Biomedical subjects

K Lawson

Publications and source records attributed to K Lawson.

At least 19 recordsLinked to original sources

PubMed2006

Modulation of potassium channels as a therapeutic approach.

Regulation of potassium (K+) channels evokes hyperpolarization or repolarization of the cell membrane to prevent or reverse cell excitability and is fundamental in the control of cellular activity throughout the range of tissue types within the human body. Genome projects predict that in excess of 80 K+ channel-related genes exist, resulting in a high degree of K+ channel diversity. In addition, dysfunction of K+ channels, as a result of mutations of the genes for the channel proteins or alterations in channel regulation, has been associated with the pathophysiology of diseases. These observations support K+ channels as therapeutic targets to regulate cellular homeostasis in pathophysiological conditions. Molecular cloning and expression of K+ channels offer important information in the identification of selective compounds to provide unique tissue management. Specific modulators have been identified for a limited number of K+ channel subtypes. Unfortunately the conversion of data obtained in the laboratory to success in the clinical setting has been limited. Tissue delivery of genes, in combination with drugs, may be an avenue enabling specific modulation of ion channel function and improved drug selectivity. Using specific examples (HERG, IKs, KCNQs, KCa, Kv1.3), issues regarding distribution, function and diversity related to advances made in the identification of modulators having therapeutic potential are discussed. The scope of this field is just emerging and the number of likely therapeutic indications for K+ channel modulators will increase as insight into the dynamics of expression of these channels in various diseases grows and the issue of the required selectivity is resolved.

Animals↗

PubMed2002

Alpha-tail production with ion-cyclotron-resonance heating of 4He-beam ions in JET plasmas.

Third-harmonic ion-cyclotron-resonance heating of 4He-beam ions has produced for the first time on the JET tokamak high-energy populations of 4He ions to simulate 3.5 MeV fusion-born alpha (alpha) particles. Acceleration of 4He ions to the MeV energy range is confirmed by gamma-ray emission from the nuclear reaction 9Be(alpha,ngamma) 12C and excitation of Alfvén eigenmodes. Concomitant electron heating and sawtooth stabilization are observed. The scheme could be used in next-step tokamaks to gain information on trapped alpha particles and to test alpha diagnostics in the early nonactivated phase of operation.

Journal Article↗

PubMed2002

Is hemifacial microsomia linked to multiple maternities?

Hemifacial microsomia describes a congenital orofacial malformation in which there is insufficient or disrupted development of the mandible affecting one side of the face. The aetiology of this condition remains unclear, but it has been postulated that twins (predominantly monozygotic) are more liable to be affected than singletons. This study investigates the incidence of multiple births amongst a large number of affected individuals and their families. Data were collected on 145 individuals with hemifacial microsomia and microtia, using postal questionnaires and interviews in a hospital setting. These data were compared with the mean age-standardised twin maternity prevalence for England and Wales between 1975 and 1995 of 1.06% and the triplet maternity prevalence for England and Wales for 1995 of 0.034% (a multiple maternity being where more than one baby is born, either alive or stillborn). The prevalence of twin maternities amongst the affected individuals was 3.96% (P>0.05) and amongst their siblings it was 4.02% (P<0.02). There was also an excess of twins in the rest of the family groups, predominantly due to a stronger history of twinning on the maternal side. As there were more twins amongst the affected individuals than in the general population, it seems likely that whatever the aetiology of hemifacial microsomia and microtia, the presence of a co-twin (or co-triplets) may make the causal event, or series of causal events, more likely to occur. This study supports the hypothesis that hemifacial microsomia and microtia are in some way linked to multiple births. Analysis of this link may provide new directions for research into the aetiology of a variety of congenital defects.

Diseases in Twins↗

PubMed2001

Peripheral channelopathies as targets for potassium channel openers.

Potassium channel openers (KCOs) are important tools that are often used to gain a greater understanding of K(+) channels. Agents that can induce or maintain the opening of K(+) channels also offer a therapeutic approach to controlling of cell excitability and offer a means of producing stability in biological systems. The pathogenesis of a broad range of peripheral disorders (e.g., LQT syndrome, hypokalemic periodic paralysis, hyperinsulinism in infancy and erectile dysfunction) are associated with dysfunctional K(+) channels due to mutations in genes encoding channel proteins. The therapeutic potential of KCOs in peripheral K(+) channelopathies is discussed. The identification of K(+) channel subtype-specific openers offers discrete modulation of cellular systems creating a realistic therapeutic advance in the treatment of K(+) channelopathies.

Adenosine Triphosphatases↗

PubMed2000

Effect of mu-calpain on m-calpain.

The free Ca(2+) concentrations required for half-maximal proteolytic activity of m-calpain are in the range of 400-800 microM and are much higher than the 50-500 nM free Ca(2+) concentrations that exist in living cells. Consequently, a number of studies have attempted to find mechanisms that would lower the Ca(2+) concentration required for proteolytic activity of m-calpain. Although autolysis lowers the Ca(2+) concentration required for proteolytic activity of m-calpain, 90-400 microM Ca(2+) is required for a half-maximal rate of autolysis of m-calpain, even in the presence of phospholipid. It has been suggested that mu-calpain, which has a lower Ca(2+) requirement than m-calpain, might proteolyze m-calpain and reduce its Ca(2+) requirement to a level that would allow it to be active at physiological Ca(2+) concentrations. We have incubated m-calpain with mu-calpain for 60 min at a ratio of 1:50 mu-calpain:m-calpain, in the presence of 50 microM free Ca(2+); this Ca(2+) concentration is high enough for more than half-maximal activity of mu-calpain, but does not activate m-calpain. Under these conditions, mu-calpain caused no detectable proteolytic degradation of the m-calpain polypeptide and did not change the Ca(2+) concentration required for proteolytic activity of m-calpain. mu-Calpain also did not degrade the m-calpain polypeptide at 1000 microM Ca(2+), which is a Ca(2+) concentration high enough to completely activate m-calpain. It seems unlikely that mu-calpain could act as an "activator" of m-calpain in living cells. Because m-calpain rapidly degrades itself (autolyzes) at 1000 microM Ca(2+) and because the subsite specificities of mu- and m-calpain are very similar if not identical, failure of mu-calpain to rapidly degrade m-calpain at 1000 microM Ca(2+) suggests a unique role of autolysis in calpain function.

Animals↗

PubMed2000

Gender, ethnicity and self-reported health: the case of African-Caribbean populations in London.

This paper explores quantitative and qualitative information on self-reported health, focusing especially on gender differences in the reporting of health problems by men and women. The research reported here particularly examines evidence relating to the African-Caribbean population in London, some of which suggests that there may be a distinctive pattern of reported illness in this ethnic group in Britain, which differentiates it from the average pattern for the majority population. Various population surveys using systematic measures have shown that women and men differ in terms of reported morbidity (particularly in the prevalence of self-reported illness and psychosocial health). This paper reviews the quantitative data available to investigate the gender differences in the African-Caribbean population, showing that the pattern seems to vary according to the measure of health used. We consider how qualitative material from research conducted in East London may complement quantitative survey data and provide possible explanations for the reported health of African-Caribbean women and men. We report on qualitative observations of the process of completing standardized questionnaire items and discussion of these by the informants. We also examine the understandings about health and illness expressed by African-Caribbean women and men during in-depth interviews.

Adolescent↗

PubMed2000

Potassium channel openers as potential therapeutic weapons in ion channel disease.

The opening of potassium (K+) channels, causing hyperpolarization of the cell membrane, is a physiological means of decreasing cell excitability. Thus, drugs with this property will demonstrate a broad clinical potential. The identification of synthetic molecules that evoke physiological responses (for example smooth muscle relaxation) by the opening of K+ channels led to a new direction in the pharmacology of ion channels. The term "potassium channel openers" was initially associated with a group of chemically diverse agents (for example, cromakalim, pinacidil, nicorandil) that evoke K+ efflux through adenosine 5'-triphosphate (ATP)-sensitive K+ channels (KATP). This finding initiated a search to identify molecules that specifically open other K+ channel subtypes (for example large conductance calcium-activated K+ channels [BKCa]). K+ channel opening properties have been demonstrated in a diverse range of synthetic chemical structures and endogenous substances. Second generation KATP channel openers (KATPCOs) demonstrate heterogeneous pharmacology indicative of independent sites of action for the different agents. Successful cloning of the KATP channel has shed light on the heterogeneity of the structure targeted by KATPCOs. Expression of the actions of KATPCOs involves three isoforms of the sulfonylurea (SUR) receptor (which forms the beta subunit of the KATP channel). The distribution of the SUR isoforms (and potential of identifying new isoforms) provides unique targets for the development of selective KATPCOs giving focused therapeutic approaches to clinical conditions for example cardiac ischemia, urinary incontinence, neurodegeneration, obesity and autoimmune diseases. BKCa channels are found in a diverse array of tissues and due to voltage and Ca sensitivity may work as a negative feedback process. A variety of small synthetic molecules (for example, NS004, fenamates) and natural product-derived compounds (DHS-I, maxikdiol) have been identified as selective BKCa channel openers which should have a profound impact in controlling diseases. The discovery of numerous variants of the alpha subunit (ion conductance pore) and beta subunit (contributes biophysical and pharmacological properties) complex of the BKCa channel gives potential to target specific tissues with selective openers. Little is known, however, about the site(s) of interaction of openers of these channels. The discovery of K+ channel subtype-specific openers and their evaluation in different diseases will determine the degree to which these channels (KATP, BKCa), or their isoforms, represent realistic therapeutic targets. Drugs already marketed that open K+ channels were discovered empirically, and most have serious safety and efficacy problems. New scientific methods, utilizing molecular insight, are implicating K+ channel dysfunction in numerous disease states and are identifying new targets for the future generation of K+ channel opening drugs.

Adenosine Triphosphate↗

PubMed2000

Is there a role for potassium channel openers in neuronal ion channel disorders?

Malfunction in ion channels, due to mutations in genes encoding channel proteins or the presence of autoantibodies, are increasing being implicated in causing disease conditions, termed channelopathies. Dysfunction of potassium (K(+)) channels has been associated with the pathophysiology of a number of neurological, as well as peripheral, disorders (e.g., episodic ataxia, epilepsy, neuromyotonia, Parkinson's disease, congenital deafness, long QT syndrome). K(+) channels, which demonstrate a high degree of diversity and ubiquity, are fundamental in the control of membrane depolarisation and cell excitability. A common feature of K(+) channelopathies is a reduction or loss of membrane potential repolarisation. The identification of K(+) channel subtype specific openers will allow the recovery of the mechanism(s) responsible for counteraction of uncontrolled cellular depolarisation. Synthetic agents that demonstrate K(+) channel opening properties are available for a variety of K(+) channel subtypes (e.g., K(ATP), BK(Ca), GIRK and M-channel). This study reviews the realistic therapeutic potential that may be gained in a broad spectrum of clinical conditions by K(+) channel openers. K(+) channel openers would therefore identify dysfunctional K(+) channel as therapeutic targets for clinical benefit, in addition being able to modulate normally functioning K(+) channels to gain clinical management of pathophysiological events irrespective of the cause.

Aminopyridines↗

PubMed2000

British Pharmacological Society Cambridge Symposia. 5-7 January 2000, Cambridge, UK.

This meeting covered a broad range of pharmacological topics, although the main themes were covered in four mini-symposia. This report concentrates on the cannabinoid, pain and cardiac ischemia symposia. The cannabinoid system was identified as a major area of potential therapeutic interest, offering a number of clinical targets that may be modified through the actions of selective ligands. Novel approaches to the treatment of neurogenic pain, where conventional analgesics have limited value, are being explored with significant success. The role of delayed preconditioning in cardiac ischemia was also addressed as a mechanism of cardioprotection.

Journal Article↗

PubMed1999

Cannabinoids.

The British Pharmacological Society conference commenced with the GC Clark symposium on cannabinoids (CBs), an area that was often represented during the general pharmacology sessions of the conference. Endocannabinoids were identified as playing important physiological roles and the CB receptors appear to offer novel therapeutic targets in a range of clinical conditions. This report concentrates on the CB aspects of the meeting.

Journal Article↗

PubMed1999