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Biomedical subjects

Brian Williams

Publications and source records attributed to Brian Williams.

At least 19 recordsLinked to original sources
PubMed2006

N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II.

Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.

Administration, Oral↗
PubMed2006

N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists.

A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.

Administration, Oral↗
PubMed2006

3,4-Fused cyclohexyl sulfones as gamma-secretase inhibitors.

The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent gamma-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain A beta in transgenic mouse models and thus have potential as possible treatments for Alzheimer's disease.

Amyloid Precursor Protein Secretases↗
PubMed2006

Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration.

Tuberculosis is the oldest of the world's current pandemics and causes 8.9 million new cases and 1.7 million deaths annually. The disease is among the most common causes of morbidity and mortality in people living with HIV. However, tuberculosis is more than just part of the global HIV problem; well-resourced tuberculosis programmes are an important part of the solution to scaling-up towards universal access to comprehensive HIV prevention, diagnosis, care, and support. This article reviews the impact of the interactions between tuberculosis and HIV in resource-limited settings; outlines the recommended programmatic and clinical responses to the dual epidemics, highlighting the role of tuberculosis/HIV collaboration in increasing access to prevention, diagnostic, and treatment services; and reviews progress in the global response to the epidemic of HIV-related tuberculosis.

AIDS-Related Opportunistic Infections↗
PubMed2005

Somatic control of germline sexual development is mediated by the JAK/STAT pathway.

Germ cells must develop along distinct male or female paths to produce the sperm or eggs required for sexual reproduction. In both mouse and Drosophila, the sexual identity of germ cells is influenced by the sex of the surrounding somatic tissue (for example, refs 1, 2, reviewed in refs 3, 4); however, little is known about how the soma controls germline sex determination. Here we show that the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway provides a sex-specific signal from the soma to the germ line in Drosophila embryonic gonads. The somatic gonad expresses a JAK/STAT ligand, unpaired (upd), in a male-specific manner, and activates the JAK/STAT pathway in male germ cells at the time of gonad formation. Furthermore, the JAK/STAT pathway is necessary for male-specific germ cell behaviour during early gonad development, and is sufficient to activate aspects of male germ cell behaviour in female germ cells. Our findings provide direct evidence that the JAK/STAT pathway mediates a key signal from the somatic gonad that regulates male germline sexual development.

Animals↗
PubMed2005

Which surgical decisions should patients participate in and how? Reflections on women's recollections of discussions about variants of hysterectomy.

Current guidance about informed consent suggests patients ought to know about the procedures involved in any treatments they agree to undergo, and have a right to be involved in decisions about their care. However, it is not clear how this guidance is and should be applied to decisions between variant surgical procedures such as abdominal or vaginal hysterectomy. We sent structured questionnaires about information provision and decision-making to 157 women who were scheduled for hysterectomy in north-east Scotland. A purposive sub-sample of 20 women was interviewed in depth post-operatively. 104 women (66%) responded to the questionnaires. 75% reported being told at outpatient clinics what kind of hysterectomy they would have, but fewer than half had been told about the advantages and disadvantages of different kinds. Between 26% and 65% of women thought they had been given too little information about various issues pertaining to different types of hysterectomy. The interview accounts suggested that gynaecologists offered women little opportunity to influence the selection of a surgical procedure. Women did not express a desire for a greater say in this selection, but appreciated being told, or would have liked to know, why particular procedures were recommended for them. There may be circumstances in which it is important for surgeons to tell patients about options they have ruled out in their particular cases. Decisions between alternative surgical procedures are often highly contingent on the dispositions and skills of individual surgeons. They raise practical and ethical issues that have been neglected in recent discussions about patient involvement in decision-making. As policy makers continue to emphasise the importance of choice and patients become increasingly aware of the existence of variant procedures, these issues need careful consideration.

Adult↗
PubMed2005

The impact of incident and prevalent herpes simplex virus-2 infection on the incidence of HIV-1 infection among commercial sex workers in South Africa.

This study investigated the impact of prevalent and incident HSV-2 infection on the incidence of HIV-1 infection in a cohort of female commercial sex workers in KwaZulu-Natal, South Africa. Prior to a vaginal microbicide trial, 416 women were screened for antibodies to HIV-1 and herpes simplex virus-2 (HSV-2) infections and a questionnaire was used to establish behavioral, social, and demographic characteristics. A total of 187 HIV-1-seronegative women were followed up at monthly intervals when blood was drawn and used to detect HIV-1 and HSV-2 antibodies. The median duration of follow-up was 2.2 years. At screening 50% of the women were HIV-1 seropositive and 84% were HSV-2 seropositive. The hazards of HIV-1 among women who were HSV-2 seropositive or seronegative throughout, or among those who seroconverted during the study, were not significantly different. When HSV-2 seroconversion was analyzed as a time-dependent covariate, the hazard ratio for HIV-1 seroconversion was 6.0 (95% CI: 2.6-14.0) times greater among women with incident than among women with prevalent HSV-2 infections. Drawing on other recent studies these data suggest that incident HSV-2 infection increases the risk of HIV-1 infection; the effect wanes with time since infection; and the effect is significantly greater for men than it is for women.

Adolescent↗
PubMed2005

Tuberculosis control in the era of HIV.

Without HIV, the tuberculosis (TB) epidemic would now be in decline almost everywhere. However, instead of looking forward to the demise of TB, countries that are badly affected by HIV are struggling against a rising tide of HIV-infected patients with TB. As a consequence, global TB control policies have had to be revised and control of TB now demands increased investment. This paper assesses what is being done to address the issue and what remains to be done.

Adolescent↗
PubMed2004

Can highly active antiretroviral therapy reduce the spread of HIV?: A study in a township of South Africa.

BACKGROUND: Calls have been made for the large-scale delivery of highly active antiretroviral therapy (HAART) to people infected with HIV in developing countries. If this is to be done, estimates of the number of people who currently require HAART in high HIV prevalence areas of sub-Saharan Africa are needed, and the impact of the widespread use of HAART on the transmission and, hence, spread of HIV must be assessed. OBJECTIVES: To estimate the proportion of people eligible for combination antiretroviral therapy and to evaluate the potential impact of providing HAART on the spread of HIV-1 under World Health Organization (WHO) guidelines in a South African township with a high prevalence of HIV-1. DESIGN: A community-based cross-sectional study in a township near Johannesburg, South Africa, of a random sample of approximately 1000 men and women aged 15 to 49 years. METHODS: Background characteristics and sexual behavior were recorded by questionnaire. Participants were tested for HIV-1, and their CD4 cell counts and plasma HIV-1 RNA loads were measured. The proportion of people whose CD4 cell count was less than 200 cells/mm and who would be eligible to receive HAART under WHO guidelines was estimated. The potential impact of antiretroviral drugs on the spread of HIV-1 in this setting was determined by estimating among the partnerships engaged in by HIV-1-positive individuals the proportion of spousal and nonspousal partnerships eligible to receive HAART and then by calculating the potential impact of HAART on the annual risk of HIV-1 transmission due to sexual contacts with HIV-1-infected persons. The results were compared with those obtained using United States Department of Health and Human Services (USDHHS) guidelines. RESULTS: The overall prevalence of HIV-1 infection was 21.8% (19.2%-24.6%), and of these people, 9.5% (6.1%-14.9%) or 2.1% (1.3%-3.3%) of all those aged 15 to 49 years would be eligible for HAART (ranges are 95% confidence limits). In each of the next 3 years 6.3% (4.6%-8.4%) of those currently infected with HIV-1 need to start HAART. Among the partnerships in which individuals were HIV-1-positive, only a small proportion of spousal partnerships (7.6% [3.4%-15.6%]) and nonspousal partnerships (5.7%, [3.0%-10.2%]) involved a partner with a CD4 cell count below 200 cells/mm and would have benefited from the reduction of transmission due to the decrease in plasma HIV-1 RNA load under HAART. Estimates of the impact of HAART on the annual risk of HIV-1 transmission show that this risk would be reduced by 11.9% (7.1%-17.0%). When using USDHHS guidelines, the proportion of HIV-1-positive individuals eligible for HAART reached 56.3% (49.1%-63.2%) and the impact of HAART on the annual risk of HIV-1 transmission reached 71.8% (64.5%-77.5%). CONCLUSIONS: The population impact of HAART on reducing sexual transmission of HIV-1 is likely to be small under WHO guidelines, and reducing the spread of HIV-1 will depend on further strengthening of conventional prevention efforts. A much higher impact of HAART is to be expected if USDHHS guidelines are used.

Adolescent↗
PubMed2004

Why older people do not participate in leisure time physical activity: a survey of activity levels, beliefs and deterrents.

BACKGROUND: Regular physical activity has been shown to have many health benefits. However, many older people are physically inactive. OBJECTIVE: To investigate why older people are reluctant to participate in leisure time physical activity and to identify strategies to encourage increased activity. DESIGN: Cross-sectional survey. SETTING: 16 general practices in Dundee, Scotland. METHODS: 409 randomly selected older people (65-84 years) who lived independently were interviewed at home. Forty-six percent of those invited to take part were recruited into the study. RESULTS: Levels of knowledge about the specific health benefits of physical activity were high. Almost all participants (95%) believed that physical activity was beneficial and 79% believed that they did enough to keep healthy. However, 36% did no leisure time physical activity and a further 17% did less than 2 hours per week. Regression modelling identified 11 factors that exerted significant independent effects on levels of leisure time physical activity. The most powerful deterrent was lack of interest (OR = 7.8). Other factors included lack of daily access to a car, shortness of breath, joint pain, dislike of going out alone or in the evening, perceived lack of fitness, lack of energy, doubting that exercise can lengthen life, not belonging to a group and doubting that meeting new people is beneficial. CONCLUSIONS: Increasing leisure time physical activities poses major challenges. Beliefs about desirable levels of activity in older people would need to be changed. Action would be needed to relieve physical symptoms and address fears about perceived ability to undertake physical activity. Finally, easily accessible facilities would be needed to encourage participation in physical activity.

Aged↗
PubMed2003

Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy and tolerability of tricyclic antidepressants with selective serotonin reuptake inhibitors in depression in primary care. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Register of the Cochrane Collaboration's depression, anxiety, and neurosis group. Reference lists of initial studies and other relevant review papers. Selected authors and experts. SELECTION OF STUDIES: Studies had to meet minimum requirements on: adequacy of sample size, adequate allocation concealment, clear description of treatment, representative source of subjects, use of diagnostic criteria or clear specification of inclusion criteria, details regarding number and reasons for withdrawal by group, and outcome measures described clearly or use of validated instruments. MAIN OUTCOME MEASURES: Standardised mean difference of final mean depression scores and relative risk of response when using the clinical global impression score. Relative risk of withdrawing from treatment at any time, and the number withdrawing due to side effects. RESULTS: 11 studies (2951 participants) compared a selective serotonin reuptake inhibitor with a tricyclic antidepressant. Efficacy between selective serotonin reuptake inhibitors and tricyclics did not differ significantly (standardised weighted mean difference, fixed effects 0.07, 95% confidence interval -0.02 to 0.15; z=1.59, P<0.11). Significantly more patients receiving a tricyclic withdrew from treatment (relative risk 0.78, 95% confidence interval 0.68 to 0.90; z=3.37, P<0.0007) and withdrew specifically because of side effects (0.73, 0.60 to 0.88; z=3.24, P<0.001). Most studies included were small and supported by commercial funding. Many studies were of low methodological quality or did not present adequate data for analysis, or both, and were of short duration, typically six to eight weeks. CONCLUSION: The evidence on the relative efficacy of selective serotonin reuptake inhibitors and tricyclic antidepressants in primary care is sparse and of variable quality. The study setting is likely to be an important factor in assessing the efficacy and tolerability of treatment with antidepressant drugs.

Antidepressive Agents, Tricyclic↗
PubMed2003

The role of cardiac morbidity in short- and long-term mortality in injured older patients who survive initial resuscitation.

BACKGROUND: Elderly patients are an increasingly larger group of injured trauma care patients. Comorbidities influence outcome. Little is known of short- and long-term mortality in the elderly who survive initial resuscitation. METHODS: Short- and long-term mortality was retrospectively analyzed in 363 consecutively injured patients (Injury severity score >15) surviving more than 3 days after admission to a level 1 trauma center (including 197 patients >60 years). Cardiac morbidity was the focus. RESULTS: Survival to hospital discharge was similar comparing older patients with the entire group. Mortality increased incrementally with age. In older patients, cardiac morbidity was observed in 28% (fatal in 7); 2-year mortality was 36% (older group) and 60% (patients sustaining cardiac complications). Most elderly (80%) were discharged to long-term care. CONCLUSIONS: Elderly who survive initial resuscitation are as likely to survive to discharge as younger patients, but long-term survival is significantly lower as age increases. Cardiac morbidity is associated with higher long-term mortality. Most elderly are discharged to long-term care.

Aged↗
PubMed2002

Environmental fate of alkylphenols and alkylphenol ethoxylates--a review.

Alkylphenol ethoxylates (APEs) are widely used surfactants in domestic and industrial products, which are commonly found in wastewater discharges and in sewage treatment plant (STP) effluents. Degradation of APEs in wastewater treatment plants or in the environment generates more persistent shorter-chain APEs and alkylphenols (APs) such as nonylphenol (NP), octylphenol (OP) and AP mono- to triethoxylates (NPE1, NPE2 and NPE3). There is concern that APE metabolites (NP, OP, NPE1-3) can mimic natural hormones and that the levels present in the environment may be sufficient to disrupt endocrine function in wildlife and humans. The physicochemical properties of the APE metabolites (NP, NPE1-4, OP, OPE1-4), in particular the high K(ow) values, indicate that they will partition effectively into sediments following discharge from STPs. The aqueous solubility data for the APE metabolites indicate that the concentration in water combined with the high partition coefficients will provide a significant reservoir (load) in various environmental compartments. Data from studies conducted in many regions across the world have shown significant levels in samples of every environmental compartment examined. In the US, levels of NP in air ranged from 0.01 to 81 ng/m3, with seasonal trends observed. Concentrations of APE metabolites in treated wastewater effluents in the US ranged from < 0.1 to 369 microg/l, in Spain they were between 6 and 343 microg/l and concentrations up to 330 microg/l were found in the UK. Levels in sediments reflected the high partition coefficients with concentrations reported ranging from < 0.1 to 13,700 microg/kg for sediments in the US. Fish in the UK were found to contain up to 0.8 microg/kg NP in muscle tissue. APEs degraded faster in the water column than in sediment. Aerobic conditions facilitate easier further biotransformation of APE metabolites than anaerobic conditions.

Biodegradation, Environmental↗