The role of sustained release isosorbide mononitrate on corticosteroid-induced hypertension in healthy human subjects.

There is evidence implicating abnormalities in the nitric oxide (NO) pathway in the development of glucocorticoid-induced hypertension (GC-HT). In humans, a reduction in NO availability during cortisol treatment has been observed. This study examined whether the NO donation may reverse the elevated blood pressure (BP) observed with cortisol treatment. A randomised double-blind, placebo-controlled, crossover study was undertaken in eight healthy men to address the effect of co-administration of isosorbide mononitrate (ISMN, 60 mg single dose, day 5) with cortisol (200 mg per day, days 1-6) and then compared with placebo (single dose, day 5) with cortisol. After a 2-week washout period, subjects crossed over to the alternate treatment. BP measurements were obtained using a mercury sphygmomanometer. Tonometry was used to estimate central pressures. There was a significant rise in mean arterial pressure with cortisol: 80 ± 3 vs 89 ± 3 mm Hg (day 1 vs day 5, cortisol+ISMN phase, P < 0.001) and 81 ± 3 vs 89 ± 3 mm Hg (day 1 vs day 5, cortisol+placebo phase, P < 0.01). ISMN significantly decreased aortic augmentation index: -17.3 ± 3.2 vs 1.8 ± 3.5%, (differences calculated from day 5-day 1, cortisol/ISMN vs cortisol+placebo, P < 0.001). These results demonstrated that GC-HT can be modified by co-administration of exogenous NO donors, consistent with the hypothesis that GC-HT is accompanied by reduced NO activity in humans.

Science funding in low- and middle-income countries: the example of vaccine research.

There has been a recent increase in funding sources and overall commitment to tackle global health issues and reduce morbidity and mortality. The Wellcome Trust, the UK's largest charity, has a long track record of funding research in global health and has developed a new research strategy to tackle these issues. Here, we describe the Wellcome Trust's approach to funding researchers in low- and middle-income countries with a focus on how our funding portfolio supports vaccine delivery and development, with specific reference to mucosal immunity.

Decreased threshold for the nitric oxide donor glyceryl trinitrate in cortisol-induced hypertension in humans.

1. Decreased nitric oxide (NO) availability is thought to be a feature of cortisol-induced hypertension in humans. 2. We hypothesized that, accordingly, the threshold for a depressor response to NO should be decreased by cortisol treatment. 3. We re-analysed data from a study of baroreflex function in normal men treated with cortisol using glyceryl trinitrate (GTN). 4. Cortisol treatment increased blood pressure and decreased the threshold dose of GTN for a fall in systolic and mean blood pressure. 5. These data support the notion that glucorticoid hypertension is associated with reduced NO bioavailability.

Association between active GB virus-C (hepatitis G) infection and HIV-1 disease in Uganda.

Although not linked to a disease, GB virus-C viraemia has been associated with an improved prognosis in HIV-1-co-infected individuals. Most studies have been conducted on men (men who have sex with men or injection drug users) infected with HIV-1 subtype B, whereas here we report on both male and female subjects from rural Uganda, predominantly infected via the heterosexual route with HIV-1 subtypes A and D. In a longitudinal study of 272 participants, 47 were GBV-C positive and 181 negative, as determined by reverse transcription-polymerase chain reaction, in both of two plasma samples taken a median of 5.0 years apart. The remainder either acquired (25) or cleared (19) infection. Multilevel regression analyses and Cox survival analyses revealed that participants chronically infected with GBV-C had a slower decline in CD4(+) T cells (P<0.001) and increased survival time (P=0.041) compared with GBV-C RNA-negative, HIV-positive adults. We show that the association between active GBV-C co-infection and improved survival of HIV-1-infected adults is not restricted to HIV subtype B, but is also observed in both males and females infected with HIV subtypes A and D.

Human immunodeficiency virus (HIV) in developing countries.

The human immunodeficiency virus (HIV) is causing the most destructive epidemic of recent times, having been responsible for the deaths of more than 25 million people since it was first recognised in 1981. This global epidemic remains out of control, with reported figures for 2005 of 40 million people infected with HIV. During 2005 there were 4.9 million new infections, showing that transmission is not being prevented, and there were 3.1 million deaths from the acquired immunodeficiency syndrome (AIDS), reflecting the lack of a definitive cure and the limited access to suppressive antiretroviral treatment in the developing countries that are most severely affected. The current state of the epidemic and the response to date are here reviewed. Present and future opportunities for prevention, treatment and surveillance are discussed, with particular reference to progress towards an HIV vaccine, the expansion of the provision of highly active antiretroviral therapy, and the need to focus control programmes on HIV as an infectious disease, rather than as a development issue.

Understanding sexual behaviour change in rural southwest Uganda: a multi-method study.

Studies report substantial sexual behaviour change in Africa in response to HIV/AIDS. Generally there seems to be an increase in condom use and a reduction in partners, with men reporting more change than women. However, it is not only important to know whether people are changing their sexual behaviour but also their reasons for changing and the consistency and extent of change. Between 1996 and 2000 a study involving 196 respondents was carried out in rural southwest Uganda to investigate the exact nature of behaviour change and the reasons for change or lack of change since people became aware of HIV/AIDS. Data were collected from three rounds of questionnaire surveys, four rounds of open in-depth interviews, six rounds of semi-structured interviews and from informal conversations and participant observation. In order to obtain a comprehensive assessment of behaviour change the data for each participant from all sources were compared and discrepancies were then followed up by re-interviewing participants. After triangulation between all sources of data, 48% of respondents had ever used a condom. Condom use in 76% of all cases was at least partly AIDS related, while 19% was exclusively for protection against HIV. Condom use tended to be sporadic: only 13% of condom users currently used a condom regularly and most of this use was for family planning. After triangulation, 45% had reduced the number of sexual partners. Of all partner reductions, 93% was at least partly AIDS related; 29% was exclusively to avoid HIV. Half of those who had reduced the number of partners either stuck to one partner or abstained. Men reported more change than women. Of those who reported no partner reduction, 89% could not reduce the number of partners because they already had only few or a single partner or abstained; most of these were women. Most of those who could change their sexual behaviour had already changed, though the degree of change (particularly condom use) was often minimal. Not only behaviour change, but also the maintenance of safe behaviour is important. Also, understanding reasons for change and extent and consistency of change are important when planning and evaluating interventions.

Aetiology of sexually transmitted infections and response to syndromic treatment in southwest Uganda.

OBJECTIVE: To determine the aetiology of genital ulcers and discharges in rural south western Uganda and to assess response to syndromic treatment. METHOD: A longitudinal, prospective study using laboratory testing and questionnaires to evaluate 561 adult men and women presenting with clinically verified genital ulcers, urethral, or vaginal discharge at a general outpatient clinic and two health centres between December 1999 and July 2001. RESULTS: One third of patients had genital ulcers and two thirds discharges. There was good response to treatment in 461/508 patients (90.7%). Herpes simplex virus type 2 was found in 95/217 (43.8%) genital ulcers. In 24.1% of ulcer cases there was also a genital discharge. HIV seropositivity was high in ulcer cases (63.2%), with significantly more HSV2 and secondary bacterial infection than in seronegative cases. Neisseria gonorrhoeae was found in 135/204 (66.2%) male genital discharges. Female genital discharges were mostly associated with bacterial vaginosis (36.1%), Trichomonas vaginalis (18.9%), and candidiasis (18.6%). CONCLUSIONS: The aetiological pattern of STI syndromes reported will help inform revision of national STI guidelines. The importance of herpes simplex virus type 2, the variation in causes of genital ulcers according to HIV serostatus, the high frequency of multiple infections and secondary bacterial contamination of genital ulcers are notable. These results help explain the lack of effect of an STI intervention on HIV incidence in a recent trial in this area.

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.

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.

The effect of tuberculin skin testing on viral load and anti-mycobacterial immune responses in HIV-1-infected Ugandan adults.

OBJECTIVE: To determine whether tuberculin skin testing (TST) is associated with an increase in human immunodeficiency virus (HIV) viral load, and to examine the effect of TST on anti-mycobacterial immune responses. DESIGN: A nested cohort study of HIV-1-infected adults. METHOD: Forty-two participants (21 TST-positive and 21 TST-negative) from a larger cohort were recruited to the study. Blood was collected for CD4+ T-cell count, whole blood was cultured, and plasma saved for viral load. These measurements were taken before, 3 days after, 3 months after, and 3 months plus 3 days after TST. Cytokine responses to culture filtrate proteins (CFP) of Mycobacterium tuberculosis and phytohaemagglutinin (PHA) were examined in the whole blood assay. RESULTS: Twenty-nine participants attended all four visits. No statistically significant change in viral load, CD4+ T-cell count, or cytokine response to PHA was observed at any visit. However, TST was associated with a transient increase in the interferon-gamma response to CFP and a lasting increase in the interleukin-5 response to CFP. CONCLUSION: There appeared to be a systemic effect of TST on the anti-tuberculosis immune response.

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.

Community sex education among adolescents in rural Uganda: utilizing indigenous institutions.

Although adolescent girls in Uganda are particularly vulnerable to HIV infection, providing relevant sexual health education to them is problematic. The senga (father's sister), is the traditional channel for socializing adolescent girls into sex and marriage among many ethnic groups in Uganda. This paper discusses the implementation and community acceptability of 'modern' sengas who were trained to provide HIV-related counselling to adolescent girls. Fourteen sengas were trained in two villages and, in the course of the 1-year study, 247 individuals made a total of 403 visits to them. By including both traditional services (such as advice on and assistance with labial elongation) and modern health and sex education, the sengas provided a 'middle road' between tradition and modernity. As a result, despite initial suspicion by the community, their activities were supported by the community generally and effective as intervention.

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.

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.

Incidence of visual loss in rural southwest Uganda.

BACKGROUND: Surveys have been conducted to measure prevalence of eye disease in Africa, but not of incidence, which is needed to forecast trends. The incidence of visual loss is reported in southwest Uganda. METHODS: A rural population residing in 15 neighbouring villages was followed between 1994-5 (R1) and 1997-8 (R2). Survey staff screened adult residents (13 years or older) for visual acuity using laminated Snellen's E optotype cards at each survey. Those who failed (VA >6/18) were evaluated by an ophthalmic clinical officer and an ophthalmologist. Incidence of visual loss (per 1000 person years (PY)) was calculated among those who had normal vision at R1. RESULTS: 2124 people were studied at both survey rounds (60.9% of those screened at R1); 48% were male. Participants in R1 were older (34.7 versus 31.5 years at R2, p<0.001). Visual loss in R2 occurred in 56 (2.8%) of 1997, yielding a crude incidence rate of 9.9, and an age standardised incidence rate of 13.2, per 1000 PY. Incidence of visual loss increased with age from 1.21 per 1000 PY among people aged 13-34 to 64.2 per 1000 PY in those aged 65 years or older (p for trend >0.001). The six commonest causes of visual loss were: cataract, refractive error, macular degeneration, chorioretinitis, glaucoma, and corneal opacity. If similar rates are assumed for the whole of Uganda, it is estimated that 30 348 people would develop bilateral blindness or bilateral visual impairment, per year. CONCLUSIONS: Cataract and refractive error were the major causes of incident visual loss in south west Uganda. These data are valuable for forecasting and planning eye services.

Social marketing of pre-packaged treatment for men with urethral discharge (Clear Seven) in Uganda.

We implemented social marketing of pre-packaged treatment for men with urethral discharge (Clear Seven) in Uganda, and studied its feasibility, acceptability and effectiveness as a possible means to treat STDs and thereby prevent HIV. Clear Seven was distributed at private health care outlets in three rural districts and two divisions of the capital. Comparisons were made with a pre-intervention period in the same sites plus one additional rural district. There were almost universally positive attitudes to Clear Seven. Cure rate (84% versus 47%), treatment compliance (93% versus 87%), and condom use during treatment (36% versus 18%) were significantly higher among Clear Seven users (n=422) than controls (n=405). Partner referral was similar but fewer Clear Seven partners were symptomatic when seeking treatment. Distribution of socially marketed pre-packaged treatment for male urethritis should be expanded in sub-Saharan Africa. Consideration should be given to developing similar kits for women.

HIV-1 epidemic trends in rural south-west Uganda over a 10-year period.

The objective of this study was to examine the epidemic trends of HIV-1 infection in a rural population cohort in Uganda followed for 10 years. The methods used were to assess incidence and prevalence trends in adults in this longitudinal cohort study. The results showed that incidence of infection has fallen significantly in all adults, and separately in males, females, young adults and older adults over the course of the study period. There was also a reduction in prevalence, especially in young men and women. There was some evidence of a cohort effect in women. The conclusions are that this study provides the first evidence of a falling incidence in a rural general population in Africa. This was an observational cohort exposed to national health education messages, giving hope that similar campaigns elsewhere in Africa could be used effectively in efforts to control the HIV epidemic.