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Biomedical subjects

J A Whitworth

Publications and source records attributed to J A Whitworth.

At least 19 recordsLinked to original sources

Progression of renal failure -- the role of hypertension.

High blood pressure plays a key role in the progression of renal failure. Hypertension is a common presentation of kidney disease and an almost invariable accompaniment of renal failure. Hypertension is also a major contributor to cardiovascular disease, the major cause of morbidity and mortality in renal failure. Hypertension is both cause and consequence of renal failure, but the precise nature and prevalence of hypertensive nephrosclerosis as a cause of renal failure remains controversial. There is strong evidence that hypertension accelerates the progression of experimental renal disease and that control of blood pressure is effective in preventing this progression. Hypertension, both accelerated and "benign" (a misnomer), has long been recognised as a poor prognostic feature in human renal disease and more recently in renal allograft survival. Blood pressure control is very effective in retarding renal disease progression. There are compelling indications for angiotensin-converting enzyme inhibitors in both non-diabetic and type 1 diabetic nephropathies, and for angiotensin receptor blockers in type 2 diabetic nephropathy. Most patients will require combination drug therapy to control blood pressure and reduce both progression of renal failure and the associated cardiovascular morbidity and mortality.

Angiotensin II Type 1 Receptor Blockers↗

Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism.

Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G-->T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.

Adult↗

The Wellcome Trust in Australasia: return on investment.

The Wellcome Trust is the world's largest medical research charity. Investment by the Trust in research in Australia and New Zealand has contributed very substantially to local research capacity through support of people, equipment and programmes. Further, the Trust's funding has -successfully leveraged additional investment from both government and charitable foundations. Current initiatives are focused on development of research partnerships between Australasia and our regional neighbours.

Australasia↗

The Sylvia and Charles Viertel Charitable Foundation: a decade of support for medical research in Australia.

The Sylvia and Charles Viertel Charitable Foundation (http://www.alfredresearch.org/external/viertel.htm) recently celebrated its first decade of support for medical research in Australia. Its contribution to Australian medical research has centred on support of outstanding young people through Senior Medical Research Fellowships and a unique grant-in-aid programme for clinical investigators.

Australia↗

Emerging drugs in the management of hypertension.

Hypertension is a global health problem, affecting developing and developed countries alike. Most patients with hypertension are undiagnosed, and most diagnosed patients are either untreated or inadequately treated. Randomised controlled trial evidence suggests diuretic therapy for hypertension is as effective as newer drugs in reducing cardiovascular events. There is good evidence for the use of specific classes of drugs in hypertensive patients with a variety of associated clinical conditions, but for uncomplicated cases, the current emphasis in hypertension management is on blood pressure lowering rather than drug class. Individual patients vary in their responses to different drug classes, and optimal therapy for the individual is determined by trial and error. Pharmacogenomics may assist in tailoring therapy for individuals in the future. Emerging drugs include newer members of classes already established in clinical practice, for example, angiotensin II receptor antagonists, aldosterone receptor antagonists, calcium antagonists and centrally acting drugs; newer fixed-dose combination therapies; and more novel therapies, for example, endothelin (ET) receptor antagonists, activators of nitric oxide (NO)-sensitive guanylyl cyclase and vasopeptidase inhibitors.

Antihypertensive Agents↗

Comparative loss and maturation of peripheral blood dendritic cell subpopulations in African and non-African HIV-1-infected patients.

OBJECTIVES: To quantify the percentage of the two major subpopulations of blood dendritic cells (DC) in HIV-1-seropositive Ugandan individuals infected with non-clade B viruses and compare this with that seen in clade B HIV-1 infected non-African individuals. DC maturation/activation status was also investigated via the expression of CD86. METHODS: The percentage of blood DC was quantified by using flow cytometry. DC were identified as the lineage (CD3, CD14, CD16, CD19, CD20, CD56)-negative, HLA-DR-positive population and the two major subpopulations were differentiated by CD11c expression. RESULTS: The percentage of blood DC was reduced significantly in HIV-1-seropositive African individuals when compared with controls (0.21 and 0.39% respectively). A similar reduction was also seen in non-African patients residing in the UK (0.19% compared with 0.36% for controls). However, there was no selective loss in either CD11c-positive or CD11c-negative subpopulations. The percentage of blood DC expressing CD86 was significantly greater in HIV-1-seropositive individuals when compared with controls and the increased expression was largely confined to CD11c-negative DC. CONCLUSIONS: Africans infected with non-clade B HIV-1 showed similar reductions in the percentage of blood DC to non-Africans infected with clade B viruses. There was no selective loss of either DC subpopulation, suggesting that the ability of DC to acquire and present antigens or to produce interferon-alpha may both be impaired in HIV-1 infection.

Adult↗

Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults.

BACKGROUND: Falciparum malaria and HIV-1 infection are two of the most important health problems facing sub-Saharan Africa. No convincing evidence of an association between symptomatic malaria and HIV-1 infection has been found. OBJECTIVE: To investigate the effect of HIV-associated immunosuppression on malarial fever rates. DESIGN: An observational cohort study in HIV-specific, primary healthcare clinics in Entebbe, Uganda, on 1371 HIV-1-infected adults participating in a randomized trial of 23-valent pneumococcal vaccine. METHODS: Cohort members underwent routine 6 monthly surveillance and had open clinic access when sick. Episodes of fever were assessed according to standardized protocols. Rates of malaria are described according to HIV immune status determined by CD4 T cell counts. RESULTS: Incidence rates of Plasmodium falciparum malarial fever showed a marked inverse relationship with CD4 T cell count; 140, 93 and 57 cases per 1000 pyo for CD4 T cell groups < 200, 200--499 and > 500 respectively, P < 0.001. Malarial fever definitions incorporating parasite density criteria (derived from asymptomatic surveillance) to correct for chance findings of fever and P. falciparum parasitaemia, did not affect the association of incidence rates with immunosuppression. CONCLUSION: These data support an interaction between symptomatic P. falciparum and HIV. Emphasis on mosquito avoidance measures should be an important component of education and counselling of HIV/AIDS patients in malaria-endemic areas, and suggests an additional HIV-related public health problem in Africa.

AIDS-Related Opportunistic Infections↗

A half-century of Australian health and medical research.

In 1951, the Journal published an overview of medical research in Australia since Federation. This concluded that, with a few notable exceptions, discoveries were few and research funding was paltry. In contrast, in 2001, Australia has become a significant contributor to international medical research. Three Australians have been awarded Nobel Prizes for research performed in Australia, and others have received international awards. Research growth has been driven by the development of the tertiary education sector and independent medical research institutes. Nevertheless, there is no room for complacency.

Australia↗

Female control of sexuality: illusion or reality? Use of vaginal products in south west Uganda.

This paper reports on a trial of vaginal products that were distributed and used by 131 women and 21 men in south west Uganda. It focuses specifically upon the issue of female control in heterosexual relationships and examines whether methods which are ostensibly under women's control, will in practice give women greater control of their sexual health. Participants were invited to select two from a range of vaginal products that included the female condom, contraceptive sponge, film, tablets, foam and gel, and use each for five weeks and their favourite product for a further three months. They were interviewed up to seven times over a five-month period. Although the women perceived that a major advantage of the products (with the exception of the female condom) was that they could be used secretly, less than 40% were using the products without their partner's knowledge after one week and this proportion declined over time with only 22% using the products secretly after ten weeks. In the main male partners were told as women felt it their duty to inform them. In general the women were very much more positive about the products than they were about the male condom, as were the men. A contributory factor to their popularity among women was the greater control they gave them. Even though, use of these products in practice often involved negotiation with male partners, the fact that use was contingent on women's action was empowering and increased somewhat their ability to control their sexual health.

Adolescent↗

Telemetric monitoring of adrenocorticotrophin-induced hypertension in mice.

1. The mouse is the animal of choice for studies involving genetic manipulation and transgenic and knockout mice are valuable tools for physiological studies. We have studied adrenocorticotrophin (ACTH)- and steroid-induced hypertension in both rat and humans. The aim of the present study was to develop a model of ACTH-induced hypertension in the mouse and to assess a chronically implanted telemetric device for measurement of blood pressure (BP). 2. Male Swiss Outbred and Quackenbush Swiss (QS) mice (35-45 g) were implanted with TA11PA-C20 BP devices (Data Sciences International, St Paul, MN, USA) under isoflurane anaesthesia. Seven to 10 days later, mice were monitored telemetrically for baseline BP for 4 days. Mice were then randomly allocated to: (i) sham treatment with normal saline s.c.; or (ii) ACTH at 500 microg/kg per day, s.c. Mice were monitored 24 h/day for 10 days. 3. Sham treatment (n = 7) did not affect BP (114 +/- 2/84 +/- 1 to 115 +/- 2/84 +/- 1 mmHg; P = NS). Adrenocorticotrophin treatment (n = 5) raised BP from 112 +/- 7/82 +/- 4 to 138 +/- 3/104 +/- 4 mmHg, which was significantly different from sham treatment (P = 0.0021 for systolic BP; P < 0.0001 diastolic BP). The increase in BP with ACTH was comparable with that seen in previous studies in humans, sheep and rat. Sham and ACTH-treated animals each lost 3% bodyweight. 4. Administration of ACTH (500 microg/kg per day) raises BP in two strains of mice, measured using a telemetry system. This model will allow the selective use of transgenic and/or knockout mice to further elucidate the mechanism of ACTH- and steroid-induced hypertension.

Adrenocorticotropic Hormone↗

Early rise in blood pressure following administration of adrenocorticotropic hormone-[1-24] in humans.

1. An elevation in blood pressure has been consistently observed 24 h after adrenocorticotropic hormone (ACTH) administration and is caused by increased ACTH-stimulated cortisol secretion, in association with increased cardiac output. The aim of the present study was to investigate the previously undefined time of onset of this increase in blood pressure in normal humans. 2. Ten normal healthy volunteers received 250 mg ACTH-[1-24], in 500 mL normal saline, infused at a constant rate over 8 h. Six subjects also received a placebo infusion (normal saline only). Blood pressure, heart rate and cortisol levels were determined hourly. Adrenocorticotropic hormone (ACTH-[1-24] plus native ACTH) was measured at 0, 1, 7 and 8 h. 3. Infusion of ACTH-[1-24] produced maximal secretion rates of cortisol, resulting in a mean peak plasma level of 985 +/- 46 nmol/L at 8 h. In response, blood pressure and heart rate rose significantly by 2 h and remained generally elevated for the duration of the infusion. 4. The early onset of haemodynamic responses is consistent with classical steroid receptor-mediated genomic mechanisms, but could be due non-genomic mechanisms. 5. The cardiovascular consequences of therapeutic use of ACTH are well recognized. This results of the present study suggest that even diagnostic administration of ACTH, delivered over a few hours, may raise blood pressure.

Adrenocorticotropic Hormone↗

Comparison of telemetric and tail-cuff blood pressure monitoring in adrenocorticotrophic hormone-treated rats.

1. The aim of the present study was to validate a telemetric blood pressure (BP) monitoring system against tail-cuff blood pressure in both adrenocorticotrophic hormone (ACTH)- and sham-treated rats. In the statistical analyses, we first tested whether there was a detectable effect on systolic blood pressure (SBP) of 10 days treatment with ACTH compared with saline. Second, we compared results of telemetered and tail-cuff measurements and, third, we developed a novel method for estimating the relative power of the two techniques. 2. Twenty-three male Sprague-Dawley rats were randomly divided into two groups: (i) ACTH (100 microg/kg per day, s.c; n = 12) treated; or (ii) sham treated (0.9% saline, s.c; n = 11). Systolic BP was measured by the telemetric system (sampled for 10 s every 2 min) continuously for 4 h (n = 16) or for 30 min (n = 23) and also by the indirect tail-cuff method daily (n = 23). Data were compared within and between groups; ordinary least products (OLP) regression analysis was then performed to test for bias between the two methods. Sample size/power estimations were also performed. 3. Adrenocorticotrophic hormone treatment raised telemetered SBP by 11 mmHg (P < 0.001) compared with 14 mmHg (P < 0.001) using the tail-cuff method. There was no fixed or proportional bias between the two methods of measurement, as shown by regression analysis. Power calculations indicate that a minimum sample size of six gives a power of telemetered to tail-cuff of 0.84/0.86 = 0.98. The power of 4 h versus 30 min BP measurements was 0.99/0.82 = 1.2. 4. Telemetry gave very similar results to the tail-cuff method. Telemetry allows for a longer period of measurement, giving greater power to the study so that fewer animals are needed.

Adrenocorticotropic Hormone↗

Nitric oxide synthase activity in adrenocorticotrophin-induced hypertension in the rat.

1. The nitric oxide (NO) system has been implicated in the pathogenesis of various forms of experimental hypertension. We studied nitric oxide synthase (NOS) activity as a possible indicator of NO production in adrenocorticotrophin (ACTH)-induced hypertension in the rat. 2. Haemodynamic, metabolic and biochemical parameters were examined in sham (saline)- and ACTH (100 microg/kg per day)-treated male Sprague-Dawley rats (n = 20). 3. Adrenocorticotrophin treatment increased systolic blood pressure, serum corticosterone, adrenal NOS activity and adrenal nitrate and nitrite concentrations and decreased bodyweight and plasma nitrate/nitrite. 4. Previous observations of diminished NO production in ACTH- and corticosterone-induced hypertension in the rat were confirmed, but could not be explained by reduced NOS activity in the present study.

Adrenocorticotropic Hormone↗

Glucocorticoid-induced hypertension: from mouse to man.

1. Adrenocorticotrophic hormone (ACTH) raises blood pressure in humans, sheep, rat and mouse. In rat and humans, but not sheep, the hypertension can be explained by glucocorticoid excess. 2. In both rat and humans, the hypertension is associated with a rise in cardiac output and renal vascular resistance. 3. In both rat and humans, the nitric oxide system is implicated in glucocorticoid hypertension. 4. In both rat and humans, hypertension due to naturally occurring glucocorticoids is not prevented by drugs that block classical glucocorticoid or mineralocorticoid receptors. 5. Abnormalities in glucocorticoid metabolism may contribute to some forms of 'essential' hypertension.

Adrenocorticotropic Hormone↗

Breastfeeding practices and attitudes relevant to the vertical transmission of HIV in rural south-west Uganda.

Breastfeeding has been associated with a doubling of the risk of HIV transmission. In developed countries, it is recommended that HIV-positive women do not breastfeed, but this is not a feasible option in most of Africa. It is therefore important to know the extent to which breastfeeding practices are amenable to change. To study this, we carried out 24 focus group discussions with 208 women attending maternity clinics in three rural sites in rural south-west Uganda. Breastfeeding starts from a few minutes to a few days after delivery; most women reported starting after 2 days. The main reason for delay is lack of milk or that the breasts are 'blocked'. Most women thought that this delay was good for the baby, or at least not harmful. Almost all women reported giving the child a soup made of boiled mushrooms before starting to breastfeed. Once they have started breastfeeding, various supplementary foods are gradually introduced at 4-6 months. Women thought that ideally breastfeeding should last for 2-3 years, but in practice most stopped after 18 months. The father and his female relatives generally decide when the child should be weaned. The women thought that commercial milk formula foods were good but could not use them because they are too expensive and anyway unavailable in rural areas. Most women were unaware that HIV could be passed to the child through breastfeeding. Various practices identified as potentially risky are common in this population. Artificial feeding is not a viable option in this area, and although women were prepared to make sacrifices to prevent vertical transmission of HIV, practices are deeply ingrained in traditional culture and will need to be addressed in future interventions. Male partners will also need to be involved.

Adolescent↗

Attitudes to voluntary counselling and testing for HIV among pregnant women in rural south-west Uganda.

UNLABELLED: This paper describes the results of a study exploring the attitudes of women attending maternity clinics to voluntary counselling and testing during pregnancy in rural areas in south-west Uganda. It was a qualitative study using focus group discussions (FGDs). Twenty-four FGDs were carried out with 208 women attending maternity clinics in three sites in rural south-west Uganda. The FGDs were all recorded and transcribed, and analysed using standard computer-based qualitative techniques. Almost all women were willing in principle to take an HIV test in the event of pregnancy, and to reveal their HIV status to maternity staff. They were anxious, however, about confidentiality, and there was a widespread fear that maternity staff might refuse to assist them when the time came to deliver if their status were known. This applied more to traditional birth attendants than to biomedical health staff. There were also rumours about medical staff intentionally killing HIV-positive patients in order to stem the spread of the epidemic. Women were concerned that if their husbands found out they were HIV-positive they would be blamed and separation or domestic violence might result. IN CONCLUSION: although VCT during pregnancy is acceptable in principle, much will need to be done to ensure confidentiality and allay women's fears of stigmatisation and discrimination during delivery. Community sensitisation will be necessary and male partners will have to be involved if interventions are to be acceptable.

Adolescent↗

Community-based HIV/AIDS education in rural Uganda: which channel is most effective?

A process evaluation was conducted to evaluate four channels (drama, video, community educators and leaflets) used in a community-based IEC (Information, Education and Communication) HIV/AIDS intervention in rural Uganda. Semi-structured interviews (n = 37) and focus groups (n = 3) were held with community members working as field staff. In addition, two questionnaire surveys (n = 105 and n = 69) and eight focus groups were conducted with the target community. Over 85% of the community had seen at least one drama or video show. They rated them as relevant and realistic. However, the messages 'taken home' were not always those intended by the plays. Access to community educators (CEs) was not equal. The CEs had a tendency to avoid the educated, rich and their older relatives. Those who had met with a CE rated them as knowledgeable and trustworthy, but felt they would rather be taught by a trained health worker. Around 80% of the community said they had seen the leaflets, but had not necessarily read them. Although appreciated by some as reference material, low literacy levels and a lack of reading culture meant that some leaflets may have gone astray. These findings suggest that a multi-channel approach may be required to overcome weaknesses inherent in individual channels.

Community Health Services↗

Effects of oral L-arginine on plasma nitrate and blood pressure in cortisol-treated humans.

OBJECTIVE: The aim of this study was to determine whether cortisol-induced hypertension can be reversed by co-administration of oral L-arginine. STUDY DESIGN: Three studies were undertaken in healthy male human subjects. The first study addressed the effect of oral L-arginine loading on plasma arginine concentration. Study 2 addressed the effect of co-administration of cortisol with L-arginine on plasma L-arginine concentrations. Study 3 was a randomized placebo crossover control comparing the effects of cortisol 80 mg/day co-administered with a placebo to cortisol 80 mg/day co-administered with L-arginine 21 g/day. METHODS: Blood pressure was measured by a random Hawksley sphygmomanometer. Plasma nitrate/nitrite concentrations were measured by a modified Greiss reaction. Plasma arginine and citrulline concentrations were measured by an automated amino acid analyser. RESULTS: Plasma arginine concentrations were doubled by oral doses of 15 g/day and 21 g/day of L-arginine (study 1). Co-administration of cortisol did not alter plasma arginine concentrations in subjects taking 21 g of L-arginine per day (study 2). Co-administration of L-arginine 21 g/day with cortisol 80 mg/day did not prevent cortisol-induced increases in blood pressure or cortisol-induced falls in plasma nitrate/nitrite concentrations. CONCLUSION: Cortisol-induced hypertension is accompanied by a fall in plasma nitrate/nitrite concentrations. Oral L-arginine administration does not prevent cortisol-induced falls in plasma nitrate/nitrite concentrations or increases in blood pressure. We propose that cortisol-induced reductions in nitrate/nitrite production occur at a point distal to L-arginine availability in the nitric oxide synthase pathway.

Administration, Oral↗