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Biomedical subjects

K Lawson

Publications and source records attributed to K Lawson.

At least 19 recordsLinked to original sources
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↗
PubMed1997

Effects of K+ channel inhibitors and antagonists on NS-004 evoked relaxations in guinea-pig isolated trachea.

The smooth muscle relaxant responses to NS-004, an activator of charybdotoxin-sensitive, large conductance Ca(2+)-dependent K+ channels (BKCa) were studied on the basal spontaneous tone in guinea-pig trachea in vitro. The sensitivity of these responses to a range of K+ channel inhibitors and antagonists were also evaluated. NS-004 (0.1-30 microM) evoked concentration-related relaxations (pIC50 5.48 +/- 0.13) on the spontaneous tone in guinea-pig tracheal rings, suspended in Krebs bicarbonate solution, with a maximum response not different to that to aminophylline (1 microM). Charybdotoxin (0.03 and 0.1 microM) or iberiotoxin (0.1 microM) significantly displaced the NS-004 concentration-response curve to the right of control with no change in maximum response. In contrast, glibenclamide (1.0 microM) apamin (0.1 microM) and dofetilide (1.0 microM) each failed to modify the responses to NS-004 on spontaneous tone in guinea-pig trachea. These results suggest that relaxations in guinea-pig tracheal smooth muscle to the substituted benzimidazolone, NS-004, involve the activation of BKCa channels.

Animals↗
PubMed1997

Patterns of cognitive development in very low birth weight children during the first six years of life.

BACKGROUND: Cognitive development in very low birth weight (VLBW, < or = 1500 g) infants typically has been reported based on mean endpoints in cross-sectional studies. These overall group means mask individual patterns of cognitive development. Given the heterogeneity of VLBW infants, it is important to identify individual patterns of development and the factors associated with the different patterns. OBJECTIVE: We sought to determine individual patterns of cognitive development over the first 6 years in VLBW children and to examine the relative influence of selected biomedical and sociodemographic factors on these patterns. METHOD: VLBW infants (N = 203) were followed from birth to six years. Cognitive scores were obtained at four yearly intervals, and biomedical and social data were obtained beginning with the neonatal period. Cluster analysis was used to identify individual patterns of cognitive development. RESULTS: Five developmental patterns were identified: average-stable (13% of the sample); average-declined to low average (24% of the sample); average-declined to below average (43% of the sample); very low-increased to low average (8% of the sample); and very low-stable (12% of the sample). The patterns could be differentiated by several biomedical factors, including birth weight, gestational age, neonatal health, and 1-year assessments of neurological status and head circumference, as well as by level of maternal education. In particular, abnormal neurological status at 1 year was associated with a pattern of very low stable scores, and a suspicious status was associated with a pattern of improving cognitive development. Maternal education was influential among children born at the upper end of the VLBW range, who had a more favorable set of biomedical factors. CONCLUSIONS: Biomedical factors are of major importance for the cognitive development of VLBW infants, and their influence increases as birth weight declines. Differences in neurological integrity at 1 year were an important indicator of different patterns of cognitive development, especially for infants at the lower end of the VLBW range.

Child Development↗
PubMed1996

Potassium channel activation: a potential therapeutic approach?

The physiological role of K+ channel opening by endogenous substances (e.g., neurotransmitters and hormones) is a recognised inhibitory mechanism. Thus, the identification of novel synthetic molecules that 'directly' open K+ channels has led to a new direction in the pharmacology of ion channels. The existence of many different subtypes of K+ channels has been an impetus in the search for new molecules demonstrating channel and, thus, tissue selectivity. This review focuses on the different classes of openers of K+ channels, the intracellular mechanisms involved in the execution of their effects, and potential therapeutic targets.

Anti-Arrhythmia Agents↗
PubMed1996

Is there a therapeutic future for "potassium channel openers'?

1. Potassium channels, which control cell electrical activity, are among the most regulated of all ion channels in biology. Promotion of activity in K+ channels by a wide range of physiological factors tends to stabilize cell function. 2. The discovery of synthetic molecules (e.g. cromakalim) that 'directly' open ATP-sensitive K+ channels has led to a new direction in pharmacology. ATP-sensitive K+ channel-opening properties have subsequently been demonstrated in a diverse range of chemical structures (synthetic and endogenous). 3. The existence of so many different subtypes of K+ channels has been an impetus in the search of new potassium channel openers with different channel selectivities and thus biological profiles. 4. The decrease in cell excitability following K+ channel opening implies a broad clinical potential in a number of pathological conditions for K+ channel openers. Preclinical and clinical evidence supports therapeutic roles of K+ channel openers in disorders of a wide range of biological cells. 5. Although lack of selectivity of current compounds remains a major hurdle, advances in K+ channel openers and K+ channel pharmacology are encouraging. Differences already observed in the pharmacology of K+ channel openers are important factors for the development of second-generation compounds, when tissue selectivity is sought. 6. The availability of subtype-selective K+ channel openers will facilitate detailed study, through a combined effort of electrophysiology, functional pharmacology and molecular biology, leading to focused therapeutic approaches for defined pathological conditions.

Adenosine Triphosphate↗
PubMed1996

Adverse psychological events occurring in the first year after predictive testing for Huntington's disease. The Canadian Collaborative Study Predictive Testing.

A total of 135 participants in the Canadian predictive testing programme for HD were followed for at least one year in one of four study groups: increased risk (n = 37), decreased risk ( n = 58), uninformative (n = 17), or not tested (n = 23). Clinical criteria for an adverse event were a suicide attempt or formulation of a suicide attempt plan, psychiatric hospitalisation, depression lasting longer than two months, a marked increase in substance abuse, and the breakdown of important relationships. Quantitative criteria, as measured by changes on the General Severity Index of the Symptom Checklist 90-R and the Beck Depression Inventory, were also used to identify people who had adverse events. Twenty of the 135 participants (14.8%) had an adverse event. There were no significant differences between those with or without an adverse event with respect to age, sex, marital status, education, psychiatric history, general psychiatric distress, or social supports at baseline. However, evidence for depression was associated with an increased frequency of adverse events (p < 0.04). The adverse events were similar and seen with equivalent frequency in those receiving an increased risk or decreased risk and persons at risk who did not receive a modification of risk. However, a significant difference was found in the timing of adverse events for the increased and decreased risk groups (p < 0.0002). In the increased risk group all of the adverse events occurred within 10 days after results whereas, in the decreased risk group, all of the adverse events occurred six months or later after reviewing test results. These results suggest that people entering into predictive testing with some evidence of clinical depression warrant special vigilance and also suggest that counselling and support should be available for all participants in predictive testing irrespective of the direction of test results.

Adolescent↗
PubMed1995

Breastfeeding duration: prenatal intentions and postnatal practices.

A study of 78 primiparas examined the role of prenatal intent and postnatal experiences in breastfeeding duration. Those fully breastfeeding 3 months after the birth of the baby had a higher level of education, timed their decision to breastfeed earlier, intended to breastfeed longer and had a more negative attitude to formula feeding. Commitment and confidence scores were not related to breastfeeding duration in first-time mothers. Breastfeeding duration was also related to the timing of the first breastfeed and extent of mother-infant contact in the 72 hours after birth but not to the number of feeding problems.

Adolescent↗
PubMed1994

Community placement for insanity acquittees: a preliminary study of residential programs and person-situation fit.

The present study, one of the first of its kind, describes the characteristics of community living placements for insanity acquittees conditionally released following hospitalization, along with the "fit" between living placement and individual characteristics. Although the small number of insanity acquittees (n = 13) and community placements (n = 9) precluded meaningful statistical analyses of results, the study provides a model for studying the characteristics of placements as well as personal characteristics of acquittees, and the interaction between the two. It also suggests the possible importance of this interaction, operationalized as "fit" between characteristics and placement. Consistent with research findings for other criminal defendants and for nonforensic psychiatric patients released from hospitalization, a better fit between acquittee and community placement may be associated with increased likelihood of success on conditional release.

Adult↗
PubMed1993

Mortality of Mexican Americans with NIDDM. Retinopathy and other predictors in Starr County, Texas.

OBJECTIVE: To determine the rate and risk factors of mortality in a cohort of Mexican Americans with NIDDM. RESEARCH DESIGN AND METHODS: A cohort of 353 Mexican Americans with NIDDM were identified between 1981 and 1986. All individuals underwent extensive evaluations that included physical, historical, ophthalmological, and laboratory assessments. This cohort was followed prospectively for a mean of 8 yr. Follow-up included mortality surveillance, death certificate extraction, and a combination of annual and intermediate examinations. RESULTS: The cohort experienced 67 mortality events. One-third of all deaths were premature < 65 yr of age) and most often were attributed to diseases of the heart (60.0%). In no case was diabetes listed as the cause of death, although it was listed as a contributing cause in 25.5% of cases. Men had a higher mortality rate than women. In both sexes, baseline retinopathy was identified as an important predictor of subsequent mortality. Mortality was significantly elevated in those with nonproliferative retinopathy and even further elevated in those with proliferative disease (relative risks of > or = 4 for proliferative disease). CONCLUSIONS: Mexican Americans with NIDDM are experiencing premature and excessive mortality compared with the general population. The results clearly link microvascular complications with macrovascular disease, but this link is not explained by a more untoward profile of traditional cardiovascular risk factors. Retinopathy appears to serve as an important monitor of the progression of diabetes and when identified would warrant aggressive action to inhibit or slow the processes leading to subsequent mortality.

Age Factors↗
PubMed1992

The antiemetic effect of lorazepam after outpatient strabismus surgery in children.

The high incidence of postoperative emesis after strabismus surgery in pediatric outpatients can be reduced by the prophylactic administration of droperidol 75 micrograms/kg intravenously. However, this may be associated with profound sedation, delayed discharge, dysphoria, agitation, and extrapyramidal symptoms in this population. Because lorazepam used as an antiemetic in children during chemotherapy decreased the incidence of nausea and vomiting, we compared the antiemetic effects of lorazepam and droperidol in a randomized, double-blind, placebo-controlled study of 129 healthy children undergoing surgical correction of strabismus. The children, aged 1-13 yr, were randomly allocated into three groups. The children in group 1 received droperidol 75 micrograms/kg intravenously; those in group 2 received lorazepam 10 micrograms/kg intravenously; and those in group 3 received placebo. Anesthesia consisted of halothane, nitrous oxide in oxygen, and atracurium. Study drugs were administered intravenously after induction of anesthesia but before surgery. In children 3-13 yr old, administration of either lorazepam or droperidol was associated with a lower (P < 0.024) incidence of postoperative vomiting. There was no difference between the antiemetic effect of lorazepam and that of droperidol. The incidence of postoperative agitation was greater in the droperidol group (P < 0.001) than in the lorazepam and placebo groups. Postdischarge vomiting was less (P < 0.009) in children younger than 3 yr of age. Lorazepam, similar to droperidol, has an antiemetic effect in outpatient children 3-13 yr old undergoing strabismus correction, but it is associated with less postoperative agitation than is droperidol.

Adolescent↗
PubMed1992

Effects of the divalent cations nickel and cadmium on contractions of rat aorta to endothelin-1.

1. The effects of inorganic and organic calcium channel antagonists on the contractile responses of rat isolated aortic rings to endothelin-1 (ET-1) were studied. 2. ET-1 (0.1-100 nM) evoked concentration-related contractile responses of the rat aorta (EC50 1.65 +/- 0.22 nM, Emax 125.8 +/- 4.5 %KClmax, n = 20). In Ca(2+)-free modified Krebs solution (containing 1 mM EGTA) aortic rings failed to contract to ET-1 (0.1-30 nM). 3. Nickel chloride (0.2-0.8 mM) attenuated the ET-1 (1-100 nM)-induced contraction of rat aorta (response (%KClmax) to 10 nM ET-1: control 132.0 +/- 8.7 and after 0.2 mM Ni2+ 90.3 +/- 14.8, 0.4 mM Ni2+ 54.7 +/- 12.3, 0.8 mM Ni2+ 10.3 +/- 4.4, n = 6/group). Cadmium chloride (10-30 microM) depressed the maxima of the concentration-response curves to ET-1 with an IC50 of 15.4 +/- 1.5 microM (n = 6). 4. The ET-1 evoked contractile responses were not modified by the dihydropyridine calcium channel antagonist, nicardipine (0.1 microM), or by omega-conotoxin (1.0 microM). Cinnarizine (10 microM), however, significantly attenuated the maximum response to ET-1 (96.9 +/- 6.0 vs 128.0 +/- 5.8 %KClmax for control), but failed to modify the EC50 value. 5. Amiloride, a Na(+)-Ca2+ exchange inhibitor, also depressed the maxima of the concentration-response curves to ET-1 with an IC50 of 0.45 +/- 0.05 mM (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗