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The resistance of mosquito vectors to insecticides is one of the biological obstacles in the fight against malaria. Understanding of the status and mechanisms underlying the insecticide resistance in Anopheles gambiae species is necessary for success of vector control efforts. The study aimed to determine the molecular forms of An. gambiae from four districts in Sierra Leone during May and June 2018, and the level of N1575Y mutation. The molecular form identification of adult female An. gambiae mosquitoes reared from larvae were carried out using polymerase chain reaction and sequencing. And the N1575Y mutations were detected using SNaPshot and sequencing. As a result, significant differences were found in the distribution of An. gambiae molecular forms among regions (P < 0.001). And a total of 638 An. gambiae sensu stricto, 106 An. coluzzi, and 4 hybrid individuals were identified. Moreover, the overall N1575Y mutation frequency was 10.2% with no statistical difference among regions (χ 2  = 3.009, P = 0.390). In addition, no significant differences in N1575Y mutation frequency were found among different An. gambiae molecular forms (P = 0.383). In conclusion, the N1575Y mutation in An. gambiae populations in Sierra Leone was reported for the first time in the present study. It provides key evidence for the necessity of monitoring vector susceptibility levels to insecticides used in this country., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The relevance of genetic factors in conferring protection to severe malaria has been demonstrated, as in the case of sickle cell trait and G6PD deficiency 1 . However, it remains unknown whether environmental components, such as dietary or metabolic variations, can contribute to the outcome of infection 2 . Here, we show that administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90%. Plasmodium sporozoites can successfully invade and initiate replication but die inside hepatocytes, thereby are unable to cause severe disease. Transcriptional analyses combined with genetic and chemical approaches reveal that this impairment of infection is mediated by oxidative stress. We show that reactive oxygen species, probably spawned from fatty acid β-oxidation, directly impact Plasmodium survival inside hepatocytes, and parasite load can be rescued by exogenous administration of the antioxidant N-acetylcysteine or the β-oxidation inhibitor etomoxir. Together, these data reveal that acute and transient dietary alterations markedly impact the establishment of a Plasmodium infection and disease outcome.

The co-endemicity of malnutrition, erythrocytopathies, transmissible diseases and iron-deficiency contribute to the prevalence of chronic anaemia in many populations of the developing world. Although iron dietary supplementation is applied or recommended in at risk populations, its use is controversial due to undesirable outcomes, particularly regarding the response to infections, including highly prevalent malaria. We hypothesized that a boosted oxidative stress due to iron supplementation have a similar impact on malaria to that of hereditary anaemias, enhancing innate response and conditioning tissues to prevent damage during infection. Thus, we have analysed antioxidant and innate responses against lethal Plasmodium yoelii during the first five days of infection in an iron-supplemented mouse. This murine model showed high iron concentration in plasma with upregulated expression of hemoxygenase-1. The sustained homeostasis after this extrinsic iron conditioning, delayed parasitemia growth that, once installed, developed without anaemia. This protection was not conferred by the intrinsic iron overload of hereditary hemochromatosis. Upon iron-supplementation, a large increase of the macrophages/dendritic cells ratio and the antigen presenting cells was observed in the mouse spleen, independently of malaria infection. Complementary, malaria promoted the splenic B and T CD4 cells activation. Our results show that the iron supplementation in mice prepares host tissues for oxidative-stress and induces unspecific cellular immune responses, which could be seen as an advantage to promote early defences against malaria infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study has been to study whether the top-down method, based on the average value identified in the Brazilian Hospitalization System (SIH/SUS), is a good estimator of the cost of health professionals per patient, using the bottom-up method for comparison. The study has been developed from the context of hospital care offered to the patient carrier of glucose-6-phosphate dehydrogenase (G6PD) deficiency with severe adverse effect because of the use of primaquine, in the Brazilian Amazon. The top-down method based on the spending with SIH/SUS professional services, as a proxy for this cost, corresponded to R$60.71, and the bottom-up, based on the salaries of the physician (R$30.43), nurse (R$16.33), and nursing technician (R$5.93), estimated a total cost of R$52.68. The difference was only R$8.03, which shows that the amounts paid by the Hospital Inpatient Authorization (AIH) are estimates close to those obtained by the bottom-up technique for the professionals directly involved in the care.

Anemia and micronutrient deficiencies are widespread in sub-Saharan Africa, but the impact of food fortification is still debated. The objective of this study was to estimate the iron and vitamin A status of preschool children (PSC) and women of reproductive age (WRA) in households consuming fortified oil and wheat flour. The survey was cross-sectional in a rural and an urban area. Data on demographics, socioeconomic status, and fortified foods were collected at households. Hemoglobin (Hb), retinol binding protein (RBP), ferritin, soluble transferrin receptors (sTfR), subclinical inflammation, and Plasmodium spp. infection data were collected. In PSC, vitamin A deficiency (VAD) was prevalent, but for each 1 mg retinol equivalents (RE)/kg of oil consumed, RBP increased by 0.37 μmol/L (p = 0.03). In WRA, there was no significant VAD in the population (0.7%). Anemia was found in 92.2% of rural and 56.3% of urban PSC (p < 0.001). PSC with access to adequately fortified flour had Hb concentrations 15.7 g/L higher than those who did not (p < 0.001). Hb levels increased by +0.238 g/L per mg/kg increase in iron fortification levels (p < 0.001). The national program fortifying vegetable oil with vitamin A and wheat flour with iron and folic acid may have contributed to improved micronutrient status of PSC from two areas in Côte d'Ivoire.

In contrast to malaria, multiple sclerosis (MS) is infrequently found in Black Africans. We describe a 29 year old Nigerian female who developed an MS-like condition with symptoms similar to relapsing-remitting MS following malaria infection, leading to a diagnosis of MS. However, absence of hyperintense lesions in the brain and spinal cord presented a conundrum since not all the diagnostic criteria for MS were met. Pathology supported genetic testing (PSGT) was applied to combine family and personal medical history, lifestyle factors, and biochemical test results for interpretation of genetic findings. This approach provides a means of identifying risk factors for different subtypes of demyelinating disease. The patient was subsequently treated according to an individualised intervention program including nutritional supplementation as well as a change in diet and lifestyle. Deficiencies of vitamin B12, iron and vitamin D were addressed. Genetic analysis revealed absence of the HLA DRB1*1501 allele, considered to be the most prominent genetic risk factor for MS. Extended mutation analysis identified variations in three genes in the folate-vitamin B12 metabolic pathway, which could have increased the patient's sensitivity to the antifolate drugs used to treat the malaria. A glutathione-S-transferase GSTM1 null allele, previously associated with neurological complications of malaria, was also detected. Furthermore, a heterozygous variation in the iron-related transmembrane protease serine 6 (TMPRSS6) gene, rs855791 was found, which could have impacted the patient's iron status following two successive blood donations and exposure to malaria preceding the MS diagnosis. PSGT identifies relevant risk factors for demyelinating disorders resembling MS and uses the data for individualised treatment programs, and to systematically build a database that can provide evidence in large patient cohorts. Follow-up investigations may be suggested, such as whole exome sequencing in selected cases, to ensure that remyelination and restoration of function are achieved.

Objective: Preventive zinc supplementation in the form of tablets or syrup reduces the incidence of diarrhoea and acute lower respiratory tract infections (RTI), but its effect on malaria is inconsistent. When zinc is administered with other micronutrients or foods, its effect is also uncertain. We assessed the effects of different amounts and sources of zinc on the frequency of diarrhoea, malaria, fever and RTI in young children., Design, Setting and Populations: This community-based, double-blind, placebo-controlled, cluster-randomised trial of 2435 children 9 months of age was carried out between April 2010 and July 2012 in rural southwestern Burkina Faso., Interventions: Participants were randomly assigned at the concession level to receive daily 1 of 4 interventions for 9 months: (1) 20 g small-quantity lipid-based nutrient supplement (SQ-LNS) without zinc and placebo tablet, (2) 20 g SQ-LNS with 5 mg zinc and placebo tablet, (3) 20 g SQ-LNS with 10 mg zinc and placebo tablet or (4) 20 g SQ-LNS without zinc and 5 mg zinc tablet. Participants were visited weekly in their homes for morbidity surveillance for 9 months, and those with uncomplicated diarrhoea and malaria received treatment from the study field workers in the community., Main Outcomes: Incidence and longitudinal prevalence of diarrhoea, malaria, fever, and lower and upper RTI by intervention group., Results: The incidence of diarrhoea, malaria and fever was 1.10 (±1.03 SD), 0.61 (±0.66 SD) and 1.49 (±1.12 SD) episodes per 100 child-days at risk, respectively, and did not differ by intervention group (p=0.589, p=0.856 and p=0.830, respectively). The longitudinal prevalence of acute lower RTI (0.1%; 95% IC 0.1-0.2%) and of upper RTI (7.8%; 95% IC 7.1-8.4%) did not differ among groups (p=0.234 and p=0.501, respectively)., Conclusions: Inclusion of 5 or 10 mg zinc in SQ-LNS and provision of 5 mg zinc dispersible tablet along with SQ-LNS had no impact on the incidence of diarrhoea, malaria and fever or the longitudinal prevalence of RTI compared with SQ-LNS without zinc in this population., Trial Registration Number: NCT00944281., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Malaria infection can cause high oxidative stress, which could lead to the development of severe forms of malaria, such as pulmonary malaria. In recent years, the role of reactive oxygen species in the pathogenesis of the disease has been discussed, as well as the potential benefit of antioxidants supplementation. The aim of this study was to investigate the effects of N-acetyl cysteine (NAC) or mushroom Agaricus sylvaticus supplementation on the pulmonary oxidative changes in an experimental model of malaria caused by Plasmodium berghei strain ANKA., Methods: Swiss male mice were infected with P. berghei and treated with NAC or AS. Samples of lung tissue and whole blood were collected after one, three, five, seven or ten days of infection for the assessment of thiobarbituric acid reactive substances (TBARS), trolox equivalent antioxidant capacity (TEAC), nitrites and nitrates (NN) and to assess the degree of parasitaemia., Results: Although parasitaemia increased progressively with the evolution of the disease in all infected groups, there was a significant decrease from the seventh to the tenth day of infection in both antioxidant-supplemented groups. Results showed significant higher levels of TEAC in both supplemented groups, the highest occurring in the group supplemented with A. sylvaticus. In parallel, TBARS showed similar levels among all groups, while levels of NN were higher in animals supplemented with NAC in relation to the positive control groups and A. sylvaticus, whose levels were similar to the negative control group., Conclusion: Oxidative stress arising from plasmodial infection was attenuated by supplementation of both antioxidants, but A. sylvaticus proved to be more effective and has the potential to become an important tool in the adjuvant therapy of malaria.

Background: Malaria and undernutrition frequently coexist, especially in pregnant women and young children. Nutrient supplementation of these vulnerable groups might reduce their susceptibility to malaria by improving immunity., Methods: Antibody immunity to antigens expressed by a placental-binding parasite isolate, a non-placental binding parasite isolate, merozoites and schizonts at enrolment (before 20 gestation weeks) and at 36 gestation weeks were measured in 1,009 Malawian pregnant women receiving a daily lipid-based nutrient supplement, multiple micronutrients or iron and folic acid, who were participants in a randomized clinical trial assessing the effects of nutrient supplementation on pregnancy outcomes and child development (registration ID: NCT01239693)., Results: Antibodies to placental-binding isolates significantly increased while antibodies to most merozoite antigens declined over pregnancy. Overall, after adjustment for covariates, the type of supplementation did not influence antibody levels at 36 gestation weeks or the rate of change in antibody levels from enrolment to 36 weeks. A negative association between maternal body mass index and opsonizing antibodies to placental-binding antigens (coefficient (95% CI) -1.04 (-1.84, -0.24), was observed. Similarly, women with higher socioeconomic status had significantly lower IgG and opsonizing antibodies to placental-binding antigens. Neither of these associations was significantly influenced by the supplementation type., Conclusions: In the current cohort nutrient supplementation did not affect anti-malarial antibody responses, but poor and undernourished mothers should be a priority group in future trials.

Background: Previous trials have shown that zinc supplementation can decrease the risk of diarrhea, pneumonia, and malaria in children; however, the effects of zinc supplementation on mortality remain unclear. This study aimed at evaluating the benefits and risks of zinc supplementation on both total mortality and cause-specific mortality., Methodology and Principal Findings: We searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials in preschool children reporting total mortality or cause-specific mortality. Relative risk (RR) was used as a measure of the effect of zinc supplementation on the risk of mortality using a random effect model. Of the 1,520 identified articles, we included 8 trials reporting data on 87,854 children. Overall, zinc supplementation had no effect on total mortality (RR, 0.76; 95% CI: 0.56-1.04; P = 0.084), diarrhea-related mortality (RR, 0.80; 95% CI: 0.53-1.20; P = 0.276), pneumonia-related mortality (RR, 0.52; 95% CI: 0.11-2.39; P = 0.399), malaria-related mortality (RR, 0.90; 95% CI: 0.77-1.06; P = 0.196), or other causes of mortality (RR, 0.98; 95% CI: 0.67-1.44; P = 0.917). Subgroup analysis indicated that zinc supplementation was associated with a reduction in total mortality risk if the participants were boys, aged greater than 12 months, and the duration of the follow-up period was less than 12 months., Conclusions/significance: Zinc supplementation does not have an effect on total mortality, diarrhea-related mortality, pneumonia-related mortality, malaria-related mortality, or other causes of mortality. Subgroup analysis suggested that zinc supplementation can effectively reduce the risk of total mortality if the participants were boys, aged greater than 12 months, and the duration of the follow-up period was less than 12 months.

The Plasmodium mitochondrial electron transport chain has received considerable attention as a potential target for new antimalarial drugs. Atovaquone, a potent inhibitor of Plasmodium cytochrome bc(1), in combination with proguanil is recommended for chemoprophylaxis and treatment of malaria. The type II NADH:ubiquinone oxidoreductase (NDH2) is considered an attractive drug target, as its inhibition is thought to lead to the arrest of the mitochondrial electron transport chain and, as a consequence, pyrimidine biosynthesis, an essential pathway for the parasite. Using the rodent malaria parasite Plasmodium berghei as an in vivo infection model, we studied the role of NDH2 during Plasmodium life cycle progression. NDH2 can be deleted by targeted gene disruption and, thus, is dispensable for the pathogenic asexual blood stages, disproving the candidacy for an anti-malarial drug target. After transmission to the insect vector, NDH2-deficient ookinetes display an intact mitochondrial membrane potential. However, ndh2(-) parasites fail to develop into mature oocysts in the mosquito midgut. We propose that Plasmodium blood stage parasites rely on glycolysis as the main ATP generating process, whereas in the invertebrate vector, a glucose-deprived environment, the malaria parasite is dependent on an intact mitochondrial respiratory chain.

Background: To our knowledge, the impact of a nutrition education program combined with an increase in bioavailable dietary iron to treat iron-deficiency anemia has never been studied in adolescent girls., Objective: To evaluate the impact of an intensive dietary program for the treatment of iron-deficiency anemia in 34 intervention and 34 control boarding-school girls aged 12 to 17 years from Benin., Methods: A quasi-experimental design consisting of 4 weeks of nutrition education combined with an increase in the content and bioavailability of dietary iron for 22 weeks was implemented in the intervention school, but not in the control school. Data were obtained from both groups from a nutrition knowledge questionnaire, 24-hour dietary recalls, anthropometric measurements, measurement of iron status indices, and screening for malarial and intestinal parasitic infections., Results: Nutrition knowledge scores and mean intakes of nutrients, including dietary iron, absorbable iron, and vitamin C, were significantly higher in the intervention group (p < .05) than in the control group after 26 weeks. Mean hemoglobin and serum ferritin values were also significantly higher in the intervention group than in the control group (122 vs. 112 g/L [p = .0002] and 32 vs. 19 microg/L [p = .04], respectively), whereas the prevalence of anemia (32% vs. 85% [p = .005] and iron-deficiency anemia (26% vs. 56% [p = .04]) was significantly lower in the intervention group than in the control group. No significant differences between the groups were observed in intestinal parasitic infections or malaria status postintervention., Conclusions: A multidietary strategy aiming to improve available dietary iron can reduce iron-deficiency anemia in adolescent girls.

Susceptibility to oxidative stress is a well-established feature of the malarial parasite. Pharmacologists have taken advantage of this property to design highly effective pro-oxidant antimalarial drugs. Less well appreciated is the fact that nutritional manipulation of host oxidative stress status by dietary means can have a profound effect on the growth of the parasite. In particular, rapid induction of vitamin E deficiency in mice by feeding highly unsaturated fatty acids (fish oil) strongly suppresses plasmodial growth. Likewise, the status of other antioxidant nutrients (e.g., riboflavin or vitamin C) may also influence the course of malarial infection under certain conditions. A combined nutritional pharmacology approach may offer some promise in controlling malaria.

Young Wistar rats developed a fulminant infection when inoculated with the rodent malaria parasite Plasmodium berghei. Rats that died during the infection exhibited a progressive paralysis of the extremities, a rapidly decreasing body temperature and minute haemorrhages in the brain. Increasing the level of protein in the diet from 4 to 8 and 16% was accompanied by an increase in morbidity and mortality from 15 to 40 and 90% respectively on day 6 of the infection. Increasing the level of dietary protein also increased the reticulocyte count of the peripheral blood in infected and non-infected rats. The attenuation of the cerebral syndrome in rats fed a diet low in protein may be related to changes in erythropoiesis or to changes in immune reactivity.

Feeding of wistar albino rats on low protein and energy diet (4% protein) caused suppression of parasitaemia when infected with Plasmodium berghei besides causing a depressed immune response. The refeeding of protein energy deficient rats on normal protein and energy diet (18% protein) for four weeks resulted in the normal course of parasitaemia after P. berghei infection. The present study was carried out to find the cause of suppression of malaria in protein energy deficient rats. The experiments revealed re-elevation of malaria parasitaemia when rats were fed on low protein diets supplemented with p-amino-benzoic acid (PABA). Moreover, the parasite persisted at subpatent levels in tissues in protein energy deficient rats and resulted in the development of antimalarial antibodies. Low protein energy diet could cause deficiency of certain essential nutrients required for the parasite, PABA being one of them, and hence suppresses the parasitaemia to subpatent levels. As a result, sufficient antigenic stimulus is provided to the host so that the host develops an immune response which might in turn help in further suppression of parasitaemia to subpatent levels.

The development of resistance to reinfection with Plasmodium berghei was studied in rats in which the primary infection had been almost totally suppressed by feeding a protein-free diet (peak parasitaemia 0.5%; patent for only the first four days after inoculation) On Days 5, 9, 15, 23 and 28 after primary inoculation groups of animals were challenged with the same strain of parasite. At the same time the diet was changed to that of a 17% casein formula. The development of resistance as judged by the level of parasitaemia following challenge reached a significant level nine days after the primary inoculation and almost complete protection by Day 23 of the study. The protective activity was immunological since it could be transferred to other animals by a single intravenous injection of a suspension of spleen cells from infected donors. The study illustrates that infected animals experiencing severe protein malnutrition are still capable of mounting a substantial immune response to malaria.