Anuraj H. Shankar

Zinc and immune function: the biological basis of altered resistance to infection.

Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation.

Countdown to 2015 for maternal, newborn, and child survival: the 2008 report on tracking coverage of interventions.

BACKGROUND The Countdown to 2015 for Maternal, Newborn, and Child Survival initiative monitors coverage of priority interventions to achieve the Millennium Development Goals (MDG) for reduction of maternal and child mortality. We aimed to report on 68 countries which have 97% of maternal and child deaths worldwide, and on 22 interventions that have been proven to improve maternal, newborn, and child survival. METHODS We selected countries with high rates of maternal and child deaths, and interventions with the most potential to avert such deaths. We analysed country-specific data for maternal and child mortality and coverage of selected interventions. We also tracked cause-of-death profiles; indicators of nutritional status; the presence of supportive policies; financial flows to maternal, newborn, and child health; and equity in coverage of interventions. FINDINGS Of the 68 priority countries, 16 were on track to meet MDG 4. Of these, seven had been on track in 2005 when the Countdown initiative was launched, three (including China) moved into the on-track category in 2008, and six were included in the Countdown process for the first time in 2008. Trends in maternal mortality that would indicate progress towards MDG 5 were not available, but in most (56 of 68) countries, maternal mortality was high or very high. Coverage of different interventions varied widely both between and within countries. Interventions that can be routinely scheduled, such as immunisation and antenatal care, had much higher coverage than those that rely on functional health systems and 24-hour availability of clinical services, such as skilled or emergency care at birth and care of ill newborn babies and children. Data for postnatal care were either unavailable or showed poor coverage in almost all 68 countries. The most rapid increases in coverage were seen for immunisation, which also received significant investment during this period. INTERPRETATION Rapid progress is possible, but much more can and must be done. Focused efforts will be needed to improve coverage, especially for priorities such as contraceptive services, care in childbirth, postnatal care, and clinical case management of illnesses in newborn babies and children.Background The Countdown to 2015 for Maternal, Newborn, and Child Survival initiative monitors coverage of priority interventions to achieve the Millennium Development Goals (MDG) for reduction of maternal and child mortality. We aimed to report on 68 countries which have 97% of maternal and child deaths worldwide, and on 22 interventions that have been proven to improve maternal, newborn, and child survival.

Anaemia in low-income and middle-income countries

Anaemia affects a quarter of the global population, including 293 million (47%) children younger than 5 years and 468 million (30%) non-pregnant women. In addition to anaemias adverse health consequences, the economic effect of anaemia on human capital results in the loss of billions of dollars annually. In this paper, we review the epidemiology, clinical assessment, pathophysiology, and consequences of anaemia in low-income and middle-income countries. Our analysis shows that anaemia is disproportionately concentrated in low socioeconomic groups, and that maternal anaemia is strongly associated with child anaemia. Anaemia has multifactorial causes involving complex interaction between nutrition, infectious diseases, and other factors, and this complexity presents a challenge to effectively address the population determinants of anaemia. Reduction of knowledge gaps in research and policy and improvement of the implementation of effective population-level strategies will help to alleviate the anaemia burden in low-resource settings.

Nutritional modulation of malaria morbidity and mortality.

This review critically examines the relationship between nutritional status and malaria. The data indicate that protein-energy malnutrition is associated with greater malaria morbidity and mortality in humans. In addition, controlled trials of either vitamin A or zinc supplementation show that these nutrients can substantially reduce clinical malaria attacks. Data for iron indicate that supplementation may minimally aggravate certain malariometric indices in some settings and also strongly improve hematologic status. Withholding of iron supplements from deficient population is, therefore, not currently indicated. Available evidence for other nutrients describe varied effects, with some deficiencies being exacerbative (e.g., thiamine), protective (e.g., vitamin E), or both exacerbative and protective in different settings (e.g., riboflavin, vitamin C). The roles of folate, other B vitamins, unsaturated fatty acids, amino acids, and selenium are also examined. Study of the interactions between nutrition and malaria may provide insight to protective mechanisms and result in nutrient-based interventions as low-cost and effective adjuncts to current methods of malaria prevention and treatment.

Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomised trial

BACKGROUND Many individuals at risk of malaria also have micronutrient deficiencies that may hamper protective immunity. Vitamin A is central to normal immune function, and supplementation has been shown to lower the morbidity of some infectious diseases. We investigated the effect of vitamin A supplementation on malaria morbidity. METHODS This randomised double-blind placebo-controlled trial of vitamin A supplementation took place in a P. falciparum endemic area of Papua New Guinea. Of 520 potentially eligible children aged 6-60 months, 480 were randomly assigned high-dose vitamin A (n=239) or placebo (n=241), every 3 months for 13 months. Malaria morbidity was assessed through weekly community-based case detection and surveillance of patients who self-reported to the health centre. Cross-sectional surveys were also done at the beginning, middle, and end of the study to assess malariometric indicators. Analyses were by intention to treat. FINDINGS The number of P. falciparum febrile episodes (temperature > or = 37.5 degrees C with a parasite count of at least 8000/microL) was 30% lower in the vitamin A group than in the placebo group (178 vs 249 episodes; relative risk 0.70 [95% CI 0.57-0.87], p=0.0013). At the end of the study P. falciparum geometric mean density was lower in the vitamin A than the placebo group (1300 [907-1863] vs 2039 [1408-2951]) as was the proportion with spleen enlargement (125/196 [64%] vs 148/207 [71%]); neither difference was significant (p=0.093 and p=0.075). Children aged 12-36 months benefited most, having 35% fewer febrile episodes (89 vs 141; relative risk 0.65 [14-50], p=0.0023), 26% fewer enlarged spleens (46/79 [58%] vs 67/90 [74%], p=0.0045), and a 68% lower parasite density (1160 [95% CI 665-2022] vs 3569 [2080-6124], p=0.0054). Vitamin A had no consistent effect on cross-sectional indices of proportion infected or with anaemia. INTERPRETATION Vitamin A supplementation may be an effective low-cost strategy to lower morbidity due to P. falciparum in young children. The findings suggest that clinical episodes, spleen enlargement, and parasite density are influenced by different immunological mechanisms from infection and anaemia.

Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival.

Mild-to-moderate zinc deficiency may be relatively common worldwide, but the public health importance of this degree of zinc deficiency is not well defined. The purpose of this review was to provide a conceptual framework for evaluating the public health importance of maternal zinc deficiency as it relates to fetal growth and development, complications of pregnancy, labor and delivery, and maternal and infant health. The mechanisms through which zinc deficiency could influence health outcomes are well described. The results of experimental studies conducted in animal models have motivated concern about the potential health effects of mild-to-moderate maternal zinc deficiency. Observational studies in human populations have produced strong associations between poor maternal zinc status and various indicators of poor pregnancy outcome, but supplementation trials have not produced strong, or even consistent results. Supplementation trials are needed to define the public health importance of maternal zinc deficiency worldwide.

Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia: a double-blind cluster-randomised trial.

Background Maternal nutrient supplementation in developing countries is generally restricted to provision of iron and folic acid (IFA). Change in practice toward supplementation with multiple micronutrients (MMN) has been hindered by little evidence of the eff ects of MMN on fetal loss and infant death. We assessed the eff ect of maternal supplementation with MMN, compared with IFA, on fetal loss and infant death in the setting of routine prenatal care services.BACKGROUND Maternal nutrient supplementation in developing countries is generally restricted to provision of iron and folic acid (IFA). Change in practice toward supplementation with multiple micronutrients (MMN) has been hindered by little evidence of the effects of MMN on fetal loss and infant death. We assessed the effect of maternal supplementation with MMN, compared with IFA, on fetal loss and infant death in the setting of routine prenatal care services. METHODS In a double-blind cluster-randomised trial in Lombok, Indonesia, we randomly assigned 262 midwives to distribute IFA (n=15 ,86) or MMN (n=15,804) supplements to 31 290 pregnant women through government prenatal care services that were strengthened by training and community-based advocacy. Women obtained supplements, to be taken daily, every month from enrolment to 90 days post partum. The primary outcome was early infant mortality (deaths until 90 days post partum). Secondary outcomes were neonatal mortality, fetal loss (abortions and stillbirths), and low birthweight. Analysis was by intention to treat. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN34151616. FINDINGS Infants of women consuming MMN supplements had an 18% reduction in early infant mortality compared with those of women given IFA (35.5 deaths per 1000 livebirths vs 43 per 1000; relative risk [RR] 0.82, 95% CI 0.70-0.95, p=0.010). Infants whose mothers were undernourished (mid upper arm circumference <23.5 cm) or anaemic (haemoglobin <110 g/L) at enrolment had a reduction in early infant mortality of 25% (RR 0.75, 0.62-0.90, p=0.0021) and 38% (RR 0.62, 0.49-0.78, p<0.0001), respectively. Combined fetal loss and neonatal deaths were reduced by 11% (RR 0.89, 0.81-1.00, p=0.045), with significant effects in undernourished (RR 0.85, 0.73-0.98, p=0.022) or anaemic (RR 0.71, 0.58-0.87, p=0.0010) women. A cohort of 11 101 infants weighed within 1 h of birth showed a 14% (RR 0.86, 0.73-1.01, p=0.060) decreased risk of low birthweight for those in the MMN group, with a 33% (RR 0.67, 0.51-0.89, p=0.0062) decrease for infants of women anaemic at enrolment. INTERPRETATION Maternal MMN supplementation, as compared with IFA, can reduce early infant mortality, especially in undernourished and anaemic women. Maternal MMN supplementation might therefore be an important part of overall strengthening of prenatal-care programmes.

Molecular assays for surveillance of antifolate-resistant malaria

to detect all known DHFR and DHPSmutations, and correlations were determined betweenDHFR and DHPS genotypes and therapeutic responsedefined as sensitive (S), RI, RII, or RIII resistance.A genotype defined by DHFR mutations Asn-108, Ile-51,and Leu-164 combined with DHPS mutations Gly-437,Glu-540, and Gly-581 was detected in 7/8 cases (87·5%) ofRIII resistance, 9/13 cases (69·2%) of RII resistance, 5/13cases (38·5%) of RI resistance, and 0/11 sensitive cases(0·0%) (figure). The Bolivia repeat mutation at codon 30,

Making stillbirths count, making numbers talk - Issues in data collection for stillbirths

BackgroundStillbirths need to count. They constitute the majority of the worlds perinatal deaths and yet, they are largely invisible. Simply counting stillbirths is only the first step in analysis and prevention. From a public health perspective, there is a need for information on timing and circumstances of death, associated conditions and underlying causes, and availability and quality of care. This information will guide efforts to prevent stillbirths and improve quality of care.DiscussionIn this report, we assess how different definitions and limits in registration affect data capture, and we discuss the specific challenges of stillbirth registration, with emphasis on implementation. We identify what data need to be captured, we suggest a dataset to cover core needs in registration and analysis of the different categories of stillbirths with causes and quality indicators, and we illustrate the experience in stillbirth registration from different cultural settings. Finally, we point out gaps that need attention in the International Classification of Diseases and review the qualities of alternative systems that have been tested in low- and middle-income settings.SummaryObtaining high-quality data will require consistent definitions for stillbirths, systematic population-based registration, better tools for surveys and verbal autopsies, capacity building and training in procedures to identify causes of death, locally adapted quality indicators, improved classification systems, and effective registration and reporting systems.

Assessment of the health system and policy environment as a critical complement to tracking intervention coverage for maternal, newborn, and child health.

In 2008, the Countdown to 2015 initiative identified 68 priority countries for action on maternal, newborn, and child health. Much attention was paid to monitoring country-level progress in achieving high and equitable coverage with interventions effective in reducing mortality of mothers, newborn infants, and children up to 5 years of age. To have a broader understanding of the environment in which health services are delivered and health outcomes are produced is essential to increase intervention coverage. Programmes to address MNCH rely on health systems to generate information needed for effective decisions and to achieve the expected outcomes. Governance and leadership are needed throughout the process not only to create policies and implement them but also to assure quality and efficiency of care, to finance health services sufficiently and in an equitable way, and to manage the health workforce. We present a systematic approach to assess the wider health system and policy environment needed to achieve positive outcomes for maternal, newborn, and child health. We report on results from 13 indicators and show gaps in policy adoption as well as weaknesses in other health system building blocks. We identify areas for future action in measurement of key indicators and their use to support decision making. We hope that this information will provide an additional dimension to the discussions on feasible and sustainable solutions to accelerate progress towards Millennium Development Goals 4 and 5, both at the global level but most importantly in individual countries.