RESUMO
Severe malarial anaemia (SMA) is the most common life-threatening complication of Plasmodium falciparum infection in African children. SMA is characterised by haemolysis and inadequate erythropoiesis, and is associated with dysregulated inflammatory responses and reduced complement regulatory protein levels (including CD35). However, a deeper mechanistic understanding of the pathogenesis requires improved animal models. In this comparative study of two closely related macaque species, we interrogated potential causal factors for their differential and temporal relationships to onset of SMA. We found that rhesus macaques inoculated with blood-stage Plasmodium coatneyi developed SMA within 2 weeks, with no other severe outcomes, whereas infected cynomolgus macaques experienced only mild/ moderate anaemia. The abrupt drop in haematocrit in rhesus was accompanied by consumption of haptoglobin (haemolysis) and poor reticulocyte production. Rhesus developed a greater inflammatory response than cynomolgus macaques, and had lower baseline levels of CD35 on red blood cells (RBCs) leading to a significant reduction in the proportion of CD35+ RBCs during infection. Overall, severe anaemia in rhesus macaques infected with P. coatneyi has similar features to SMA in children. Our comparisons are consistent with an association of low baseline CD35 levels on RBCs and of early inflammatory responses with the pathogenesis of SMA.
Assuntos
Anemia/sangue , Anemia/parasitologia , Eritrócitos/metabolismo , Malária/sangue , Plasmodium/metabolismo , Receptores de Complemento 3b/sangue , Anemia/patologia , Animais , Eritrócitos/parasitologia , Eritrócitos/patologia , Feminino , Inflamação/sangue , Inflamação/parasitologia , Inflamação/patologia , Macaca fascicularis , Macaca mulatta , Malária/parasitologia , Malária/patologia , Especificidade da EspécieRESUMO
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals received baclofen (30â¯mg/day) or placebo in a naturalistic outpatient setting for one week, and then performed a controlled laboratory experiment which included alcohol cue-reactivity, fixed-dose priming, and self-administration procedures. Blood samples were collected, and the following neuroendocrine markers were measured: ghrelin, leptin, amylin, glucagon-like peptide-1 (GLP-1), insulin, prolactin, thyroid-stimulating hormone, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH). During the outpatient phase, baclofen significantly increased blood concentrations of acyl-ghrelin (pâ¯=â¯0.01), leptin (pâ¯=â¯0.01), amylin (pâ¯=â¯0.004), and GLP-1 (pâ¯=â¯0.02). Significant drugâ¯×â¯time-point interaction effects for amylin (pâ¯=â¯0.001) and insulin (pâ¯=â¯0.03), and trend-level interaction effects for GLP-1 (pâ¯=â¯0.06) and ACTH (pâ¯=â¯0.10) were found during the laboratory experiment. Baclofen, compared to placebo, had no effect on alcohol drinking in this study (p'sâ¯≥â¯0.05). Together with previous studies, these findings shed light on the role of the GABAergic system and GABA-B receptors in the shared neurobiology of alcohol-, feeding-, and stress-related behaviors.