Amino acid derangements in adults with severe falciparum malaria.

Amino acid derangements are common in severe falciparum malaria and have been associated with endothelial dysfunction (L-arginine), metabolic acidosis (alanine and lactate), and disease severity (phenylalanine and tryptophan metabolites). Whether these amino acid perturbations reflect isolated pathogenic mechanisms or if they are part of overall changes in amino acid metabolism is unclear. To investigate this, we prospectively simultaneously quantified a broad range of plasma free amino acids (PFAA) using HPLC-MRM-Mass spectrometry in relation to presenting symptoms in adults with severe malaria (n = 88), septicaemia (n = 88), uncomplicated malaria (n = 71), and healthy controls (n = 48) from Bangladesh. The total plasma concentration of measured amino acids was significantly reduced in each of the patient groups when compared to normal levels observed in healthy local controls: uncomplicated malaria -54%, severe malaria -23%, and sepsis -32%, (p = <0.001). Inspection of amino acid profiles revealed that in each group the majority of amino acids were below normal levels, except for phenylalanine. Among patients with severe malaria, L-lactate was strongly associated with an increase of the total amino acid concentration, likely because this reflects tissue hypoxia. Our data confirm previously described amino acid abnormalities, likely resulting from overall changes in the concentration of PFAA.

Point-of-care lung ultrasound for the detection of pulmonary manifestations of malaria and sepsis: An observational study.

INTRODUCTION: Patients with severe malaria or sepsis are at risk of developing life-threatening acute respiratory distress syndrome (ARDS). The objective of this study was to evaluate point-of-care lung ultrasound as a novel tool to determine the prevalence and early signs of ARDS in a resource-limited setting among patients with severe malaria or sepsis. MATERIALS AND METHODS: Serial point-of-care lung ultrasound studies were performed on four consecutive days in a planned sub study of an observational cohort of patients with malaria or sepsis in Bangladesh. We quantified aeration patterns across 12 lung regions. ARDS was defined according to the Kigali Modification of the Berlin Definition. RESULTS: Of 102 patients enrolled, 71 had sepsis and 31 had malaria. Normal lung ultrasound findings were observed in 44 patients on enrolment and associated with 7% case fatality. ARDS was detected in 10 patients on enrolment and associated with 90% case fatality. All patients with ARDS had sepsis, 4 had underlying pneumonia. Two patients developing ARDS during hospitalisation already had reduced aeration patterns on enrolment. The SpO2/FiO2 ratio combined with the number of regions with reduced aeration was a strong prognosticator for mortality in patients with sepsis (AUROC 91.5% (95% Confidence Interval: 84.6%-98.4%)). CONCLUSIONS: This study demonstrates the potential usefulness of point-of-care lung ultrasound to detect lung abnormalities in patients with malaria or sepsis in a resource-constrained hospital setting. LUS was highly feasible and allowed to accurately identify patients at risk of death in a resource limited setting.

Iron superoxide dismutases targeted to the glycosomes of Leishmania chagasi are important for survival.

Kinetoplastid glycosomes contain a variety of metabolic activities, such as glycolysis, beta-oxidation of fatty acids, lipid biosynthesis, and purine salvage. One advantage of sequestering metabolic activities is the avoidance of cellular oxidative damage by reactive oxygen species produced as a by-product of metabolism. Little is known about how glycosomes themselves withstand these toxic metabolites. We previously isolated an iron superoxide dismutase from Leishmania chagasi that is expressed at low levels in the early logarithmic promastigote stage and increases toward the stationary promastigote and amastigote stages. We have since identified a second highly homologous Lcfesodb gene that is expressed at high levels in the early logarithmic promastigote stage and decreases toward the stationary promastigote and amastigote stages. Localization studies using green fluorescent protein fusions have revealed that LcFeSODB1 and LcFeSODB2 are localized within the glycosomes by the last three amino acids of their carboxyl termini. To better understand the specific role that FeSODB plays in parasite growth and survival, a single-allele knockout of the Lcfesodb1 gene was generated. The parasites with these genes exhibited a significant reduction in growth when endogenous superoxide levels were increased with paraquat in culture. Furthermore, the FeSODB1-deficient parasites exhibited a significant reduction in survival within human macrophages. Our results suggest that LcFeSODB plays an important role in parasite growth and survival by protecting glycosomes from superoxide toxicity.