Cognitive Dysfunction Is Sustained after Rescue Therapy in Experimental Cerebral Malaria, and Is Reduced by Additive Antioxidant Therapy

Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders

Summary of primary screening results.

<p>Values of individual parameters of Cerebral Malaria (CM) at days 3 and 6 post-infection are shown. Animals infected with malarial parasite (PbA, Pch, PyNXL and PyXL) were compared to animals of the same background inoculated with uninfected RBC. Data are shown as median (upper/lower quartile) or mean ± SD when appropriated. N = 12–15/group.</p><p>*p<0.05 or less by Wilcoxon Signed Rank Test.</p

Additive antioxidant treatment prevents cognitive impairment after CM.

<p>C57BL/6 (A and B) and SW mice (C and D) (n = 12–20/group) were infected with PbA or PyXL, respectively (10⁶ PRBC). As a control, one group was inoculated with the same number of uninfected RBC (n = 6/group). Starting on day 6 post infection, infected mice were divided into 2 groups and treated orally with chloroquine (25 mg/kg b.w.), chloroquine plus desferoxamine (DFX, 20 mg/kg b.w., i.p.), chloroquine plus N-acetylcysteine (NAC, 20 mg/kg b.w., i.p.) or with the combination of chloroquine/DFX/NAC for 7 days. On day 15 and 16 post-infection all the animals were submitted to open field task training and test sessions, respectively. Data are expressed as mean ± S.E.M. of crossings (<i>A and C</i>) and rearings (<i>B and D</i>) in training (<i>gray bars</i>) and test (<i>black bars</i>) sessions; *significant difference between groups in training and test sessions (<i>p</i><0.05, Student's T test). Panels E–M ilustrate histological examinations (H&E staining) of different brain regions in non-infected (RBC), infected (PRBC, PbA 10⁶) and mice treated with the combination of chloroquine/DFX/NAC (PbA+Cq+AOX). E–G) cerebral cortex; H–J) hippocampus; K–M) and cerebellum. Microvascular congestion and plugging (arrows) were detected in all analyzed regions in PbA-infected mice, but were not seen in controls or treated animals rescued with chloroquine and additive antioxidants. Scale bar, 100 µm.</p

Time-course of parasitemia and survival rate of C57BL6, BALB/c and Swiss Webster (SW) mice after infection with PbA, Pch, PyNXL or PyXL (n = 12–20/group).

<p>Date on parasitemia (A and B) are shown as mean ± SEM. Comparisons of C57BL6-PbA versus C57BL6-Pch (#), C57BL6-PbA versus BALB/c-PbA (*) and C57BL6-Pch versus BALB/c-PbA (+), were significant by Tukey's Multiple Comparison Test (A). (θ) and (∞) indicate p<0.05 in relation to day 3 post-infection during PyNXL and PyXL infection, respectively (B). Survival curves (C and D) were evaluated by Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests.</p

Institutionalized elderly: functional capacity and physical fitness

O objetivo deste estudo foi explorar a relação entre a aptidão física e a capacidade funcional de residentes em instituições de longa permanência para idosos de baixa renda. Foi realizada avaliação em seis instituições localizadas em três regiões do país. Amostra foi composta de 78 idosos, com média de idade de 77,4 anos (DP = 7,9). A avaliação da aptidão física aplicando-se testes da AAHPERD adaptada para idosos institucionalizados, e da capacidade funcional pela escala de Katz, constatou que a aptidão física, em seus cinco componentes, em média era regular na flexibilidade, coordenação, agilidade e resistência aeróbia, era boa no componente força. Já o Índice de Aptidão Física Geral (IAFG), em média era regular. Os resultados demonstram que quanto maior o grau de dependência dos idosos institucionalizados menor é a força e o resultado do IAFG e, quanto melhor é a coordenação e a agilidade melhor é o nível de independência para a realização das atividades da vida diária. As implicações estão em contribuir com os programas de exercícios físicos adequados na manutenção e/ou recuperação da funcionalidade.This study analyzed the relationship between physical fitness and functional capacity in 78 residents of long-stay institutions for low-income elderly located in five regions of Brazil. The majority of the sample consisted of women, and mean age was 77.4 years (SD = 7.9). Physical fitness was assessed with the AAHPERD test, adjusted for institutionalized elderly. The Katz scale was used for functional capacity. The five components of physical fitness rated fair for flexibility, coordination, agility, and aerobic endurance and good for strength. The mean general physical fitness (GPF) index was fair. According to the findings, the greater the degree of dependency in institutionalized elderly, the lesser their strength and GPF level; meanwhile, better coordination and agility are associated with greater independence for performing activities of daily living. The results can contribute to appropriate physical exercise programs for maintenance and/or recovery of functionality.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Ministério da Saúd

The ability to recognize new objects is impaired in mice after CM.

<p>C57BL/6 and BALB/c mice (n = 12–20/group) were infected with PbA (10⁶ PRBC) and treated with chloroquine starting at day 6 post-infection. Control groups were inoculated with the same number of uninfected RBC. On day 15 all the animals were submitted to memory recognition task. Results are shown as mean ± S.E.M. of the object recognition index calculated as described in Materials and <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000963#s4" target="_blank">Methods</a>. *p<0.05 Kruskal–Wallis analyses of variance followed by Mann–Whitney U-tests.</p