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B Williams

Publications and source records attributed to B Williams.

At least 55 records · Page 3Linked to original sources
PubMed2001

The carboxy-terminal calcium binding sites of calmodulin control calmodulin's switch from an activator to an inhibitor of RYR1.

Calcium and calmodulin both regulate the skeletal muscle calcium release channel, also known as the ryanodine receptor, RYR1. Ca(2+)-free calmodulin (apocalmodulin) activates and Ca(2+)-calmodulin inhibits the ryanodine receptor. The conversion of calmodulin from an activator to an inhibitor is due to Ca(2+) binding to calmodulin. We have previously shown that the binding sites for apocalmodulin and Ca(2+)-calmodulin on RYR1 are overlapping with the Ca(2+)-calmodulin site located slightly N-terminal to the apocalmodulin binding site. We now show that mutations of the calcium binding sites in either the N-terminal or the C-terminal lobes of calmodulin decrease the affinity of calmodulin for the ryanodine receptor, suggesting that both lobes interact with RYR1. Mutation of the two C-terminal Ca(2+) binding sites of calmodulin destroys calmodulin's ability to inhibit ryanodine receptor activity at high calcium concentrations. The mutated calmodulin, however, can still bind to RYR1 at both nanomolar and micromolar Ca(2+) concentrations. Mutating the two N-terminal calcium binding sites of calmodulin does not significantly alter calmodulin's ability to inhibit ryanodine receptor activity. These data suggest that calcium binding to the two C-terminal calcium binding sites within calmodulin is responsible for the switching of calmodulin from an activator to an inhibitor of the ryanodine receptor.

Amino Acid Sequence↗
PubMed2001

Estimating HIV incidence rates from age prevalence data in epidemic situations.

We present a method of estimating HIV incidence rates in epidemic situations from data on age-specific prevalence and changes in the overall prevalence over time. The method is applied to women attending antenatal clinics in Hlabisa, a rural district of KwaZulu/Natal, South Africa, where transmission of HIV is overwhelmingly through heterosexual contact. A model which gives age-specific prevalence rates in the presence of a progressing epidemic is fitted to prevalence data for 1998 using maximum likelihood methods and used to derive the age-specific incidence. Error estimates are obtained using a Monte Carlo procedure. Although the method is quite general some simplifying assumptions are made concerning the form of the risk function and sensitivity analyses are performed to explore the importance of these assumptions. The analysis shows that in 1998 the annual incidence of infection per susceptible woman increased from 5.4 per cent (3.3-8.5 per cent; here and elsewhere ranges give 95 per cent confidence limits) at age 15 years to 24.5 per cent (20.6-29.1 per cent) at age 22 years and declined to 1.3 per cent (0.5-2.9 per cent) at age 50 years; standardized to a uniform age distribution, the overall incidence per susceptible woman aged 15 to 59 was 11.4 per cent (10.0-13.1 per cent); per women in the population it was 8.4 per cent (7.3-9.5 per cent). Standardized to the age distribution of the female population the average incidence per woman was 9.6 per cent (8.4-11.0 per cent); standardized to the age distribution of women attending antenatal clinics, it was 11.3 per cent (9.8-13.3 per cent). The estimated incidence depends on the values used for the epidemic growth rate and the AIDS related mortality. To ensure that, for this population, errors in these two parameters change the age specific estimates of the annual incidence by less than the standard deviation of the estimates of the age specific incidence, the AIDS related mortality should be known to within +/-50 per cent and the epidemic growth rate to within +/-25 per cent, both of which conditions are met. In the absence of cohort studies to measure the incidence of HIV infection directly, useful estimates of the age-specific incidence can be obtained from cross-sectional, age-specific prevalence data and repeat cross-sectional data on the overall prevalence of HIV infection. Several assumptions were made because of the lack of data but sensitivity analyses show that they are unlikely to affect the overall estimates significantly. These estimates are important in assessing the magnitude of the public health problem, for designing vaccine trials and for evaluating the impact of interventions.

Adolescent↗
PubMed2001

Vascular endothelial growth factor increases Rana vascular permeability and compliance by different signalling pathways.

Vascular endothelial growth factor (VEGF) chronically increases microvascular permeability, compliance and vessel diameter. To determine the signalling pathways by which VEGF exerts these effects, we investigated the role of Ca2+ influx and mitogen-activated protein kinase (MAPK) phosphorylation on the increase in hydraulic conductivity (Lp), diameter and compliance in mesenteric microvessels in the anaesthetised frog (Rana species). The VEGF-mediated chronically increased permeability was attenuated by co-perfusion of VEGF with 5 mM NiCl2, previously shown to inhibit Ca2+ influx. MAPK phosphorylation inhibition by PD98059 did not affect the chronic increase in Lp. To determine whether other agonists which increased Ca2+ influx also chronically increased Lp, the effect of ATP perfusion on chronic Lp was measured. ATP perfusion also chronically increased Lp. The chronic increase in Lp was therefore dependent on an initial transient Ca2+ influx, and not MAPK activation, and was not unique to VEGF stimulation. Inhibition of Ca2+ influx did not inhibit the increase in microvascular diameter or compliance brought about by VEGF. Both these increases were inhibited by PD98059. The VEGF-mediated increase in compliance and diameter was therefore dependent on MAPK activation, not on Ca2+ influx. The chronic increase in Lp stimulated by VEGF perfusion 24 h previously was reduced when the vessel was perfused with 5 mM NiCl2. The sustained, high Lp was therefore dependent on Ca2+ influx. The endothelial cell calcium concentration ([Ca2+]i) of vessels previously perfused with VEGF or ATP, and with a chronically increased Lp, was not significantly increased compared to [Ca2+]i of endothelial cells in vessels before agonist perfusion These experiments show that VEGF acts through different pathways to stimulate increased permeability and compliance. The data are consistent with the hypothesis that VEGF chronically increases Lp through an acute stimulation of Ca2+ influx, but increases compliance and diameter by acute stimulation of the MAPK signalling pathway. They also suggest that the increase in Lp is dependent on a sustained Ca2+ influx, even though the endothelial [Ca2+]i is not raised.

Adenosine Triphosphate↗
PubMed2001

HIV infection among youth in a South African mining town is associated with herpes simplex virus-2 seropositivity and sexual behaviour.

OBJECTIVES: To determine the seroprevalence of HIV and herpes simplex virus-2 (HSV-2) by age and gender among young people aged 14--24 years in a South African town and to identify risk factors for HIV infection. DESIGN: A community-based, cross-sectional study was conducted on a random sample of men (n = 723) and women (n = 784) living in a township in the Carletonville district of South Africa. METHODS: Potential demographic and behavioural risk factors associated with HIV were recorded by questionnaire and biological tests were performed on serum and urine. Data analysis was performed using multivariate logistic regression. RESULTS: Among men and women the prevalence of HIV infection was 9.4 and 34.4%, respectively, and of positive HSV-2 serology was 17.0 and 53.3%, respectively. Among 24-year-old women the prevalence of HIV was 66.7% [95% confidence interval (CI), 54.6--77.3%]. HSV-2 seropositivity was a strong independent risk factor for HIV infection with odds ratios of 5.3 (95% CI, 2.7--10.3) for men and 8.4 (95% CI, 4.9--14.2) for women. There was no independent effect of age at first sex or serological markers of other sexually transmitted infections on HIV infection. CONCLUSIONS: HIV infection among young women increases rapidly after the onset of sexual activity and reaches extremely high levels by 24 years of age. These findings suggest that rates of HIV transmission from men to women are high and that HSV-2 plays a major role in the spread of HIV in this population.

Adolescent↗
PubMed2001

Angiotensin II and the pathophysiology of cardiovascular remodeling.

Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system. These include remodeling of the left ventricle, alterations in the morphology and mechanical properties of the vasculature, and the development of endothelial dysfunction. Recent studies have shown that angiotensin II is capable of mediating these changes via its interaction with the angiotensin II type 1 receptor. These nonhemodynamic effects of angiotensin II are independent of its effect on blood pressure. Thus, elevated levels of angiotensin II may lead directly to many hypertension-associated pathologies. Recent evidence that mechanical strain, oxidized low-density lipoprotein cholesterol, and aldosterone can cause upregulation of angiotensin II type 1 receptors indicates that activation of the renin-angiotensin system is not necessary for the actions of angiotensin II to be amplified. Because the strain on the vessel wall may be increased under conditions of hypertension, increased arterial pressure may amplify the actions of angiotensin II without a discernible increase in plasma angiotensin II levels. In both the myocardium and the peripheral vasculature, fibrosis is a major component of the remodeling that occurs in hypertension. There is substantial evidence that transforming growth factor beta-1 (TGF-beta(1)) mediates angiotensin-II-induced fibrosis in patients with hypertension and in those with a variety of nephropathies. Mechanical strain also induces fibrosis in a mechanism mediated by TGF-beta(1). This cytokine thus represents a common pathway by which angiotensin II and increased arterial pressure may induce cardiovascular fibrosis.

Angiotensin II↗
PubMed2001

Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer.

BACKGROUND: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. METHODS: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. CONCLUSIONS: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

Adult↗
PubMed2001

Work disability among people with ankylosing spondylitis.

OBJECTIVE: To investigate work disability among people with ankylosing spondylitis (AS) in terms of correlates and coping mechanisms. METHODS: The sample group (n = 133) was recruited through 2 sources: 1) consecutive patients attending outpatient clinics over a 6-month period, and 2) a random sample of members of the National Ankylosing Spondylitis Society. We used a cross-sectional survey with data collected by self-administered questionnaires and telephone interviews with a randomly selected subsample (n = 6). RESULTS: The majority of participants were men. The mean age was 49 years; the mean disease duration was 28 years. Thirty-one percent were unable to work because of AS, with an additional 15% reporting changes to their working lives attributable to AS (e.g., reduction in hours worked, change of job). Compared with being in full-time work, work disability was associated with being older, longer disease duration, lower educational standard, comorbidity, greater physical impairment, pain, fatigue, stiffness, anxious and depressed mood, and lower self-esteem. Descriptive data added further insight into the experience of work disability and coping with AS in a work environment. CONCLUSION: Work disability is worthy of further investigation to determine exact prevalence rates and psychosocial implications. Work disability could be addressed with simple interventions or adaptations in the workplace.

Adaptation, Psychological↗
PubMed2001

Cloned pigs generated from cultured skin fibroblasts derived from a H-transferase transgenic boar.

Cloned pigs were produced from cultured skin fibroblasts derived from a H-transferase transgenic boar. One 90 day fetus and two healthy piglets resulted from nuclear transfer by fusion of cultured fibroblasts with enucleated oocytes. The cells used in these studies were subjected to an extensive culture time, freezing and thawing, and clonal expansion from single cells prior to nuclear transfer. PCR and FACS analysis determined that the cloned offspring contained and expressed the H-transferase transgene. Microsatellite analysis confirmed that the clones were genetically identical to the boar. The cell culture and nuclear transfer procedures described here will be useful for applications requiring multiple genetic manipulations in the same animal.

Animals↗
PubMed2001

Use of oral montelukast in the treatment of asthma.

Montelukast, a new leukotriene modifier, has several benefits in the treatment of asthma in adults and children including improved relief of asthma symptoms, rapid onset, a safety profile comparable with placebo, and oral, once-daily dosing means excellent adherence.

Acetates↗
PubMed2001

Patient education for people with arthritis in rural communities: the UK experience.

Research literature, based largely on studies conducted in the USA and Australia, suggests that rural and urban residents differ on health status variables. This assumption was examined in an exploratory study conducted in the UK. The experience of arthritis in rural communities was explored through interviews and comparisons were made between rural and urban participants attending an educational intervention designed to improve self-management ability. Results showed that rural residents valued their independence and the sense of community spirit. Contrary to expectations, urban rather than rural residents showed greater psychological distress. However, the effectiveness of the educational intervention was found to be independent of location; both urban and rural dwellers appeared to derive similar benefits.

Arthritis↗
PubMed2001

Does neonatal ocular misalignment predict later abnormality?

PURPOSE: A longitudinal prospective study was carried out to ascertain the significance of neonatal ocular misalignments. METHODS: Pre-school vision screening and hospital records were examined to determine the visual outcome of 1150 infants classified into 'often' (> 15% of waking hours), 'occasionally' (< 15%) or 'never' having an ocular misalignment (neonatal squint) in the first 8 weeks of life. Chi2 and Fisher's exact tests and ANOVA were used to analyse the data. RESULTS: When compared with infants who had squinted occasionally or never, frequent squinting in the neonatal period (which occurred in 7.7% of the subjects) was significantly associated with having been prescribed spectacles (p = 0.04), both for hypermetropia (p = 0.04) and for myopia (p = 0.05). Frequent squinters also had a higher incidence of significant esodeviation (p = 0.04) and were more likely to be > 21 days premature (p = 0.05). Small numbers of abnormalities made statistical analysis limited, but there were weak trends towards more myopic and oblique astigmatism in the 'never' group. The esotropias in the 'often' group were more frequently intermittent than those found in the other groups. CONCLUSIONS: Occasional squinting in the first 8 weeks of life appears to be normal neonatal behaviour. Frequent squinting trebles the chances of developing a significant esodeviation or refractive error severe enough to require spectacles before 5 years of age but incidence of abnormality still does not exceed 9%.

Analysis of Variance↗
PubMed2001

Opioid analgesic prescribing and use - an audit of analgesic prescribing by general practitioners and The Multidisciplinary Pain Centre at Royal Brisbane Hospital.

AIMS: This study evaluated the use of and need for opioids in patients attending the Multidisciplinary Pain Centre at the Royal Brisbane Hospital (RBH). METHODS: All consecutive in-patient admissions in 1998 were reviewed. A 10-point scoring system based on the World Health Organization (WHO) analgesic ladder was devised to facilitate comparison of analgesic prescribing on admission and at the time of discharge. A conversion table was used to standardize opioid analgesic doses to an oral morphine equivalent. RESULTS: Of the 370 patients reviewed, 233 (81%) were by their general practitioners. Records of 288 (78%) were available for full review and 270 (94%) of these had noncancer pain. On admission, 239 (83%) were taking an opioid analgesic, with 135 (47%) taking strong opioids (e.g. morphine, oxycodone, methadone). There was a significant decrease in the mean total daily oral morphine equivalent prescribed on discharge 36.9 mg (95% CI: 33.4, 40.4) compared with that on admission 88.7 mg (95% CI: 77.6, 99.8) (P < 0.001). There was a significant decrease (P < 0.05) in the proportion of patients taking a primary opioid on discharge 153 (58%) compared with admission 239 (83%), although the proportion of patients taking a strong opioid on discharge 150 (52%) compared with admission 135 (47%) was not significantly different (P > 0.05). The proportion of patients taking a laxative showed a significant increase on discharge 110 (73%) compared with admission 38 (28%) (P < 0.05). CONCLUSIONS: Our analgesic prescribing scoring system and opioid conversion table have the potential to be developed further as tools for assessing opioid analgesic prescribing. The significant decrease in total daily oral morphine equivalents signifies the value of prescribing in accordance with the WHO analgesic ladder, and the necessity of general practitioner education. The management of chronic pain is complex, and it requires interventions additional to pharmacological therapy. Evaluation by a multidisciplinary team, coupled with experience in and an understanding of analgesic prescribing and rehabilitation provides an effective basis for improving the management of patients with chronic pain.

Acetaminophen↗
PubMed2001

Long-term asthma control with oral montelukast and inhaled beclomethasone for adults and children 6 years and older.

BACKGROUND: Leukotriene receptor antagonists have demonstrated clinical benefits in chronic asthma studies of up to 3 months in duration. The effects of these agents over extended periods of time have not been reported. OBJECTIVE: To describe the long-term effect of oral montelukast, a potent and specific cysteinyl leukotriene receptor antagonist, compared with inhaled corticosteroids in both adult and paediatric patients with chronic asthma. METHODS: Male and female patients with chronic, stable asthma (adults aged 15-85 years, children aged 6-14 years), who had completed double-blind, placebo-controlled clinical studies, participated in three extension studies with oral montelukast taken once daily (10 mg tablet for adults, 5 mg chewable tablet for paediatric patients) or inhaled corticosteroids (beclomethasone 200 microg twice daily for adults, beclomethasone 100 microg or equivalent three times daily for children). A double-blind adult extension study was 37 weeks in duration; open-label adult extension studies were 156 (adults) and 112 (paediatric) weeks in duration. A total of 436, 374, and 245 patients entered these extension studies, respectively. RESULTS: Treatment with both montelukast and inhaled corticosteroids resulted in improvement in multiple parameters of asthma control. Improvements in daytime symptom scores were generally comparable among treatment groups. No tachyphylaxis to the effects of montelukast was evident. In the adult open-label study, however, the effect of beclomethasone on mean forced expiratory volume in 1 second (FEV1) gradually decreased from start of the study to the end of the follow-up treatment period. CONCLUSION: Both montelukast and inhaled corticosteroids were effective in controlling mild to moderate chronic asthma; the relative effectiveness of montelukast and beclomethasone were similar in open-label conditions. The hypothesis, that clinical practice conditions (e.g., adherence) may have a significant impact on the effectiveness of these therapies, should be tested in future clinical trials.

Acetates↗
PubMed2001

Disclosure of minor mental health problems: an exploratory theoretical study.

AIM: The aim of this study was to explore people's experiences, concerns and beliefs about disclosing minor mental health problems by focusing on the ways in which such disclosures are interpreted. BACKGROUND: Approximately half of people with mental health problems do not seek help. The decision to consult represents just one aspect of the process of revealing one's illness to others. People with mental health problems are known to be reluctant to reveal the existence of those problems through fear of how others might then view them. DESIGN: A qualitative approach was employed. In-depth interviews were carried out with 47 users and nonusers of community mental health services. Interviews were tape-recorded, transcribed and analysed. RESULTS: The data suggest that when people reveal minor mental health problems others interpret these in relation to a number of perceived contextual factors. These include perceptions of the severity and duration of any possible causes, the inner 'strength' of the person, the expected ability of the person to either solve or suppress the experience, and the form and context of the expression itself. The data presented included individuals who were seeking help for relatively 'minor' mental health problems (primarily depression and anxiety) and individuals who had no current mental health problems but routinely managed expressions of their own emotions. Throughout the data there appeared to be no distinct difference between these two groups other than one of the severity of psychological experience. CONCLUSION: The key elements involved in the interpretation of people's expressions of sadness were essentially the same as those involved in the interpretation of expressions of depression. An appreciation of these contextual factors influencing the interpretation and disclosure of minor mental health problems may aid the development of more person-centred mental health services and inform the content of health education in the mental health field.

Adaptation, Psychological↗