Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming

Epidemiological studies in many distinct human populations have associated low weight or thinness at birth with a substantially increased risk of cardiovascular and metabolic disorders, including hypertension and insulin resistance/type 2 diabetes, in adult life. The concept of fetal "programming" has been advanced to explain this phenomenon. Prenatal glucocorticoid therapy reduces birthweight, and steroids are known to exert long-term organizational effects during specific "windows" of development. Therefore, we hypothesized that fetal overexposure to endogenous glucocorticoids might underpin the link between early life events and later disease. In rats, birthweight is reduced following prenatal exposure to the synthetic glucocorticoid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental "barrier" to endogenous glucocorticoids. Although the offspring regain the weight deficit by weaning, as adults they exhibit permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis activity. Moreover, physiological variations in placental 11beta-HSD2 activity near term correlate directly with fetal weight. In humans, 11beta-HSD2 gene mutations produce a low birthweight, and some studies show reduced placental 11beta-HSD2 activity in association with intrauterine growth retardation. Moreover, low birthweight babies have higher plasma cortisol levels throughout adult life, indicating that hypothalamic-pituitary-adrenal axis programming also occurs in humans. The molecular mechanisms of glucocorticoid programming are beginning to be unraveled and involve permanent and tissue-specific changes in the expression of key genes, notably of the glucocorticoid receptor itself. Thus, glucocorticoid programming may explain, in part, the association between fetal events and subsequent disorders in adult life.     

Preventing recurrent tuberculosis in high HIV-prevalent areas in sub-Saharan Africa: what are the options for tuberculosis control programmes?

Several studies conducted in sub-Saharan Africa have pointed to an increased risk of recurrent TB in patients who are HIV-seropositive. Routine case notification data from the Malawi Tuberculosis Programme, which has improved its registration practices in the last two years, shows that recurrent TB (smear-positive and smear-negative TB) constitutes 9% of total notifications. The objectives of reducing rates of recurrent TB are 1) to complement other interventions to decrease TB incidence rates and transmission of disease, 2) to reduce TB-specific morbidity and mortality and 3) to restore confidence amongst health care staff and patients about the effectiveness of the current TB control strategy. Four possible options for reducing recurrent TB are discussed, and for each option this includes the evidence for effectiveness, current practice and operational considerations. The options are 1) using rifampicin and isoniazid (RH) in the continuation phase of treatment, 2) extending the duration of the continuation phase, 3) providing post-treatment isoniazid prophylaxis to HIV-positive patients who have completed treatment and 4) treating HIV-positive TB patients with highly active antiretroviral therapy (HAART). The last three options all require that TB patients know their HIV serostatus. The authors suggest that this issue of recurrent TB should be considered as one of the important areas for debate and action when considering the dual TB/HIV epidemic.     

Maximizing HIV partner notification opportunities for index patients and their sexual partners in Malawi

Introduction

HIV testing and counselling (HTC) is important to effect positive sexual behaviour change and is an entry point to treatment, care, and psychosocial support. One of the most practical initiatives to increase HTC is to encourage sexual partners of HIV-infected persons to test for HIV. However, partner notification strategies must be feasible in the healthcare setting and acceptable to the population.

Methods

We conducted a qualitative study during the pilot phase of an HIV partner notification trial to complement its assessment of feasibility and acceptability of methods of partner notification. We performed in-depth interviews with 16 consecutive HIV-positive index participants who consented and their 12 identifiable sexual partners. We also conducted two focus group discussions with healthcare workers to supplement the patient perspectives.In the main study, newly diagnosed HIV cases (index cases) were randomized to one of three methods of partner notification: passive, contract, and provider referral. Clients in the passive referral group were responsible for notifying their sexual partners themselves. Individuals in the contract referral group were given seven days to notify their partners, after which a healthcare provider contacted partners who had not reported for counselling and testing. In the provider group, a healthcare provider notified partners directly.

Results

Although most index participants and partners expressed a preference for passive notification, they also highlighted benefits for provider-assisted notification and the universal right for all HIV-exposed persons to know their HIV exposure and benefit from HIV testing and access antiretroviral treatment. Several participants mentioned couples counselling as a way to diffuse tension and get accurate information. All mentioned benefits to HIV testing, including the opportunity to change behaviour.

Conclusions

Provider-assisted partner notification is not preferred, but it is acceptable and may complement the passive method of notification. Couples counselling should also be encouraged.     

Poor attendance at a child TB contact clinic in Malawi.

SETTING: Child tuberculosis (TB) contact clinic, Queen Elizabeth Central Hospital, Blantyre, Malawi. DESIGN: Patients registered with smear-positive pulmonary TB (PTB) were encouraged to bring childhood household contacts to the clinic for assessment and management. Data of TB cases registered over the same period were collected from the Blantyre District TB Office. RESULTS: Attendance at the contact clinic was very poor, representing only 7.7% of all adults registered with smear-positive PTB over 17 months, and was significantly lower for potential male source cases than females (OR 0.36, 95% CI 0.23-0.55, P < 0.001). DISCUSSION: Improved uptake and implementation of child contact management in Malawi is a challenge.     

Prevalence and correlates of depression among HIV-infected and -affected older people in rural South Africa

Background

Little is known about depression in older people in sub-Saharan Africa, the associated impact of HIV, and the influence on health perceptions.

Objectives

Examine the prevalence and correlates of depression; explore the relationship between depression and health perceptions in HIV-infected and -affected older people.

Methods

In 2010, 422 HIV-infected and -affected participants aged 50+ were recruited into a cross-sectional study. Nurse professionals interviewed participants and a diagnosis of depressive episode was derived from the Composite International Diagnostic Interview (Depression module) using the International Classification of Diseases diagnostic criteria and categorised as major (MDE) or brief (BDE).

Results

Overall, 42.4% (n=179) had a depressive episode (MDE: 22.7%, n=96; BDE: 19.7%, n=83). Prevalence of MDE was significantly higher in HIV-affected (30.1%, 95% CI 24.0–36.2%) than HIV-infected (14.8%, 95% CI 9.9–19.7%) participants; BDE was higher in HIV-infected (24.6%, 95% CI 18.7–30.6%) than in HIV-affected (15.1%, 95% CI 10.3–19.8%) participants. Being female (aOR 3.04, 95% CI 1.73–5.36), receiving a government grant (aOR 0.34, 95% CI 0.15–0.75), urban residency (aOR 1.86, 95% CI 1.16–2.96) and adult care-giving (aOR 2.37, 95% CI 1.37–4.12) were significantly associated with any depressive episode. Participants with a depressive episode were 2–3 times more likely to report poor health perceptions.

Limitations

Study limitations include the cross-sectional design, limited sample size and possible selection biases.

Conclusions

Prevalence of depressive episodes was high. Major depressive episodes were higher in HIV-affected than HIV-infected participants. Psycho-social support similar to that of HIV treatment programmes around HIV-affected older people may be useful in reducing their vulnerability to depression.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Impact of pyrethroid resistance on operational malaria control in Malawi

The impact of insecticide resistance on insect-borne disease programs is difficult to quantify. The possibility of eliminating malaria in high-transmission settings is heavily dependent on effective vector control reducing disease transmission rates. Pyrethroids are the dominant insecticides used for malaria control, with few options for their replacement. Their failure will adversely affect our ability to control malaria. Pyrethroid resistance has been selected in Malawi over the last 3 y in the two major malaria vectors Anopheles gambiae and Anopheles funestus, with a higher frequency of resistance in the latter. The resistance in An. funestus is metabolically based and involves the up-regulation of two duplicated P450s. The same genes confer resistance in Mozambican An. funestus, although the levels of up-regulation differ. The selection of resistance over 3 y has not increased malaria transmission, as judged by annual point prevalence surveys in 1- to 4-y-old children. This is true in areas with long-lasting insecticide-treated nets (LLINs) alone or LLINs plus pyrethroid-based insecticide residual spraying (IRS). However, in districts where IRS was scaled up, it did not produce the expected decrease in malaria prevalence. As resistance increases in frequency from this low initial level, there is the potential for vector population numbers to increase with a concomitant negative impact on control efficacy. This should be monitored carefully as part of the operational activities in country.The push for malaria elimination and eventual eradication will be heavily dependent on our ability to reduce disease transmission. A recent editorial suggests that we have the tools to take on this challenge in African malaria heartlands (1). This is predicated on ensuring that vector control prevention and drug treatment tools are fully deployed, reaching every person at risk. There will need to be improved delivery of these tools and better clinical management of malaria cases. In highly endemic areas our ability to reduce malaria transmission will be dependent on vector control, before the focus can shift to killing the parasite in infected people. Two forms of vector control, indoor residual spraying (IRS) and the distribution of long-lasting insecticide-treated nets (LLINs) have been demonstrated to reduce transmission when properly deployed against insecticide susceptible mosquito populations. The use of both interventions has dramatically increased since 2000 in many malaria endemic countries, with increased donor funding to attain the Roll Back Malaria targets and support the malaria elimination agenda (2).IRS and LLINs function by reducing the female mosquito daily survival rate and human biting frequency. Pyrethroids are the only insecticides recommended for use on LLINs, and only four chemical classes of insecticides that attack two target sites are available for IRS, and again pyrethroids dominate the IRS market. Resistance to pyrethroids has been selected in Anopheles gambiae and Anopheles funestus, the major African malaria vectors, although the frequency and level (fold) resistance conferred can vary dramatically. The impact of this resistance on the ability of either control intervention to reduce disease transmission is poorly understood, and current monitoring and evaluation practices are not sufficiently robust to assess this unless catastrophic failures occur. The perceived threat of pyrethroid resistance is now sufficiently high for the World Health Organization (WHO) to convene an international multidonor effort to counteract this.Operationally significant pyrethroid resistance has the potential to limit effective malaria control, owing to the small number of alternative public health insecticides. Pyrethroid resistance in malaria vectors has increased dramatically over the last decade (3, 4), particularly in Africa, where the bulk of malaria-related mortality occurs. Typically resistance is monitored by bioassays, for which the WHO has defined a diagnostic dosage for each insecticide that kills susceptible anopheline mosquitoes (5). Mosquitoes surviving the diagnostic dosage are an indication that resistance has been selected and that an operational problem may be developing, but bioassays alone do not signify control failure.Little operational monitoring of the underlying mechanisms of resistance occurs. Two mechanisms are predominantly responsible for insecticide resistance: changes in the insecticide target site, reducing binding of the insecticide, and increases in the rate at which the insecticide is metabolized (6). Information on the resistance mechanisms is more predictive than bioassays, providing information on the level of resistance and potential cross-resistance between insecticides. For example, two common mutations in the sodium channel convey low-level resistance to pyrethroids and higher-level resistance to dichlorodiphenyltrichloroethane (DDT) in An. gambiae (7, 8), whereas a cytochrome P450-based metabolic regulatory mechanism conveys very high-level pyrethroid and low-level carbamate resistance in An. funestus (9).Vector control interventions are being rapidly scaled up in Malawi, where malaria is highly endemic. Malaria accounts for 34% of all outpatient hospital visits and is the main cause of hospital admissions in children aged <5 y (10). Before 2007 sporadic WHO bioassays were undertaken, which indicated that the two major malaria vectors, An. gambiae and An. funestus, remained fully susceptible to pyrethroids. In 2007 pyrethroid-impregnated LLINs were distributed through antenatal and under-5 clinics at district and central hospitals countrywide. The numbers distributed were sufficient to achieve the Roll Back Malaria targets of 80% of pregnant women and children aged <5 y sleeping under a treated net. In 2008, a pilot study of IRS with the pyrethroid lambda cyhalothrin (ICON, Syngenta) was initiated in Nkhota Khota District, supported by the President’s Malaria Initiative (PMI). The initial program targeted 26,950 houses, and was expanded to 74,772 houses in 2009. Approximately 4 million LLINs were procured and ∼2 million distributed during this time. In 2010 the PMI-supported IRS was expanded to cover the whole of Nkohta Khota district, and the Malawian Ministry of Health supported IRS in a further six districts.A series of sentinel sites were established during this period to track the effect of this rapid increase in insecticide selection pressure on the local vectors and assess any impact on malaria transmission. This was particularly pertinent owing to the high levels of pyrethroid resistance reported in the southern part of neighboring Mozambique in An. funestus, which had prompted a switch from pyrethroids to carbamates or DDT for IRS in the Lubombo Spatial Development Initiative area of Mozambique (11, 12).     

Malaria elimination in Malawi: research needs in highly endemic, poverty-stricken contexts

Malaria control in the impoverished, highly endemic settings of sub-Saharan Africa remains a major public health challenge. Successes have been achieved only where sustained, concerted, multi-pronged interventions have been instituted. As one of the world's poorest countries, Malawi experiences malaria incidence rates that have remained high despite a decade of gradually expanding and more intensive prevention efforts. The Malawi International Center for Excellence in Malaria Research (ICEMR) is beginning work to augment the knowledge base for reducing Plasmodium transmission and malaria morbidity and mortality. Among ICEMR goals, we intend to better assess patterns of infection and disease, and analyze transmission by Anopheles vector species in both urban and rural ecological settings. We will evaluate parasite population genetics and dynamics, transmission intensities and vector ecologies, social and environmental determinants of disease patterns and risk, and human-vector-parasite dynamics. Such context-specific information will help to focus appropriate prevention and treatment activities on efforts to control malaria in Malawi. In zones of intense and stable transmission, like Malawi, elimination poses particularly thorny challenges - and these challengers are different from those of traditional control and prevention activities. Working toward elimination will require knowledge of how various interventions impact on transmission as it approaches very low levels. At present, Malawi is faced with immediate, context-specific problems of scaling-up prevention and control activities simply to begin reducing infection and disease to tolerable levels. The research required to support these objectives is critically evaluated here.