Malaria Is Associated with Diminished Levels of Ascorbic Acid: A Systematic Review and Meta-Analysis.

Background: It is still unclear how ascorbic acid levels relate to the pathogenesis of malaria. This systematic review synthesized different ascorbic acid levels in malaria patients with different severity levels of malaria and Plasmodium species. Methods: The systematic review protocol was registered in the PROSPERO database (CRD42023394849). A systematic search of PubMed, Embase, MEDLINE, Ovid, Scopus, and Google Scholar was conducted to identify studies that reported ascorbic acid and malaria. The pooled standardized mean difference (Cohen's d) with 95% confidence intervals (CIs) was calculated using the random-effects model. Results: A total of 1480 articles were obtained from the searches of the databases, and 30 studies were included for syntheses. The meta-analysis revealed that patients with malaria had lower levels of ascorbic acid than those without malaria or uninfected controls (p < 0.01, Cohen's d = -3.71, 95% CI = -4.44 to -2.98, I2 = 98.87%, 30 studies). Comparable levels of ascorbic acid were observed between patients with severe malaria and those with nonsevere malaria (p = 0.06, Cohen's d = -1.39, 95% CI = -2.85 to 0.07, I2 = 96.58%, 4 studies). Similarly, levels of ascorbic acid were comparable between patients with Plasmodium falciparum and Plasmodium vivax malaria (p = 0.34, Cohen's d = -1.06, 95% CI = -3.23 to 1.12, I2 = 97.30%, 3 studies). Conclusions: The meta-analysis reveals diminished levels of ascorbic acid in malaria cases. Manipulating the host's nutritional status, such as by supplementing it with ascorbic acid to restore reactive oxygen species balance, may alter the progression of malarial infection and prevention of disease severity. Antioxid. Redox Signal. 40, 460-469.

Prevalence and factors associated with anaemia in children aged 6-24 months living a high malaria transmission setting in Burundi.

BACKGROUND: In very young children, anaemia has been linked to increased morbidity, mortality and poor cognitive development. Although Burundi has a high burden of anaemia, which may be worsened by the high burden of malaria, little is known about the extent of the problem in very young children who are most at risk of severe disease. We estimated the prevalence, and assessed the factors associated with anaemia in children aged 6-24 months using baseline data collected as part of an on-going study evaluating the effect of Micronutrient supplementation on anaemia and cognition among children in high malaria transmission settings in Burundi. METHODS: Between February and March 2020, surveys were conducted in 498 households within the catchment area of Mukenke Health Center. One child aged 6-24 months was selected per household to participate in the survey. Following written informed consent, we administered a questionnaire to the child's primary caregiver to capture information on child's demographics, nutritional status, food intake, health (status, and morbidity and treatment-seeking practices), as well as the household markers of wealth. A physical exam was conducted, and a blood sample was collected to: 1) assess for presence of plasmodium infection using a rapid diagnosis test; 2) estimate the haemoglobin levels using a portable haemocue machine. A stool sample was also collected to examine for the presence of helminth infections. RESULTS: The prevalence of anaemia was 74.3% (95% confidence interval [CI] 61.5%-84.0%), with most of the anaemic study participants classified as having moderate anaemia (59.2%). A total of 62 (12.5%) participants had positive malaria rapid diagnosis tests. Factors significantly associated with higher odds of developing anaemia included not receiving deworming medication (adjusted Odd ratio [aOR] = 3.54, 95% CI 1.79-6.99, p<0.001), the child's home location (Mukenke II: aOR = 2.22, 95% CI 1.89-2.62, p<0.001; Mukenke: aOR = 2.76, 95% CI 2.46-3.10, p<0.001 and Budahunga: aOR = 3.12, 95% CI 2. 94-3.31, p<0.001) and the child's age group (Children aged 6-11 months: aOR = 2.27, 95% CI 1.32-3.91, p<0.001). Education level was inversely associated with less odds of anaemia: child's primary care giver with a secondary (aOR = 0.67; 95% CI: 0.47-0.95, p = 0,024) and tertiary education level (aOR = 0.48; 95% CI: 0.38-0.61, p<0.001). CONCLUSION: Anaemia is highly prevalent among young children in high malaria transmission setting. Anaemia is more prevalent among children who not dewormed and those with malaria. To prevent the long-term adverse outcomes of the anaemia in children, policy makers should focus on improving uptake of the deworming and malaria prevention programs, promote preventive interventions and improve the education of women especially in families with very young children.

Associations of maternal iron deficiency with malaria infection in a cohort of pregnant Papua New Guinean women.

BACKGROUND: Iron deficiency (ID) is common in malaria-endemic settings. Intermittent preventative treatment of malaria in pregnancy (IPTp) and iron supplementation are core components of antenatal care in endemic regions to prevent adverse pregnancy outcomes. ID has been associated with reduced risk of malaria infection, and correspondingly, iron supplementation with increased risk of malaria infection, in some studies. METHODS: A secondary analysis was conducted amongst 1888 pregnant women enrolled in a malaria prevention trial in Papua New Guinea. Maternal ID was defined as inflammation-corrected plasma ferritin levels < 15 µg/L at antenatal enrolment. Malaria burden (Plasmodium falciparum, Plasmodium vivax) was determined by light microscopy, polymerase chain reaction, and placental histology. Multiple logistic and linear regression analyses explored the relationship of ID or ferritin levels with indicators of malaria infection. Models were fitted with interaction terms to assess for modification of iron-malaria relationships by gravidity or treatment arm. RESULTS: Two-thirds (n = 1226) and 13.7% (n = 258) of women had ID and peripheral parasitaemia, respectively, at antenatal enrolment (median gestational age: 22 weeks), and 18.7% (120/1,356) had evidence of malaria infection on placental histology. Overall, ID was associated with reduced odds of peripheral parasitaemia at enrolment (adjusted odds ratio [aOR] 0.50; 95% confidence interval [95% CI] 0.38, 0.66, P < 0.001); peripheral parasitaemia at delivery (aOR 0.68, 95% CI 0.46, 1.00; P = 0.050); and past placental infection (aOR 0.35, 95% CI 0.24, 0.50; P < 0.001). Corresponding increases in the odds of infection were observed with two-fold increases in ferritin levels. There was effect modification of iron-malaria relationships by gravidity. At delivery, ID was associated with reduced odds of peripheral parasitaemia amongst primigravid (AOR 0.44, 95% CI 0.25, 0.76; P = 0.003), but not multigravid women (AOR 1.12, 95% CI 0.61, 2.05; P = 0.720). A two-fold increase in ferritin associated with increased odds of placental blood infection (1.44, 95% CI 1.06, 1.96; P = 0.019) and active placental infection on histology amongst primigravid women only (1.24, 95% CI 1.00, 1.54; P = 0.052). CONCLUSIONS: Low maternal ferritin at first antenatal visit was associated with a lower risk of malaria infection during pregnancy, most notably in primigravid women. The mechanisms by which maternal iron stores influence susceptibility to infection with Plasmodium species require further investigation.

Effects of Iron Supplements on Heme Scavengers in Pregnancy.

In malaria endemic countries, anemia in pregnant women occurs as a result of erythrocyte destruction by Plasmodium infections and other causes including malnutrition. Iron supplementation is recommended as treatment of iron-deficiency anemia. Erythrocyte destruction results in increased release of cytotoxic free heme that is scavenged by haptoglobin (Hp), hemopexin (Hx) and heme oxygenase-1 (HO-1). Paradoxically, iron supplementation in pregnant women has been reported to enhance parasitemia and increase levels of free heme. The relationship between free heme, heme scavengers, and birth outcomes has not been investigated, especially in women who are on iron supplementation. We hypothesized that parasite-infected pregnant women on routine iron supplementation have elevated heme and altered expression of heme scavengers. A cross-sectional study was conducted to determine the association between plasma levels of free heme, HO-1, Hp, Hx, and malaria status in pregnant women who received routine iron supplementation and their birth outcomes. Heme was quantified by colorimetric assay and scavenger protein concentration by ELISA. We demonstrated that iron-supplemented women with asymptomatic parasitemia had increased free heme (mean 75.6 µM; interquartile range [IQR] 38.8-96.5) compared with nonmalaria iron-supplemented women (mean 34.9 µM; IQR 17.4-43.8, P < 0.0001). Women with preterm delivery had lower levels of Hx (mean 656.0 µg/mL; IQR 410.9-861.3) compared with women with full-term delivery (mean: 860.9 µg/mL; IQR 715.2-1055.8, P = 0.0388). Our results indicate that iron supplementation without assessment of circulating levels of free heme and heme scavengers may increase the risk for adverse pregnancy outcomes.

Iron supplementation in anemic Zanzibari toddlers is associated with greater loss in erythrocyte iron isotope enrichment.

BACKGROUND: Heavy parasitic loads increase the risk of iron (Fe) deficiency anemia, which remains prevalent globally. Where parasites are common, understanding the influence of parasitic infections on Fe incorporation and erythropoiesis in toddlers is especially important. OBJECTIVES: The aim of this study was to identify the impacts of malarial and helminth infections on red blood cell (RBC) Fe incorporation and subsequent changes in RBC Fe isotope enrichment for 84 days postdosing in toddlers at high risk for parasitic infections. METHODS: Fe incorporation was measured in a group of Zanzibari toddlers (n = 71; 16-25 months) using a stable Fe isotopic method. At study entry, an oral stable Fe isotope was administered. Blood was collected 14 (D14) and 84 (D84) days postdosing for the assessment of Fe status indicators and RBC isotopic enrichment. Blood and stool samples were collected and screened for malaria and helminth parasites. Factors associated with changes in RBC Fe isotope enrichment were identified using regression models. RESULTS: Toddlers who had larger weight-for-age z-scores, lower total body Fe, and helminth infections (n = 26) exhibited higher RBC Fe incorporation. RBC Fe isotope enrichment decreased from D14 to D84 by -2.75 percentage points (P < 0.0001; n = 66). Greater loss in RBC Fe isotope enrichment from D14 to D84 was observed in those who received Fe supplementation, those with either helminths or both malarial and helminth infections, and in those with greater RBC Fe incorporation on D14. CONCLUSIONS: Toddlers who received Fe supplementation exhibited significantly greater losses of RBC Fe isotope enrichment over time. We speculate this greater loss of RBC Fe enrichment is indicative of increased erythropoiesis due to the provision of Fe among anemic or helminth-infected toddlers.

Pathophysiology of Anemia in HIV-Infected Children Exposed to Malaria.

Anemia is a common condition in HIV-infected children; however, its pathophysiology and the contribution of frequent causes of anemia such as iron deficiency (ID) and malaria are poorly understood. We carried out an ancillary study on the effect of HIV on anemia as part of a case-control study on risk factors of anemia among Mozambican children aged 1-59 months with documented HIV status. Of them, 390 children were admitted to the hospital with anemia (hemoglobin [Hb] < 11 g/dL), whereas 272 children without anemia (Hb ≥ 11 g/dL) were recruited in the community. We assessed differences by HIV status in the presentation of anemia etiological factors and the effect of HIV infection on the association of each factor with anemia. Among the 99 HIV-infected and 563 uninfected children included, HIV-infected anemic children had an increased risk of undernutrition (P < 0.0001), Epstein-Barr virus infection (P < 0.0001), bacteremia (P = 0.0060), a decreased risk of malaria (P < 0.0001), and a similar risk of ID (P = 0.7371) compared with anemic-uninfected children. HIV-infected children were significantly less likely to have anemia associated with Plasmodium falciparum hyperparasitemia (P = 0.0444) and had a lower prevalence of parasitemia in the bone marrow (BM) (P < 0.0001) than anemic-uninfected children. Levels of BM erythropoiesis and dyserythropoiesis were comparable between groups. These findings suggest that the pathophysiology of anemia among HIV-infected malaria-exposed children is not related to HIV-specific effects. For unclear reasons, HIV-infected children had reduced risk of malaria infection, whereas ID prevalence was comparable in HIV-infected and uninfected children, suggesting that iron supplementation recommendations should not be different in HIV-infected children.

Micronutrient levels and their effects on the prognosis of visceral leishmaniasis treatment, a prospective cohort study.

BACKGROUND: Micronutrients are minerals and vitamins and they are essential for normal physiological activities. The objectives of the study were to describe the progress and determinants of micronutrient levels and to assess the effects of micronutrients in the treatment outcome of kalazar. METHODS: A prospective cohort study design was used. The data were collected using patient interviews, measuring anthropometric indicators, and collecting laboratory samples. The blood samples were collected at five different periods during the leishmaniasis treatments: before starting anti-leishmaniasis treatments, in the first week, in the second week, in the third week, and in the 4th week of anti-leishmaniasis treatments. Descriptive statistics were used to describe the profile of patients and to compare the treatment success rate. The generalized estimating equation was used to identify the determinants of serum micronutrients. RESULTS: The mean age of the patients were 32.88 years [SD (standard deviation) ±15.95]. Male constitute 62.3% of the patients and problematic alcohol use was present in 11.5% of the patients. The serum zinc level of visceral leishmaniasis patients was affected by alcohol (B - 2.7 [95% CI: - 4.01 - -1.5]), DDS (B 9.75 [95% CI: 7.71-11.79]), family size (B -1.63 [95% CI: - 2.68 - -0.58]), HIV (B -2.95 [95% CI: - 4.97 - -0.92]), and sex (B - 1.28 [95% CI: - 2.5 - -0.07]). The serum iron level of visceral leishmaniasis patients was affected by alcohol (B 7.6 [95% CI: 5.86-9.35]), family size (B -5.14 [95% CI: - 7.01 - -3.28]), malaria (B -12.69 [95% CI: - 14.53 - -10.87]), Hookworm (- 4.48 [- 6.82 - -2.14]), chronic diseases (B -7.44 [95% CI: - 9.75 - -5.13]), and HIV (B -5.51 [95% CI: - 8.23 - -2.78]). The serum selenium level of visceral leishmaniasis patient was affected by HIV (B -18.1 [95% CI: - 20.63 - -15.58]) and family size (B -11.36 [95% CI: - 13.02 - -9.7]). The iodine level of visceral leishmaniasis patient was affected by HIV (B -38.02 [95% CI: - 41.98 - -34.06]), DDS (B 25 .84 [95% CI: 22.57-29.1]), smoking (B -12.34 [95% CI: - 15.98 - -8.7]), chronic illness (B -5.14 [95% CI: - 7.82 - -2.46]), and regular physical exercise (B 5.82 [95% CI: 0.39-11.26]). The serum vitamin D level of visceral leishmaniasis patient was affected by HIV (B -9.43 [95% CI: - 10.92 - -7.94]), DDS (B 16.24 [95% CI: 14.89-17.58]), malaria (B -0.61 [95% CI: - 3.37 - -3.37]), and family size (B -1.15 [95% CI: - 2.03 - -0.28]). The serum vitamin A level of visceral leishmaniasis patient was affected by residence (B 0.81 [95% CI: 0.08-1.54]), BMI (B 1.52 [95% CI: 0.42-2.6]), DDS (B 1.62 [95% CI: 0.36-2.88]), family size (B -5.03 [95% CI: - 5.83 - -4.22]), HIV (B -2.89 [95% CI: - 4.44 - -1.34]),MUAC (B 0.86 [95% CI: 0.52-1.21]), and age (B 0.09 [95% CI: 0.07-0.12]). CONCLUSION: The micronutrient levels of visceral leishmaniasis patients were significantly lower. The anti-leishmaniasis treatment did not increase the serum micronutrient level of the patients.

Moringa oleifera treatment increases Tbet expression in CD4+ T cells and remediates immune defects of malnutrition in Plasmodium chabaudi-infected mice.

BACKGROUND: Malaria is a worldwide problem that affects millions of people yearly. In rural areas where anti-malarial drugs are not easily accessible, many people use herbal treatments, such as Moringa oleifera, to treat a variety of diseases and ailments including malaria. While Moringa is reported to possess potent and curative anti-malarial properties, previous studies have mostly been restricted to assessment of parasitaemia. In this study, the effect of Moringa on malaria immunity in a murine model was investigated. METHODS: Using a high dose (60 mg/mouse) for a short time (7 days) or low dose Moringa (30 mg/mouse) for a longer time (3 weeks), cytokine production, and Tbet expression by effector CD4+ T cells (Teff) were determined. Mice were also treated with Moringa after infection (curatively) or before infection (prophylactically) to determine the effect of the plant extract on parasitaemia and immunity. Given that Moringa also possess many nutritional benefits, the contribution of Moringa on malnourished malaria infected mice was determined. Malnutrition was induced by limiting access to food to only 4 h a day for 4 weeks, while control mice had unlimited access to mouse laboratory chow. All data was collected by flow cytometry and analysed using one-Way ANOVA or two tailed Student's t test. RESULTS: Moringa-treated mice had increased numbers of effector CD4+ T cells accompanied by an increase in Tbet expression compared to control untreated mice. Mice that were treated with Moringa curatively also exhibited increased effector CD4+ T cell numbers, IFN-gamma and TNF secretion. Interestingly, the mice that were treated prophylactically had significantly higher Tbet expression. In the absence of adaptive immunity, high parasitaemia was observed in the RAG1 knockout mice. The food limited mice (malnourished) had reduced numbers of CD4+ T cells, TNF proportions, and significantly greater Tbet expression compared to the control group. Supplementation with Moringa in the limited group slightly restored CD4+ T cell activation, IL-2, and IL-10 production. CONCLUSIONS: Taken together, these data suggest that Moringa treatment leads to increased CD4+ T cell activation, Th1 differentiation and production of pro-inflammatory cytokines after malaria infection. Thus, Moringa may be immunologically useful in the treatment of malaria and malnutrition. Further investigations are required to identify the active components in Moringa.

Immediate Transfusion in African Children with Uncomplicated Severe Anemia.

BACKGROUND: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes. METHODS: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole. RESULTS: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group. CONCLUSIONS: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).

Excess risk of preterm birth with periconceptional iron supplementation in a malaria endemic area: analysis of secondary data on birth outcomes in a double blind randomized controlled safety trial in Burkina Faso.

BACKGROUND: Iron supplementation before a first pregnancy may improve the future health of mother and baby by reducing maternal anaemia. Iron supplementation could, however, increase malaria infections, notably in primigravidae who are most susceptible. The pathogenicity of other iron-utilizing pathogens could also increase, causing inflammation leading to increased risk of adverse birth outcomes. This paper reports pre-specified secondary birth outcomes from a safety trial in Burkina Faso in an area of high malaria endemicity. Primary outcomes from that trial had investigated effects of long-term weekly iron supplementation on malaria and genital tract infections in non-pregnant and pregnant women. METHODS: A double-blind, randomized controlled trial. Nulliparous, mainly adolescent women, were individually randomized periconceptionally to receive weekly either 60 mg elemental iron and 2.8 mg folic acid, or 2.8 mg folic acid alone, continuing up to the first antenatal visit for those becoming pregnant. Secondary outcomes were ultrasound-dated gestational age, fetal growth, placental malaria, chorioamnionitis and iron biomarkers. Seasonal effects were assessed. Analysis was by intention to treat. RESULTS: 478 pregnancies occurred to 1959 women: 258/980 women assigned iron and folic acid and 220/979 women assigned folic acid alone. Malaria prevalence at the first antenatal visit was 53% (iron) and 55% (controls). Mean birthweight was 111 g lower in the iron group (95% CI 9:213 g, P = 0.033). Mean gestational ages were 264 days (iron) and 269 days (controls) (P = 0.012), with 27.5% under 37 weeks compared to 13.9% in controls (adjRR = 2.22; 95% CI 1.39-3.61) P < 0.001). One-third of babies were growth restricted, but incidence did not differ by trial arm. Half of placentae had evidence of past malaria infection. C-reactive protein > 5 mg/l was more common prior to births < 37 weeks (adjRR = 2.06, 95% CI 1.04-4.10, P = 0.034). Preterm birth incidence during the rainy season was ~ 50% in the iron arm and < 20% in controls (P = 0.001). Chorioamnionitis prevalence peaked in the dry season (P = 0.046), with no difference by trial arm (P = 0.14). CONCLUSION: Long-term weekly iron supplementation given to nulliparous women in a malaria endemic area was associated with higher risk of preterm birth in their first pregnancy. Trial Registration NCT01210040. Registered with Clinicaltrials.gov on 27th September 2010.

Treatment-seeking behaviour for febrile illnesses and its implications for malaria control and elimination in Savannakhet Province, Lao PDR (Laos): a mixed method study.

BACKGROUND: How people respond to febrile illness is critical to malaria prevention, control, and ultimately elimination. This article explores factors affecting treatment-seeking behaviour for febrile illnesses in a remote area of Lao PDR. METHODS: Household heads or their representatives (n = 281) were interviewed using a structured questionnaire. A total of twelve focus group discussions (FGDs) each with eight to ten participants were conducted in four villages. In addition, observations were recorded as field notes (n = 130) and were used to collect information on the local context, including the treatment seeking behaviour and the health services. RESULTS: Almost three-quarters (201/281) of respondents reported fever in past two months. Most (92%, 185/201) sought treatment of which 80% (149/185) sought treatment at a health centre. Geographic proximity to a health centre (AOR = 6.5; CI = 1.74-24.25; for those < 3.5 km versus those > 3.6 km) and previous experience of attending a health centre (AOR = 4.7; CI = 1.2-19.1) were strong predictors of visiting a health centre for febrile symptoms. During FGDs, respondents described seeking treatment from traditional healers and at health centre for mild to moderate illnesses. Respondents also explained how if symptoms, including fever, were severe or persisted after receiving treatment elsewhere, they sought assistance at health centres. Access to local health centres/hospitals was often constrained by a lack of transportation and an ability to meet the direct and indirect costs of a visit. CONCLUSION: In Nong District, a rural area bordering Vietnam, people seek care from health centres offering allopathic medicine and from spiritual healers. Decisions about where and when to attend health care depended on their economic status, mobility (distance to the health centre, road conditions, availability of transport), symptoms severity and illness recognition. Current and future malaria control/elimination programmes could benefit from greater collaboration with the locally accessible sources of treatments, such as health volunteers and traditional healers.

Hypoglycemia induced by Plasmodium berghei infection is prevented by treatment with Tinospora crispa stem extract.

During Plasmodium malaria parasite infection in a human, the intraerythrocytic stages lead to the clinical manifestations of the disease, especially hypoglycemia. Hypoglycemia is a recognized feature of severe malaria and linked with a high risk of mortality for children. Hence, the present study aimed to investigate the protective effect of T. crispa stem extract on hypoglycemia induced by P. berghei infection tested with a mouse model. ICR mice were inoculated with 1 × 107 parasitized erythrocytes of P. berghei ANKA (PbANKA) by intraperitoneal injection and given 50, 100, and 200 mg/kg of ethanolic extract for 4-consecutive days. The results showed that T. crispa stem extract exerted a protective effect (100%) on hypoglycemia induced by PbANKA infection at doses of 100 and 200 mg/kg. A significantly (p < .05) prolonged mean survival time (28.0 ±â€¯1.9 days) of the extract treated mice was also observed. Additionally, no effect on blood glucose levels was seen in normal mice treated with all doses of extract. It can be concluded that T. crispa stem extract may have beneficial properties in protecting against hypoglycemia, and in increasing survival time during malaria infection.

Efficacy of standardized extract of Hibiscus sabdariffa L. (Malvaceae) in improving iron status of adults in malaria endemic area: A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Indigenous community of Mkuranga district have been using aqueous extract of H. sabdariffa L. for treating anemia. However, there have been neither safety nor efficacy studies to validate this medicinal product in anemia. AIM: The purpose of this study was to establish efficacy and safety of standardized aqueous extract of H. sabdariffa L. in anemic adults. MATERIALS AND METHODS: This was a randomized controlled clinical trial in which 130 adults' men and women aged 18-50 years were involved after meeting the inclusion criteria. Initially, standardized aqueous extract of H. sabdariffa L. was prepared using optimized extraction parameters. Stratified randomization was used to randomize participants into four fixed dose groups. The first group received oral dose of 1000ml while the 2nd group was randomized to receive 1500ml orally. The last two groups were given a dose of 2000ml of extract and 200mg ferrous sulphate tablet respectively. Primary endpoint was the actual change of iron status indicators at the end of 30 days follow up period as compared to those recorded at baseline. Adverse effects were assessed at every 10th day scheduled visit. In all arms, HB and hematopoietic parameters were measured using HemoCue hemoglobinometer® (HemoCue, Ängelholm, Sweden) and hematology analyzer® respectively at the trial site. Follow up was done for 30 days. A total of 82 participants were included for analysis. RESULTS: A standardized aqueous extract of H. sabdariffa L. did not improve iron status in anemic adults in malaria endemic region (P>0.005). However, there was evidence to support the safety of the extract for human consumptions as herbal supplement. Iron and organic acids contents of H. sabdariffa L. extract showed the potential of improving hematopoietic parameters. Studies with bigger sample size are therefore needed to establish the efficacy of the extract when concurrently used with malaria chemoprophylaxis in malaria endemic areas.

A Large Outbreak of Thiamine Deficiency Among Illegal Gold Miners in French Guiana.

From September 2013 to July 2014, several gold miners working in the tropical forest consulted the Maripasoula Health Center in French Guiana for edema and findings consistent with right-sided cardiac failure. Of the 42 cases of beriberi that were diagnosed, one patient died. The laboratory and clinical investigation demonstrated vitamin B1 deficiency in most of the patients tested. Furthermore, 30 of 42 patients responded favorably to 500 mg of intravenous or intramuscular thiamine supplementation. In addition, dietary investigation showed insufficient thiamine intake in these patients. We concluded that patients had acquired beriberi because of diet restrictions, hard labor, and infectious diseases, notably malaria. In 2016, cases were still being reported. We recommend screening for compatible symptoms in gold miners, thiamine supplementation, and nutritional intervention.

Small-quantity lipid-based nutrient supplements containing different amounts of zinc along with diarrhea and malaria treatment increase iron and vitamin A status and reduce anemia prevalence, but do not affect zinc status in young Burkinabe children: a cluster-randomized trial.

BACKGROUND: We assessed the effects of providing a package of interventions including small-quantity lipid-based nutrient supplements (SQ-LNS) containing 0, 5 or 10 mg zinc and illness treatment to Burkinabe children from 9 to 18 months of age, on biomarkers of zinc, iron and vitamin A status at 18 months and compared with a non-intervention cohort (NIC). METHODS: Using a two-stage cluster randomized trial design, communities were randomly assigned to the intervention cohort (IC) or NIC, and extended family compounds within the IC were randomly assigned to different treatment groups. IC children (n = 2435) were provided with 20 g SQ-LNS/d containing 0, 5 or 10 mg zinc, 6 mg of iron and 400 µg of vitamin A along with malaria and diarrhea treatment. NIC children (n = 785) did not receive the intervention package. At 9 and 18 months, hemoglobin (Hb), zinc, iron and vitamin A status were assessed in a sub-group (n = 404). Plasma concentrations of zinc (pZC), ferritin (pF), soluble transferrin receptor (sTfR) and retinol-binding protein (RBP) were adjusted for inflammation. RESULTS: At baseline, 35% of children had low adjusted pZC (<65 µg/dL), 93% were anemic (Hb <110 g/L), 25% had low adjusted pF (<12 µg/L), 90% had high adjusted sTfR (>8.3 mg/L) and 47% had low adjusted RBP (<0.94 µmol/L), with no group-wise differences. Compared with the NIC, at 18 months IC children had significantly lower anemia prevalence (74 vs. 92%, p = 0.001) and lower iron deficiency prevalence (13% vs. 32% low adjusted pF and 41% vs. 71% high adjusted sTfR, p < 0.001), but no difference in pZC. Mean adjusted RBP was greater at 18 months in IC vs. NIC (0.94 µmol/L vs. 0.86 µmol/L, p = 0.015), but the prevalence of low RBP remained high in both cohorts. Within the IC, different amounts of zinc had no effect on the prevalence of low pZC or indicators of vitamin A deficiency, whereas children who received SQ-LNS with 10 mg zinc had a significantly lower mean pF at 18 months compared to children who received SQ-LNS with 5 mg zinc (p = 0.034). CONCLUSIONS: SQ-LNS regardless of zinc amount and source provided along with illness treatment improved indicators of iron and vitamin A status, but not pZC. TRIAL REGISTRATION: NCT00944281 (July 21, 2009).

Effect of a short course of iron polymaltose on acquisition of malarial parasitaemia in anaemic Indonesian schoolchildren: a randomized trial.

BACKGROUND: Concern exists about the safety of iron supplementation given to individuals in malarious areas. The possible unfavourable impact of iron supplementation on malaria might be less when slow-release iron compounds are used instead of ferrous salts, because no toxic non-transferrin bound iron is formed. The aim of this study was to determine the effect of iron supplementation using the slow-release iron compound iron polymaltose (IPM) on the acquisition of malarial parasitaemia. METHODS: A randomized, placebo-controlled trial was performed in schoolchildren aged 5-18 years with mild or moderate anaemia on the Indonesian island Flores. Microscopic malaria-negative children were randomized to receive 8 weeks of IPM (6 mg elemental iron/kg/day) or placebo . The primary outcomes were the occurrence of microscopically detectable malarial parasitaemia at week 4, 8, 12 and 16 after start of treatment and the proportion of participants with real-time (RT) PCR positive malarial parasitaemia at week 16. RESULTS: 294 Children were assigned to the IPM group and 297 to the placebo group. Whereas IPM supplementation failed to increased haemoglobin or ferritin concentrations, the IPM group had a significantly higher rate of occurrence of microscopically detectable parasitaemia [hazard ratio 2.2, 95% C.I. 1.2-4.0; P = 0.01]. This higher rate was confined to iron-replete children. At the end of the study, 89% of the children in the IPM group had remained free from microscopically detectable parasitaemia vs 95% of children in the placebo group. The proportion of plasmodial RT-PCR positive children was similar in both groups at week 16 (IPM group 16.6% vs placebo group 14.3%; P = 0.47). When analysis was restricted to iron-replete children (serum ferritin ≥30 µg/l), there was a trend for a higher proportion being RT-PCR positive at week 16 in the IPM group compared with the placebo group (20 vs 13.3%; P = 0.07). Erythrocyte microcytosis was an independent risk factor for microscopically detectable malarial parasitaemia. CONCLUSIONS: A short course of IPM should be used cautiously in anaemic children in malaria endemic areas, as it has limited efficacy in treating iron deficiency, while it increases the rate of microscopic malarial parasitaemia in those with replete iron stores. Trial registration ISRCTN 83091970. Registered 16 May 2012 (retrospectively registered).

Puzzling and ambivalent roles of malarial infections in cancer development and progression.

Scientific evidence strongly suggests that parasites are directly or indirectly associated with carcinogenesis in humans. However, studies have also indicated that parasites or their products might confer resistance to tumour growth. Plasmodium protozoa, the causative agents of malaria, exemplify the ambivalent link between parasites and cancer. Positive relationships between malaria and virus-associated cancers are relatively well-documented; for example, malaria can reactivate the Epstein-Barr Virus, which is the known cause of endemic Burkitt lymphoma. Nevertheless, possible anti-tumour properties of malaria have also been reported and, interestingly, this disease has long been thought to be beneficial to patients suffering from cancers. Current knowledge of the potential pro- and anti-cancer roles of malaria suggests that, contrary to other eukaryotic parasites affecting humans, Plasmodium-related cancers are principally lymphoproliferative disorders and attributable to virus reactivation, whereas, similar to other eukaryotic parasites, the anti-tumour effects of malaria are primarily associated with carcinomas and certain sarcomas. Moreover, malarial infection significantly suppresses murine cancer growth by inducing both innate and specific adaptive anti-tumour responses. This review aims to present an update regarding the ambivalent association between malaria and cancer, and further studies may open future pathways to develop novel strategies for anti-cancer therapies.

Iron and malaria: a dangerous liaison?

Malaria increases the burden of anemia in low-income countries, where, according to 2012 data from the World Health Organization, 40% of children are anemic. Moreover, iron is a cofactor for Plasmodium falciparum development, raising fears that iron supplementation might be harmful in patients with P. falciparum infection. The primary objective of this narrative review is to describe current knowledge on the iron-malaria association, including recent findings and substantive qualitative results. Between 2012 and 2016 the MEDLINE database was searched for literature published about malaria and iron levels. Observational studies reported some protection of iron supplementation against malaria among iron-deficient children, while older clinical trials reported increased susceptibility to malaria among iron-supplemented children. However, iron supplements were not significantly associated with increased malaria risk in recent clinical trials or in a 2016 Cochrane review. Evidence of an iron-malaria association is limited by the following factors: the protective effect of control interventions, the limited follow-up of children, and the lack of homogenous iron indicators. The effects of previous health status and possible thresholds in iron levels should be investigated using a gold-standard combination of iron markers. Moreover, the benefits of iron supplementation require further evaluation.

Delaying Iron Therapy until 28 Days after Antimalarial Treatment Is Associated with Greater Iron Incorporation and Equivalent Hematologic Recovery after 56 Days in Children: A Randomized Controlled Trial.

BACKGROUND: Iron therapy begun concurrently with antimalarial treatment may not be well absorbed because of malaria-induced inflammation. Delaying the start of iron therapy may permit better iron absorption and distribution. OBJECTIVE: We compared erythrocyte iron incorporation in children who started iron supplementation concurrently with antimalarial treatment or 28 d later. We hypothesized that delayed iron supplementation would be associated with greater incorporation and better hematologic recovery. METHODS: We enrolled 100 children aged 6-59 mo with malaria and hemoglobin concentrations of 50.0-99.9 g/L who presented to Mulago Hospital, Kampala, into a randomized trial of iron therapy. All children were administered antimalarial treatment. Children with zinc protoporphyrin (ZPP) ≥80 µmol/mol heme were randomly assigned to start iron supplementation concurrently with the antimalarial treatment [immediate iron (I) group] or 28 d later [delayed iron (D) group]. All children were administered iron-stable isotope (57)Fe on day 0 and (58)Fe on day 28. We compared the percentage of iron incorporation at the start of supplementation (I group at day 0 compared with D group at day 28, aim 1) and hematologic recovery at day 56 (aim 2). RESULTS: The percentage of iron incorporation (mean ± SE) was greater at day 28 in the D group (16.5% ± 1.7%) than at day 0 in the I group (7.9% ± 0.5%; P < 0.001). On day 56, concentrations of hemoglobin and ZPP and plasma ferritin, soluble transferrin receptor (sTfR), hepcidin, and C-reactive protein did not differ between the groups. On day 28, the hemoglobin (mean ± SD) and plasma iron markers (geometric mean; 95% CI) reflected poorer iron status in the D group than in the I group at this intervening time as follows: hemoglobin (105 ± 15.9 compared with 112 ± 12.4 g/L; P = 0.04), ferritin (39.3 µg/L; 23.5, 65.7 µg/L compared with 79.9 µg/L; 58.3, 110 µg/L; P = 0.02), sTfR (8.9 mg/L; 7.4, 10.7 mg/L compared with 6.7 mg/L; 6.1, 7.5 mg/L; P = 0.01), and hepcidin (13.3 ng/mL; 8.3, 21.2 ng/mL compared with 38.8 ng/mL; 28.3, 53.3 ng/mL; P < 0.001). CONCLUSIONS: Delaying the start of iron improves incorporation but leads to equivalent hematologic recovery at day 56 in Ugandan children with malaria and anemia. These results do not demonstrate a clear, short-term benefit of delaying iron. This trial was registered at clinicaltrials.gov as NCT01754701.

Is selective prenatal iron prophylaxis better than routine prophylaxis: final results of a trial (PROFEG) in Maputo, Mozambique.

OBJECTIVE: To compare routine versus selective (ie, screening and treatment for anaemia) prenatal iron prophylaxis in a malaria-endemic and HIV-prevalent setting, an extended analysis including previously missing data. DESIGN: A pragmatic randomised controlled clinical trial. SETTING: 2 health centres in Maputo, Mozambique. PARTICIPANTS: Pregnant women (≥18 years old; non-high-risk pregnancy) were randomly allocated to routine iron (n=2184) and selective iron (n=2142) groups. INTERVENTIONS: In the routine group, women received 60 mg ferrous sulfate plus 400 µg folic acid daily. In the selective group, women received 1 mg of folic acid daily and haemoglobin (Hb) screening at each visit; with low Hb (cut-off 9 g/dL) treatment (120 mg+800 µg of folic acid daily) for a month. PRIMARY OUTCOMES: preterm birth, low birth weight; secondary outcomes: self-reported malaria, labour complications, caesarean section, perinatal death, woman's death. Nurses collected pregnancy data. Birth data were abstracted from hospital records for 52% of women and traced using various methods and linked with probabilistic matching for 24%. Women's deaths were collected from death registers. RESULTS: Birth data were available for 3301 (76%) of the women. Outcomes were similar in the two groups: preterm births (27.1% in the selective vs 25.3% in the routine group), low birthweight infants (11.0% vs 11.7%), perinatal deaths (2.4% vs 2.4%) and caesarean sections (4.0% vs 4.5%). Women's deaths during pregnancy or <42 days postpartum were more common in the selective group (0.8% among the two best matched women) than in the routine group (0.4%). Extra deaths could not be explained by the cause of death, Hb level or HIV status at recruitment. CONCLUSIONS: Birth outcomes were similar in the two iron groups. There might have been more women's deaths in the selective iron group, but it is unclear whether this was due to the intervention, other factors or chance finding. TRIAL REGISTRATION NUMBER: NCT00488579.