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IL-12p40 deficiency leads to uncontrolled Trypanosoma cruzi dissemination in the spinal cord resulting in neuronal death and motor dysfunction.

ABSTRACT: Chagas' disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory component associated to the fatal neurological disorder occurring in this mouse model. Forelimb paralysis in infected IL-12p40KO mice was associated with 60% (p<0.05) decrease in spinal cord neuronal density, glutamate accumulation (153%, p<0.05) and strong demyelization in lesion areas, mostly in those showing heavy protein nitrosylation, all denoting a neurotoxic degenerative profile. Quantification of T. cruzi 18S rRNA showed that parasite burden was controlled in the spinal cord of WT mice, decreasing from the fifth week after infection, but progressive parasite dissemination was observed in IL-12p40KO cords concurrent with significant accumulation of the astrocytic marker GFAP (317.0%, p<0.01) and 8-fold increase in macrophages/microglia (p<0.01), 36.3% (p<0.01) of which were infected. Similarly, mRNA levels for CD3, TNF-?, IFN-?, iNOS, IL-10 and arginase I declined in WT spinal cords about the fourth or fifth week after infection, but kept increasing in IL-12p40KO mice. Interestingly, compared to WT tissue, lower mRNA levels for IFN-? were observed in the IL-12p40KO spinal cords up to the fourth week of infection. Together the data suggest that impairments of parasite clearance mechanisms in IL-12p40KO mice elicit prolonged spinal cord inflammation that in turn leads to irreversible neurodegenerative lesions.

SUBMITTER: Bombeiro AL

PROVIDER: S-EPMC3495776 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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IL-12p40 deficiency leads to uncontrolled Trypanosoma cruzi dissemination in the spinal cord resulting in neuronal death and motor dysfunction.

Bombeiro André Luis AL Gonçalves Lígia Antunes LA Penha-Gonçalves Carlos C Marinho Claudio Romero Farias CR D'Império Lima Maria Regina MR Chadi Gerson G Álvarez José Maria JM

PloS one 20121112 11

Chagas' disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory co ...[more]

PMID: 23152844

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Project description:BackgroundTranscutaneous spinal cord stimulation (tSCS) is a non-invasive modality in which electrodes can stimulate spinal circuitries and facilitate a motor response. This review aimed to evaluate the methodology of studies using tSCS to generate motor activity in persons with spinal cord injury (SCI) and to appraise the quality of included trials.MethodsA systematic search for studies published until May 2021 was made of the following databases: EMBASE, Medline (Ovid) and Web of Science. Two reviewers independently screened the studies, extracted the data, and evaluated the quality of included trials. The electrical characteristics of stimulation were summarised to allow for comparison across studies. In addition, the surface electromyography (EMG) recording methods were evaluated.ResultsA total of 3753 articles were initially screened, of which 25 met the criteria for inclusion. Studies were divided into those using tSCS for neurophysiological investigations of reflex responses (n = 9) and therapeutic investigations of motor recovery (n = 16). The overall quality of evidence was deemed to be poor-to-fair (10.5 ± 4.9) based on the Downs and Black Quality Checklist criteria. The electrical characteristics were collated to establish the dosage range across stimulation trials. The methods employed by included studies relating to stimulation parameters and outcome measurement varied extensively, although some trends are beginning to appear in relation to electrode configuration and EMG outcomes.ConclusionThis review outlines the parameters currently employed for tSCS of the cervicothoracic and thoracolumbar regions to produce motor responses. However, to establish standardised procedures for neurophysiological assessments and therapeutic investigations of tSCS, further high-quality investigations are required, ideally utilizing consistent electrophysiological recording methods, and reporting common characteristics of the electrical stimulation administered.

Dataset Information

IL-12p40 deficiency leads to uncontrolled Trypanosoma cruzi dissemination in the spinal cord resulting in neuronal death and motor dysfunction.

Publications

IL-12p40 deficiency leads to uncontrolled Trypanosoma cruzi dissemination in the spinal cord resulting in neuronal death and motor dysfunction.

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