In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.

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Background: Household air pollution associated with biomass (wood, dung, charcoal, and crop residue) burning for cooking is estimated to contribute to approximately 4 million deaths each year worldwide, with the greatest burden seen in low and middle-income countries. We investigated the relationship between solid fuel type and respiratory symptoms in Uganda, where 96% of households use biomass as the primary domestic fuel. Materials and Methods: Cross-sectional study of 15,405 pre-school aged children living in charcoal or wood-burning households in Uganda, using data from the 2016 Demographic and Health Survey. Multivariable logistic regression analysis was used to identify the associations between occurrence of a cough, shortness of breath, fever, acute respiratory infection (ARI) and severe ARI with cooking fuel type (wood, charcoal); with additional sub-analyses by contextual status (urban, rural). Results: After adjustment for household and individual level confounding factors, wood fuel use was associated with increased risk of shortness of breath (AOR: 1.33 [1.10–1.60]), fever (AOR: 1.26 [1.08–1.48]), cough (AOR: 1.15 [1.00–1.33]), ARI (AOR: 1.36 [1.11–1.66] and severe ARI (AOR: 1.41 [1.09–1.85]), compared to charcoal fuel. In urban areas, Shortness of breath (AOR: 1.84 [1.20–2.83]), ARI (AOR: 1.77 [1.10–2.79]) and in rural areas ARI (AOR: 1.23 [1.03–1.47]) and risk of fever (AOR: 1.23 [1.03–1.47]) were associated with wood fuel usage. Conclusions: Risk of respiratory symptoms was higher among children living in wood compared to charcoal fuel-burning households, with policy implications for mitigation of associated harmful health impacts.

The in vitro activity of the prodrug amodiaquine and its metabolite monodesethyl-amodiaquine has been studied for three strains of Plasmodium falciparum: LS-2, LS-3, and LS-1. Both compounds showed significant activity against all three strains; the activity of amodiaquine was slightly higher than that of the metabolite. By use of a checkerboard design, interaction studies with both compounds yielded evidence of significant synergism; means of the sums of the fractional inhibitory concentrations were 0.0392 to 0.0746 for strain LS-2, 0.1567 to 0.3102 for strain LS-3, and 0.025 to 0.3369 for strain LS-1. In further investigations, the interaction of amodiaquine with monodesethyl-amodiaquine was tested at clinically relevant concentrations of both compounds. In these studies, involving amodiaquine at picomolar and femtomolar concentrations, the compound was found to exert high potentiating activity on monodesethyl-amodiaquine. This interaction produced mean ratios of observed to expected activity of 0.0505 to 0.0642 for strain LS-2, 0.0882 to 0.3820 for strain LS-3, and 0.0752 to 0.2924 for strain LS-1. The synergistic activity was most marked at monodesethyl-amodiaquine/ amodiaquine ratios up to 100,000:1 but was still evident at higher ratios.The widespread increase of resistance to chloroquine in Plasmodium falciparum has resulted in renewed interest in amodiaquine (AQ) as a replacement for chloroquine in the treatment of malaria, especially in sub-Saharan Africa. Although AQ belongs to the same chemical class of compounds as chloroquine, the 4-aminoquinolines, this drug often shows adequate clinical-parasitological efficacy in chloroquine-resistant infections. Furthermore, adverse reactions reported previously, such as agranulocytosis (14) and hepatitis (20), were mainly associated with the prophylactic use of AQ, and more recent reports show that therapeutic regimens are well tolerated (22). Therefore, the World Health Organization has again listed AQ as a drug for treatment of chloroquine-resistant falciparum malaria (40).During and after absorption, orally administered AQ is rapidly metabolized to desethylamodiaquine (DAQ) and other derivatives of lesser antimalarial significance (9). Clinically, the antimalarial activity of AQ is exerted mainly through DAQ (37). Earlier in vitro studies indicated that DAQ and AQ have equal activity against P. falciparum (8). Other observations suggest that the two compounds possess independent modes of action (7,27). However, recent comparative in vitro studies with fresh isolates of P. falciparum showed a significant correlation between the activities of the two compounds that indicates similarities in the way they act against the parasite (12).Chloroquine-resistant falciparum malaria on the African continent was first detected in Kenya and Tanzania. During the past 2 decades it has extended to practically all parts of tropical Africa (32,39). AQ has been shown to maintain high efficacy in the areas of malaria endemicity in the continent where chloroquine resistance is st...

Background A variety of public health interventions have been undertaken in low- and middle-income countries (LMICs) to prevent morbidity and mortality associated with household air pollution (HAP) due to cooking, heating and lighting with solid biomass fuels. Pregnant women and children under five are particularly vulnerable to the effects of HAP, due to biological susceptibility and typically higher exposure levels. However, the relative health benefits of interventions to reduce HAP exposure among these groups remain unclear. This systematic review aims to assess, among pregnant women, infants and children (under 5 years) in LMIC settings, the effectiveness of interventions which aim to reduce household air pollutant emissions due to household solid biomass fuel combustion, compared to usual cooking practices, in terms of health outcomes associated with HAP exposure. Methods This protocol follows standard systematic review processes and abides by the PRISMA-P reporting guidelines. Searches will be undertaken in MEDLINE, EMBASE, CENTRAL, WHO International Clinical Trials Registry Platform (ICTRP), The Global Index Medicus (GIM), ClinicalTrials.gov and Greenfile, combining terms for pregnant women and children with interventions or policy approaches to reduce HAP from biomass fuels or HAP terms and LMIC countries. Included studies will be those reporting (i) pregnant women and children under 5 years; (ii) fuel transition, structural, educational or policy interventions; and (iii) health events associated with HAP exposure which occur among pregnant women or among children within the perinatal period, infancy and up to 5 years of age. A narrative synthesis will be undertaken for each population-intervention-outcome triad stratified by study design. Clinical and methodological homogeneity within each triad will be used to determine the feasibility for undertaking meta-analyses to give a summary estimate of the effect for each outcome. Discussion This systematic review will identify the effectiveness of existing HAP intervention measures in LMIC contexts, with discussion on the context of implementation and adoption, and summarise current literature of relevance to maternal and child health. This assessment reflects the need for HAP interventions which achieve measurable health benefits, which would need to be supported by policies that are socially and economically acceptable in LMIC settings worldwide. Systematic review registration PROSPERO CRD42020164998

Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood–brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM.

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