies are undertaken, and the coupling of delivery device and skin-diffusion models (in order to model the complete transdermal drug-delivery process) is also considered.

Administration, Cutaneous↗
PubMed1997

Mathematical modelling of avascular-tumour growth.

A system of nonlinear partial differential equations is proposed as a model for the growth of an avascular-tumour spheroid. The model assumes a continuum of cells in two states, living or dead, and, depending on the concentration of a generic nutrient, the live cells may reproduce (expanding the tumour) or die (causing contraction). These volume changes resulting from cell birth and death generate a velocity field within the spheroid. Numerical solutions of the model reveal that after a period of time the variables settle to a constant profile propagating at a fixed speed. The travelling-wave limit is formulated and analytical solutions are found for a particular case. Numerical results for more general parameters compare well with these analytical solutions. Asymptotic techniques are applied to the physically relevant case of a small death rate, revealing two phases of growth retardation from the initial exponential growth, the first of which is due to nutrient-diffusion limitations and the second to contraction during necrosis. In this limit, maximal and "linear' phase growth speeds can be evaluated in terms of the model parameters.

Animals↗
PubMed1996

Lithium revisited.

Explore the source record for details and available documents.

Bipolar Disorder↗
PubMed1996

A multiple-pathway model for the diffusion of drugs in skin.

A mathematical model for the diffusion of drugs in skin is presented. The penetration of the drug by both transcellular and intercellular pathways, as well as its interchange between these pathways, is considered. A pharmacologically motivated asymptotic limit is identified and analysed to obtain, in particular, an analytical expression for the flux of drug to the blood at steady state. Relevant model data is discussed, and some numerical results are also presented.

Administration, Topical↗
PubMed1994

Laminin in the cutaneous basement membrane as a potential target in lewisite vesication.

The epidermal-dermal junction has a complex molecular architecture, with numerous components playing key roles in adhesion of the epidermis to the dermis. The purpose of this study was to examine structural components of the epidermal-dermal junction as potential targets for toxicity by lewisite (dichloro(2-chlorovinyl)arsine). This was accomplished by (1) immunocytochemical mapping of laminin, type IV collagen, and bullous pemphigoid antigen (BPA) in lewisite-treated isolated perfused porcine skin flaps (IPPSF), (2) evaluation of protease activity in IPPSF blister fluid against laminin substrate from murine EHS tumor and human keratinocytes, and (3) examination of human keratinocyte laminin for direct chemical modification by lewisite. Lewisite-induced epidermal-dermal separation was localized to the lamina lucida. Localization of the separation suggested that laminin, a cysteine-rich and highly protease-sensitive adhesive glycoprotein, is a potential target for lewisite action. It was hypothesized that chemical modification of laminin directly (via chemical alkylation of laminin thiols by the arsenical) or indirectly (due to lewisite-induced cytotoxic release of proteases) could result in blister formation. Employing sensitive methodology, no evidence of proteolytic activity against EHS tumor laminin or human keratinocyte laminin was identified in the blister fluid. In addition, no evidence for direct chemical modification of laminin by lewisite was demonstrated. However, up to 36% of the thiol groups in human keratinocyte laminin immunoprecipitates was potentially available for reaction with alkylating agents. While these studies did not demonstrate a lewisite-induced chemical modification of laminin, they do not rule out the possibility that other adhesive molecules of the basement membrane are targets for lewisite action. Further evaluation of the molecular role that these binding modalities play in vesicant-induced separation may provide new insights into therapeutic and prophylactic strategies against the toxicity of such compounds and contribute to a better understanding of basement membrane biochemistry.

Alkylation↗
PubMed1992

Characterization of lewisite toxicity in isolated perfused skin.

Lewisite (L) is a potent organic arsenical that causes rapid onset of pain and severe vesication on contact with epithelial tissues. The isolated perfused porcine skin flap (IPPSF) is an in vitro model that has shown potential as a model for cutaneous vesicant research. The objective of this study was to characterize IPPSF responses after topical exposure to six concentrations of L ranging from 0.07 to 5.0 mg/ml (n = 4/treatment plus controls). Biochemical markers of viability (glucose utilization (CGU) and lactate dehydrogenase (LDH) release), vascular resistance (VR), venous arsenic flux, and morphological parameters (light and electron microscopy) were evaluated. In addition, lewisite lesions were characterized at 1, 3, 5, and 8 hr after exposure (n = 4/time plus controls) using these morphological parameters, as well as enzyme histochemistry. Macroscopic and microscopic lesions caused by L exposure were dose related. Mild decreases in CGU were noted with the higher concentrations of L, while generally increased responses in LDH release and VR were seen. Marked increases in LDH activity were noted in the blister fluid of IPPSFs treated with 5.0 mg/ml of L. Also, significant cutaneous arsenic flux was noted at the 5.0 mg/ml dose of L. The formation of gross blisters, the location and characterization of epidermal-dermal junction separation, and the time course of lesion production paralleled the description of L-induced lesions in humans. The sensitivity of the IPPSF to L exposure and the similarity of lesions to those described for humans suggests that this model provides a relevant in vitro model with which to study mechanisms of chemical vesication and arsenic toxicity, as well as protective and therapeutic intervention for vesicant exposure.

Administration, Topical↗
PubMed1991

Effects of organic solvent vehicles on the viability and morphology of isolated perfused porcine skin.

Although many organic solvents are known to be cutaneous irritants, they are commonly utilized as vehicles in percutaneous absorption and toxicity studies. The isolated perfused porcine skin flap (IPPSF) is an alternative animal model that has been used to study percutaneous absorption and cutaneous toxicity. The purpose of this study was to evaluate the effect of five organic solvents (ethanol, acetone, dimethyl sulfoxide (DMSO), toluene, and cyclohexane) on biochemical viability parameters, vascular response, and epidermal morphology of the IPPSF. Cumulative glucose utilization (CGU), the ratio of lactate production/glucose utilization (L/CGU ratio), and the leakage of lactate dehydrogenase (LDH) were used as biochemical indicators of alterations in glucose metabolism and flap viability. Only ethanol resulted in a statistically significant decrease in the average rate of CGU over the perfusion period. All of the solvent treatments resulted in slight increases in LDH release versus the controls. Vascular resistance (VR) was measured to examine the response of the cutaneous vasculature to these solvents, and most treatments resulted in a decreased VR in the terminal phases of perfusion. Ethanol was the only solvent to cause an apparent increase in terminal VR. Light microscopy demonstrated a moderate increase in intracellular edema in the DMSO, toluene, and acetone flaps. Ultrastructural evaluation showed focal blebbing of the nuclear envelope and vesiculation of the rough endoplasmic reticulum in cells of the stratum basale and stratum spinosum layers with DMSO treatment. The IPPSF allowed the evaluation of subtle biochemical, vascular, and morphological changes associated with non-occlusive topical exposure to these organic solvents. These findings support the necessity of documenting vehicle effects which might mask or otherwise alter subtle, but potentially important, compound-specific responses.

Acetone↗
PubMed1990

Cutaneous toxicity of 2-chloroethyl methyl sulfide in isolated perfused porcine skin.

Previous research has shown the isolated perfused porcine skin flap (IPPSF) to be a novel in vitro experimental model for investigating xenobiotic percutaneous absorption. In this study, the IPPSF was used to biochemically and morphologically assess the dermatotoxicity of 2-chloroethyl methyl sulfide (CEMS), a monofunctional analog of the vesicant, sulfur mustard. IPPSFs were perfused in a recirculating perfusion system and were treated with 97% CEMS (n = 4) or served as controls (n = 4). Additional IPPSFs were perfused in a nonrecirculating perfusion system and were treated with CEMS (n = 4) or were controls (n = 4). After dosing, each IPPSF was perfused for 8 hr. Cumulative glucose utilization (GU) and lactate production/glucose utilization ratio (L/GU ratio) were used as viability parameters. The average rate of GU for CEMS was significantly lower than control (p less than 0.05) in the recirculating and nonrecirculating IPPSFs. The L/GU ratio for CEMS was not significantly different (p greater than 0.05) from control for either perfusion system. CEMS resulted in a marked increase in vascular resistance versus control in both perfusion systems. Gross vesicles and bullae formation occurred in six of the CEMS-treated IPPSFs. Light microscopy revealed subepidermal vesicle formation above the basement membrane and extensive basal cell pyknosis in all IPPSFs treated with CEMS. No macroscopic or microscopic lesions were noted in the control flaps. Transmission electron microscopy revealed separation between the lamina lucida and the lamina densa of the basal lamina, with intracellular vacuolization and mitochondrial swelling occurring in the stratum basale and stratum spinosum cells of IPPSFs treated with CEMS. These lesions are similar to those described after human exposure to sulfur mustard. Full characterization of the morphological and biochemical changes seen after topical exposure of the IPPSF to vesicants may shed light on the pathogenesis of cutaneous toxicity of these compounds in vivo and serve as a relevant model to assess protective strategies against vesicant exposure.

Animals↗
PubMed1990

Pharmacokinetics of lithium in patients treated with controlled release lithium formulations.

There has long been discussion as to the relative merits of the lithium formulations available in the UK. Two of these have been shown to exhibit similar pharmacokinetics in normal volunteers and both are now marketed as controlled release formulations. In this study the serum lithium profiles of these formulations were compared in patients at two centres during the first 4 h after the dose, and at 24 h. We were unable to show any significant difference between the formulations in respect of maximum serum lithium concentrations or the concentration at each time point.

Adult↗
PubMed1989

Sparrows discriminate between diets differing in valine or lysine concentrations.

White-crowned Sparrows (WCS) were given free access to pairs of semisynthetic diets that were either adequate or subadequate (25% of requirement) in valine or lysine. Within 2 to 4 days WCS chose a ratio of the paired diets that allowed them to maintain body mass or restore any losses quickly. On the initial choice days the birds transiently reduced total daily food intake (TDFI) roughly in proportion to their intake of the subadequate diet. The initial decrease of TDFI was greater and the latency in choosing an effective ratio of the paired diets was 2-3 days longer with valine than with lysine diets in well-nourished test birds. In malnourished birds fed only the subadequate test diet for 3 days, valine-deficient birds increased TDFI and body mass more promptly than did lysine-deficient birds when offered a choice of adequate and subadequate diets. The form of the test amino acid (CAA = crystalline, PB = protein-bound) had little effect on choice behavior, but sudden transfer of WCS from a PB acclimation diet to test diets with a large total CAA concentration increased the latency of effective choice by 2-3 days. A brief acclimation (2-3 days) to a CAA diet precludes any bias between nutritionally equivalent CAA and PB diets. The small differences in choice dynamics between valine and lysine and between dietary forms may help to identify mechanisms involved in food choice but are probably ecologically insignificant to free-living WCS. These birds are very adept at selecting diets that satisfy their amino acid requirements.

Animals↗