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Biomedical subjects

L G Gordon

Publications and source records attributed to L G Gordon.

At least 19 recordsLinked to original sources
PubMed1994

Problems in the understanding of cell volume regulation.

The constancy of cell volume under physiological conditions is generally thought to reflect a balance between solute influx and efflux and is therefore critically dependent on the properties of the plasma membrane. Despite a number of unanswered questions, a large amount of experimental data can be accommodated within this pump-leak framework and can by analysed using the simple assumptions of osmotic equality between cells and their surrounding fluid, and fluid electroneutrality. Experimentally, cell volume may be altered in vitro either by changing cell solute content under isosmotic conditions or by changing medium osmolality. Exposure to anisosmotic media may provoke a variety of cell responses that minimise the volume change. However, much of this experimental work has been performed under extreme conditions in vitro that would never be experienced by vertebrate cells in vivo; its relevance to pathophysiological situations is questionable. It is argued that regulation of cell volume should not be seen in isolation but as part of the process, cell homeostasis, by which cells attempt to minimise changes in composition when faced with perturbations in their environment. Given the variety of processes and the large numbers of membrane transporters, an understanding of how cells respond to such perturbations requires a combination of modelling and experimentation. A simple example of this approach is presented.

Animals↗
PubMed1994

Mapping quantitative trait loci for ethanol-induced anesthesia in LSxSS recombinant inbred and F2 mice: methodology and results.

QTL (quantitative trait locus) mapping is an exciting new technique currently being applied to many quantitative traits. We review the animal models and molecular genetic techniques of QTL mapping with particular reference to ethanol-induced anesthesia (sleep time). Sleep time is an easily obtained measure of initial sensitivity to ethanol. We are using three-stage strategy to map QTLs causing the difference in sleep time between selected strains of mice. This project has been expedited by the use of polymorphic genetic markers (simple sequence repeats) which are amplifiable by the polymerase chain reaction. Over 115 strain distribution patterns have been characterized in the 27 LSxSS recombinant inbred strains. Provisional QTLs have been identified in the RI strains and will be confirmed or rejected in an F2 population of 1063 mice. A new statistical technique, interval mapping, allows the use of all polymorphic markers simultaneously to locate QTLs.

Anesthesia↗
PubMed1992

Electrical transients produced by the toad bladder in response to altered serosal composition at constant osmolality.

The effects of step-changes in the ionic composition of the serosal medium bathing the toad urinary bladder under voltage-clamped conditions have been studied. A decrease in the K+ concentration from 4 to 3 mmol/l in the serosal fluid increased transiently the transepithelial current which after 30 min returned to the initial value. The peak current was reached after 3 min. The current response of the bladder to the reverse step in K+ concentration, from 3 to 4 mmol/l was much smaller. Surprisingly, the partial replacement of Cl- with gluconate produced a transient increase in current. It is suggested that secondary active transport plays an important role in this phenomenon and leads to an increased apical Na+ conductance. The second phases of the biphasic responses to Na/K+ and Cl-/gluconate substitutions have been interpreted as osmotic effects. Since the exchange of solutions in these studies was isoosmotic but not necessarily isotonic, experiments were also performed with osmotic changes in the serosal fluid for the purpose of comparison.

Animals↗
PubMed1991

Contributions of secondary active transport processes to membrane potentials.

Equations are developed to examine the effects of secondary active transport processes on the steady-state membrane potential of symmetrical cells. It is shown that, with suitable modifications, equations of the type developed by Goldman, Hodgkin and Katz may be derived to accommodate the contributions to the membrane potential of both electroneutral and electrogenic transporters. Where the membrane potential is a function of the dominant medium ions (Na, K, and Cl), other contributions can come only from an electrogenic Na pump and from neutral co- and counter-transporters if, and only if, these involve the dominant ions. Experimental approaches to measure the parameters necessary to solve the equations developed here are discussed.

Animals↗
PubMed1991

Application of membrane potential equations to tight epithelia.

It is shown that equations developed to analyze the contributions of secondary active transport processes to symmetrical cells (Gordon, L.G.M., Macknight, A.D.C., 1991, J. Membrane Biol. 120:139-152) can be used, with minor modifications, to analyze the steady-state membrane potential in epithelia under the unique situation of short circuiting. Only under such conditions is there a single intracellular potential relative to both the mucosal and serosal media. The equations are investigated in relation to a model tight epithelium--the toad urinary bladder. It is shown that the properties of the membrane transport pathways are such that the intracellular potential under short-circuit conditions must be more negative than often reported. Given measurements of membrane potential and of voltage-divider ratio, it is possible to use the equations to estimate the absolute values of the membrane permeabilities and conductances under short-circuit conditions.

Animals↗
PubMed1991

Poor prognosis for malignant melanoma in Northern Ireland: a multivariate analysis.

All cases of cutaneous malignant melanoma, CMM, diagnosed in Northern Ireland between 1974-1978 were reviewed, classified and followed up until the end of 1984. The overall 5 year survival is 54%, among the worst reported in recent literature. Multivariate analysis of these cases confirms some previous findings from other studies, but also reveals features not apparent in univariate analysis. Prognosis worsens with increasing thickness and the presence of ulceration. Likewise histopathological type has an independent effect on survival, ALM having the worst prognosis. Tumour profile emerges as a significant feature affecting prognosis, flat lesions having the poorest outlook, given their thickness. Survival is worse with increasing age. Anatomical site is less important than suggested by previous univariate analysis. Sex has little influence on prognosis when adjusted for the other variables. Cell type and pigmentation are of no prognostic value. Several features including diagnostic delay contribute to the poor overall survival for CMM in Northern Ireland. Educational intervention is essential if this trend is to be reversed.

Female↗
PubMed1990

Transient electrical phenomenon of the voltage-clamped toad urinary bladder.

1. The effects of changes in voltage on the transepithelial current through the toad urinary bladder have been studied using Ussing chambers. 2. Step changes in voltage produced two transient currents of duration seconds and minutes respectively. 3. Amiloride, which was used to block all active transport, also eliminated the transient nature of the current responses, indicating that the phenomena were cellular in origin. In the presence of amiloride, amphotericin B regenerated the short-circuit current and the transient behaviour. 4. The effects of substituting gluconate for Cl- in the medium were examined. Similar transient responses were observed, indicating that they were not due to changes in a plasma membrane Cl- conductance. 5. The shape and magnitude of the first current transient changed with (i) changes in the mucosal Na+ concentration, (ii) the magnitude of the transepithelial voltage step, (iii) the addition of antidiuretic hormone, (iv) changes in the serosal K+ concentration, or (v) the addition of ouabain. 6. The second current transient was similarly affected by such challenges. 7. In some bladders the voltage step produced current oscillations similar to those obtained after the epithelium had been challenged with a serosal osmotic step (Gordon, 1988). 8. The results suggest that two major processes are initiated by a transepithelial voltage step. The first involves a change in the K+ conductance of the basolateral membrane and the second is associated with the alteration of cellular ion content and Na+ pump rate.

Action Potentials↗
PubMed1988

Electrical transients produced by the toad urinary bladder in response to altered medium osmolality.

1. The effects of changes in media osmolality on the transepithelial current through the toad urinary bladder under voltage-clamp conditions have been studied. Over the limited range (+/- 24 mosmol/kg H2O) used in these investigations, changes in the osmolality of the mucosal bathing fluid produced no changes in transepithelial current. 2. Changes in osmolality of the serosal fluid greatly affected the transepithelial current with a decrease (increase) in osmolality producing a sustained increase (decrease) in current. 3. The changes in steady-state current were approximately proportional to the magnitude of the osmotic steps and were reproducible and reversible if the osmolalities of the solutions were confined to a domain of 220-260 mosmol/kg H2O. 4. Amiloride, which was used to block all active current, also eliminated the electrical responses to an osmotic pulse, indicating that the responses were of cellular origin. 5. The effects of substituting gluconate for medium chloride were examined. Similar responses were observed, indicating that they were not due to changes in a plasma membrane chloride conductance. 6. The transient currents observed during the changes from one steady state to the other often contained an oscillatory component, the amplitude and the degree of damping of which varied between bladders. The amplitude of the oscillations, but not their frequency, could be varied by altering the magnitude of the osmotic pulse and by changing the imposed transepithelial voltage. Decreasing the electrical potential of the mucosal solution with respect to that of the serosal solution decreased the amplitude of the oscillations, as did increased serosal potassium or substitution of gluconate for serosal chloride. The period of the oscillations always remained within the range of 9-12 min. 7. The results suggest that two major processes are initiated by an osmotic step in the serosal bathing medium. The first involves the establishment of new ion gradients and the second, alterations in sodium pump activity. In addition, there is evidence for a voltage-dependent sodium conductance in the apical membrane.

Action Potentials↗
PubMed1986

The incidence and pathogenesis of invasive cutaneous malignant melanoma in Northern Ireland.

Three hundred and four suspected cases of malignant melanoma diagnosed in Northern Ireland over a 5 year period have been reviewed. Two hundred and forty fulfilled the diagnostic criteria of invasive cutaneous malignant melanoma (CMM) and were accepted as suitable for analysis an incidence of 3.12. The female to male ratio for CMM in this study is 3:1. This excess of female lesions occurs at all major anatomical sites and for all tumour types. There are many thick melanomas in the province, and 67% of cases were greater than 1.7 mm thick. Each tumour type has a distinctive age curve. The implications of these findings are discussed. The evidence suggests that intrinsic factors are as important as extrinsic factors.

Adult↗
PubMed1980

Effect of amiloride on conductance of toad urinary bladder.

The transepithelial conductance of toad bladder epithelia and the amplitude of the fluctuations of this conductance caused by the action of the underlying smooth muscle have been further investigated. In particular, amiloride was found to reduce both tissue conductance and its fluctuating component to the same extent. Analysis suggests that the steady-state conductance of the toad urinary bladder may be associated only with the paracellular pathway for ions.

Amiloride↗
PubMed1978

Cellular and shunt conductances of toad bladder epithelium.

Toad urinary bladders were mounted in Ussing-type chambers and volt-age-clamped. At nonzero voltages only, small fluctuations in current, delta I, and therefore in tissue conductance, delta Gt, were detected. These fluctuations were caused by the smooth muscle of the underlying tissue which could be monitored continuously and simultaneously with the current, I. Inhibition of the smooth muscle contraction with verapamil (2 X 10(-5) M) abolished the fluctuations in I and Gt. Amiloride (10(-4) M) had no significant effect on the magnitude of delta Gt, oxytocin increased Gt without affecting delta Gt, and mucosal hypertonicity produced by mannitol increased delta Gt. These results are consistent with the hypothesis that two parallel pathways exist for passive current flow across the toad urinary bladder: one, the cellular pathway, was not affected by smooth muscle activity; the other, the paracellular pathway, was the route whose conductance was altered by the action of the smooth muscle. Thus the relationship between the cellular and shunt conductances of the epithelium of the toad urinary bladder, under a variety of conditions, can be investigated by utilizing the effects of the movement of the smooth muscle.

Amiloride↗
PubMed1976

Kinetics and stability of alamethicin conducting channels in lipid bilayers.

It is already well-established that conduction in lipid bilayers containing alamethicin arises from the presence of complexes in which there are several molecules of the polypeptide. It is with the nature of these complexes that this paper is primarily concerned. While it is clear that increasing alamethicin concentration and increasing potential across the membrane favour their formation, the nature of the reactions involved has not yet been elucidated. Attempts have therefore been made to clarify the sequence of events leading to the establishment of a complex in its conducting state. It has been concluded that the most likely mechanism involves, initially, a non-field-dependent aggregation of the alamethicin, in the plane of the membrane, into non-conducting oligomers. These then appear to undergo movement normal to the membrane (which is field dependent) to form the conducting species. Temperature studies have shown that the various conducting states of the oligomer have effectively equal enthalpies, and that the activation energies for transitions between these states are all approx. 1.2kcal/mol. The corresponding rate constants are very sensitive to the lipid composition of the membrane and a variety of different systems has been examined in order to clarify the origins of this effect. The only conclusion from this part of the work is that lipid fluidity might be involved.

Alamethicin↗
PubMed1975

Potential-dependent conductances in lipid membranes containing alamethicin.

This article is concerned primarily with the mechanism of the potential-dependent conductance induced in artificial lipid membranes by the cyclic polypeptide andibiotic alamethicin. It has already been shown from studies of the fluctuations that can be detected in very small membrane currents that alamethicin forms transient pores of some 0.6 nm in diameter and that, for small inorganic ions, these are poorly selective. The origin of these pores, their spatial distribution and interaction are discussed. It is demonstrated that the sensitivity of the membrane conductance to the applied potential arises only to a slight extent from the current-voltage relations for the individual pores, and that the main effect stems from the influence of the potential on the frequency of opening of the pores. From the properties of lipid membranes containing alamethicin in a wide variety of electrolytes, and from other evidence, it is concluded that the polypeptide reacts to the electric field more probably because it has dipole moment than because it binds ions. It is proposed that the conducting complex is capable of functioning in either of two orientations, and that it is these two possibilities that give rise to certain differences in the single channel characteristics for the two directions of the field.

Alamethicin↗