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1.
World Neurosurg ; 136: e393-e397, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31931248

RESUMO

OBJECTIVE: During surgery, shoulder traction is often used for better fluoroscopic imaging of the lower cervical spine. Traction on the C5 root has been implicated as a potential cause of C5 palsy after cervical spine surgery. Using magnetic resonance imaging, this study was undertaken to determine the impact of upper extremity traction on the C5 root orientation. METHODS: In this study, 5 subjects underwent coronal magnetic resonance imaging of the cervical spine and left brachial plexus. Using a wrist restraint, sequential traction on the left arm with 10, 20, and 30 lb. was applied. Measurements of the angle between the spinal axis and C5 nerve root and the angle between the C5 nerve root and the upper trunk of the brachial plexus were obtained. The measurements were taken by a trained neuroradiologist and analyzed for significance. RESULTS: The angle between the C5 nerve root and the vertical spinal axis remained within 3 and 4 degrees of the mean and was not found to be associated with increased traction weight (P = 0.753). The angle between the C5 root and the upper trunk increased with increasing weight and was found to be statistically significant (P = 0.003). CONCLUSIONS: While the cause of C5 palsy is likely multifactorial, this study provides evidence that, in the awake volunteer, upper extremity traction leads to C5 root and upper trunk tension. These results suggest that shoulder traction in the anesthetized patient could lead to tension of the C5 nerve root and subsequent injury and palsy.


Assuntos
Cuidados Intraoperatórios/efeitos adversos , Paralisia/etiologia , Tração/efeitos adversos , Adulto , Idoso , Plexo Braquial/diagnóstico por imagem , Vértebras Cervicais/diagnóstico por imagem , Feminino , Fluoroscopia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paralisia/patologia , Raízes Nervosas Espinhais/patologia
2.
Cells ; 8(3)2019 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-30832324

RESUMO

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer's disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.


Assuntos
Autofagia , Proteostase , Receptores sigma/metabolismo , Animais , Autofagia/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Furanos/farmacologia , Células HEK293 , Células HeLa , Humanos , Paralisia/patologia , Fosforilação/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Proteostase/efeitos dos fármacos , Receptores sigma/agonistas
3.
J Orthop Res ; 37(5): 1153-1163, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30839119

RESUMO

Reduced mechanical loading can lead to disuse osteoporosis, resulting in bone fragility. Disuse models report macroscopic bone loss due to muscle inactivity and immobilization, yet only recently has there been quantification of the effects of disuse on the vascular pores and osteocyte network, which are believed to play an important role in mechanotransduction via interstitial fluid flow. The goal of this study was to perform a high-resolution analysis of the effects of muscle inactivity on intracortical porosity and osteocyte lacunar density in skeletally mature rats. Muscle paralysis was induced in 20-week-old female Sprague Dawley rats by injection of botulinum neurotoxin. Rats were injected in the right hindlimb muscles with either Botox (BTX, n = 8) or saline solution (CTRL, n = 8), with a third group used as baseline controls (n = 8). Four weeks after injection, Botox caused a ∼60% reduction in hindlimb muscle mass. High-resolution micro-CT analysis showed that Botox-induced muscle paralysis increased vascular canal porosity and reduced osteocyte lacunar density within the tibial metaphysis cortex. Cortical thickness and other areal properties were diminished in the proximal tibial metaphysis, whereas no differences were found in the mid-diaphysis. Within the BTX group, the injected limbs showed a lower cancellous bone volume fraction relative to the contralateral limb. These results indicate that diminished muscle activity alters the vascular canal porosity and osteocyte lacunar density in cortical bone, which could alter interstitial fluid flow, affecting molecular transport and the transmission of mechanical signals to osteocytes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.


Assuntos
Osso Esponjoso/patologia , Osso Cortical/patologia , Paralisia/patologia , Comportamento Sedentário , Animais , Toxinas Botulínicas Tipo A , Osso Esponjoso/diagnóstico por imagem , Osso Cortical/diagnóstico por imagem , Feminino , Marcha , Imageamento Tridimensional , Osteócitos , Paralisia/fisiopatologia , Porosidade , Distribuição Aleatória , Ratos Sprague-Dawley , Microtomografia por Raio-X
4.
Brain Dev ; 41(5): 443-451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30594353

RESUMO

OBJECIVE: To clarify the neuroimaging findings of children with acute flaccid myelitis during an outbreak of EV-D68 infection. METHODS: We performed a detailed review of the spinal and cranial MRI results of 54 children with acute flaccid myelitis. We focused on the range of longitudinal lesions, the localization and appearance of lesions within a horizontal section, Gadolinium-enhancement, and changes over time. RESULTS: All children had longitudinal spinal lesions involving central gray matter. Twenty-six children had lesions spanning the entire spine. Six of them had weakness in all limbs, whereas seven had weakness of only one limb. Thirty-eight children had lesions in both gray and white matter and limb weakness tended to be more severe in these children. During the acute period, spinal lesions showed bilateral ill-defined widespread T2 hyperintensity. During the subacute period, lesions were well defined and confined to the anterior horn. The distribution of limb weakness was correlated with the appearance of lesions during the subacute period. Gadolinium enhancement was performed in 37 children, and enhancement was seen in the cauda equina in 29 children. Enhancement was infrequent within 2 days after onset but was seen in almost all children thereafter. Twenty-two children had brainstem lesions continuous with spinal lesions. CONCLUSION: Extensive longitudinal spinal lesions were characteristic in children with acute flaccid myelitis. Lesions were usually bilateral and widespread during the acute period, whereas localization to the anterior horn could become obvious. Although enhancement of the cauda equina was often observed, its appearance was sometimes delayed.


Assuntos
Enterovirus Humano D/patogenicidade , Infecções por Enterovirus/complicações , Substância Cinzenta/diagnóstico por imagem , Mielite , Paralisia , Substância Branca/diagnóstico por imagem , Doença Aguda , Criança , Pré-Escolar , Surtos de Doenças , Feminino , Substância Cinzenta/patologia , Humanos , Lactente , Japão , Imagem por Ressonância Magnética , Masculino , Mielite/diagnóstico por imagem , Mielite/etiologia , Mielite/patologia , Mielite/fisiopatologia , Paralisia/diagnóstico por imagem , Paralisia/etiologia , Paralisia/patologia , Paralisia/fisiopatologia , Substância Branca/patologia
5.
J Clin Neurosci ; 59: 332-334, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30448297

RESUMO

We report an extremely rare case showing a fifth cervical spine (C5) level pure motor cervical spinal cord injury (SCI). A 55-year-old-man lost consciousness and fell into a bathtub. Immediately after regaining consciousness, the patient had right arm drop alone. He was referred to our department for investigation of right arm drop 4 months later. Neurological examination revealed motor weakness of the right deltoid muscle. MRI of the cervical spine revealed a C3-4 level central disc herniation compressing the spinal cord. An electromyogram study revealed bilateral neurogenic discharges in the deltoid, supraspinatus and infraspinatus muscles. We diagnosed a C5 segmental pure motor SCI. We chose conservative therapy for the present patient. At the latest follow-up visit, the patient showed modest recovery of motor weakness. Although it is unusual, this case illustrates the possibility that C5 segmental pure motor palsy can occur as one of the manifestations of cervical SCI.


Assuntos
Paralisia/diagnóstico por imagem , Traumatismos da Medula Espinal/diagnóstico por imagem , Acidentes por Quedas , Braço/fisiopatologia , Vértebras Cervicais/lesões , Eletromiografia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paralisia/etiologia , Paralisia/patologia , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/patologia
7.
Int J Mol Sci ; 19(11)2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30463256

RESUMO

Microsomal prostaglandin E synthetase-1 (mPGES-1) is an inducible terminal enzyme for the production of prostaglandin E2 (PGE2). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, mPGES-1 is induced in vascular endothelial cells (VECs) around inflammatory foci and facilitates inflammation, demyelination, and paralysis. Therefore, we investigated the role of CD31-positive VECs in mPGES-1-mediated EAE aggravation using immunohistochemical analysis and imaging of wild-type (wt) and mPGES-1-deficient (mPGES-1-/-) mice. We demonstrated that EAE induction facilitated vascularity in inflammatory lesions in the spinal cord, and this was significantly higher in wt mice than in mPGES-1-/- mice. In addition, endothelial interleukin-1ß (IL-1ß) production was significantly higher in wt mice than in mPGES-1-/- mice. Moreover, endothelial PGE2 receptors (E-prostanoid (EP) receptors EP1⁻4) were expressed after EAE induction, and IL-1ß was induced in EP receptor-positive VECs. Furthermore, IL-1 receptor 1 expression on VECs was increased upon EAE induction. Thus, increased vascularity is one mechanism involved in EAE aggravation induced by mPGES-1. Furthermore, mPGES-1 facilitated the autocrine function of VECs upon EP receptor induction and IL-1ß production, modulating mPGES-1 induction in EAE.


Assuntos
Progressão da Doença , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/patologia , Células Endoteliais/enzimologia , Interleucina-1beta/metabolismo , Microssomos/enzimologia , Prostaglandina-E Sintases/metabolismo , Regulação para Cima , Animais , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Paralisia/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Interleucina-1/metabolismo , Receptores de Prostaglandina E/metabolismo , Medula Espinal/patologia
8.
World Neurosurg ; 119: e1029-e1034, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30144617

RESUMO

BACKGROUND: Adamkiewicz arteries vasospasm in spinal cord subarachnoid hemorrhage (SAH) can affect the spinal cord. Although muscle dysfunction of extremities is a common problem after spinal cord ischemia induced by SAH, to our knowledge there are no studies on degenerative changes in peripheral nerves. We studied the histopathologic changes in sciatic nerves after spinal SAH. METHODS: This study was carried out on 19 rabbits. Five of them were used as control animals, 5 were in the sham group, and 9 were in the study group. For the procedure, 0.5 cm3 of serum saline for the sham group and autologous arterial blood for the study group was injected into the lumbar subarachnoid space at the L5 level. After 2 weeks of follow-up, the sciatic nerve roots at the L5-S3 levels with spinal cords and sciatic nerves were bilaterally extracted to the levels of the collum femoris. The specimens were evaluated by stereologic methods, and degenerated sciatic nerve axons were estimated by Cavalieri methods. Kruskal-Wallis and Mann-Whitney U tests were used for data analysis. Differences of P < 0.005 were evaluated as significant. RESULTS: The mean number of degenerated axon density per square millimeter of sciatic nerve at the collum femoris level was 7 ± 2/mm2 in the control group, 23 ± 7/mm2 in the sham group (P < 0.005), and 125 ± 32/mm2 in the SAH group (P < 0.00005). Statistical analysis showed that spinal SAH may cause axonal degeneration in the peripheral nerves. CONCLUSIONS: We concluded that SAHs frequently affect the spinal cord and result in axonal injury to peripheral nerves, of which there is no mention in the literature.


Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Debilidade Muscular/fisiopatologia , Degeneração Neural/fisiopatologia , Paralisia/fisiopatologia , Nervo Isquiático/fisiopatologia , Hemorragia Subaracnóidea/fisiopatologia , Animais , Modelos Animais de Doenças , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/patologia , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Degeneração Neural/etiologia , Degeneração Neural/patologia , Paralisia/etiologia , Paralisia/patologia , Coelhos , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Isquemia do Cordão Espinal/etiologia , Isquemia do Cordão Espinal/patologia , Isquemia do Cordão Espinal/fisiopatologia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/patologia
9.
Sci Rep ; 8(1): 9818, 2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959358

RESUMO

Medically relevant cases of snakebite in Europe are predominately caused by European vipers of the genus Vipera. Systemic envenoming by European vipers can cause severe pathology in humans and different clinical manifestations are associated with different members of this genus. The most representative vipers in Europe are V. aspis and V. berus and neurological symptoms have been reported in humans envenomed by the former but not by the latter species. In this study we determined the toxicological profile of V. aspis and V. berus venoms in vivo in mice and we tested the effectiveness of two antivenoms, commonly used as antidotes, in counteracting the specific activities of the two venoms. We found that V. aspis, but not V. berus, is neurotoxic and that this effect is due to the degeneration of peripheral nerve terminals at the NMJ and is not neutralized by the two tested antisera. Differently, V. berus causes a haemorrhagic effect, which is efficiently contrasted by the same antivenoms. These results indicate that the effectiveness of different antisera is strongly influenced by the variable composition of the venoms and reinforce the arguments supporting the use polyvalent antivenoms.


Assuntos
Antivenenos/farmacologia , Reações Cruzadas/imunologia , Junção Neuromuscular/patologia , Paralisia/patologia , Mordeduras de Serpentes/prevenção & controle , Venenos de Víboras/antagonistas & inibidores , Viperidae/classificação , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Reações Cruzadas/efeitos dos fármacos , Feminino , Soros Imunes/farmacologia , Camundongos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Junção Neuromuscular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Paralisia/induzido quimicamente , Fosfolipases A2 , Ratos , Mordeduras de Serpentes/induzido quimicamente , Mordeduras de Serpentes/patologia , Venenos de Víboras/toxicidade , Viperidae/fisiologia
10.
Methods Mol Biol ; 1806: 179-191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29956277

RESUMO

The C. elegans nematode is a powerful genetic tool for the study of aging, developmental biology, and neurodegenerative diseases. They are a small and simple model, but its well-known genome and presence of many human orthologs has made it an ideal model to study the effects of PGRN in vivo. Here, we will describe the protocols used by our laboratory to study how PGRN affects C. elegans neuronal morphology and locomotion behavior through the use of a loss-of-function model of the nematode otholog of the GRN gene, pgrn-1. Although these protocols have been used by us to specifically study the pgrn-1 gene, the experiments are applicable to any of the animal's genes.


Assuntos
Caenorhabditis elegans/metabolismo , Biologia Molecular/métodos , Neurônios/metabolismo , Progranulinas/metabolismo , Animais , Axônios/patologia , Bioensaio , Deleção de Genes , Movimento , Degeneração Neural/patologia , Neurônios/patologia , Paralisia/patologia , Reação em Cadeia da Polimerase , Interferência de RNA
11.
Spinal Cord ; 56(8): 733-740, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29904189

RESUMO

STUDY DESIGN: Experimental study. OBJECTIVES: To evaluate the efficacy of Angiotensin-converting enzyme inhibitor Ramipril, as a mitigator of radiation-induced spinal cord injury. SETTING: Stony Brook University, Stony Brook, NY, USA. METHODS: Total of 22 rats were irradiated with single doses of 23.6-33 Gy at the C4-T2 spinal levels. After irradiation, the rats were randomized to the radiation only control group and the Ramipril-treated (radiation + Ramipril) experimental group. Ramipril 1.5 mg/kg/day was given in the drinking water starting 1 week after radiation through the study duration. RESULTS: All the rats irradiated with 28.5-33 Gy became paralyzed at 125 ± 4 days, whereas no rats became paralyzed after 23.6 Gy. The time to develop paralysis was delayed to 135 ± 4 days in Ramipril-treated group (P < 0.001). H&E and LFB showed microscopic structural restoration and remyelination with Ramipril treatment. VEGF expression was increased in the irradiated spinal cord, and the number of VEGF-positive cells was significantly decreased by Ramipril treatment (P < 0.001). Immunohistochemical stain with Iba-1 showed increased microglial infiltration in the irradiated spinal cords. The number of Iba-1-positive microglia was significantly reduced by Ramipril treatment (P < 0.05). CONCLUSION: Ramipril reduced the rate of paralysis even at the paralysis-inducing radiation doses. It also significantly delayed the onset of paralysis. Neuroinflammation and endothelial cell damage may be the key mediators of radiation injury. Ramipril can be readily translatable to clinical application as a mitigatory of radiotherapeutic toxicity.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Microglia/efeitos dos fármacos , Lesões Experimentais por Radiação/tratamento farmacológico , Ramipril/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/etiologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Inflamação/fisiopatologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/patologia , Microglia/fisiologia , Microglia/efeitos da radiação , Paralisia/tratamento farmacológico , Paralisia/etiologia , Paralisia/patologia , Paralisia/fisiopatologia , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Distribuição Aleatória , Ratos Endogâmicos F344 , Remielinização/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Regeneração da Medula Espinal/efeitos dos fármacos
12.
Biomed Pharmacother ; 103: 1302-1311, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864912

RESUMO

Multiple sclerosis (MS) is a progressive inflammatory autoimmune demyelinating disease of the brain and spinal cord. Glucocorticoids (GCs) are the standard treatment of MS, however they have several drawbacks like oxidative stress and apoptosis. This study was designed to evaluate some possible antioxidant, anti-apoptotic and immune modulatory effects of Acetyl-l-carnitine (ALCAR) when used either alone or as an add-on therapy with dexamethasone for treatment of a relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) as a model of MS. This experiment was performed on 50 female Sprague Dawley rats divided into; normal control group, untreated EAE group, EAE group treated by dexamethasone, EAE group treated by ALCAR, and EAE group treated by both dexamethasone and ALCAR. The clinical score of the motor deficit of EAE was recorded daily. At the end of experiment, rats were sacrificed and the brain and spinal cord were processed for assessment of reduced glutathione (GSH), malondialdehyde (MDA) and caspase-3 activity. Histopathological changes and immunohistochemical expression of Bcl-2 and CD4+ T cell were carried out. Combination of both dexamethasone and ALCAR provided marked antioxidant and anti-apoptotic effects represented by significant decrease in MDA, caspase-3 and significant increase in GSH, Bcl-2 expression, and it also exhibited marked immunosuppressive effect represented by significant decrease in CD4+ T cells expression with significant improvement in clinical outcome when compared to untreated EAE group or to dexamethasone treated group. These findings pave the way for using ALCAR as an adjuvant therapy during long-term use of dexamethasone in MS.


Assuntos
Acetilcarnitina/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Encefalomielite Autoimune Experimental/tratamento farmacológico , Acetilcarnitina/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Caspase 3/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Glutationa/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paralisia/complicações , Paralisia/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/patologia
13.
Glia ; 66(9): 1960-1971, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29726608

RESUMO

Myelinating glial cells (MGCs), oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS), generate myelin sheaths that insulate axons. After myelination is completed in adulthood, MGC functions independent from myelin are required to support axon survival, but the underlying mechanisms are still unclear. Dicer is a key enzyme that is responsible for generating functional micro-RNAs (miRNAs). Despite the importance of Dicer in initiating myelination, the role of Dicer in mature MGCs is still unclear. Here, Dicer was specifically deleted in mature MGCs in 2-month old mice (PLP-CreERT; Dicer fl/fl) by tamoxifen administration. Progressive motor dysfunction was observed in the Dicer conditional knockout mice, which displayed hind limb ataxia at 3 months post recombination that deteriorated into paralysis within 5 months. Massive axonal degeneration/atrophy in peripheral nerves was responsible for this phenomenon, but overt demyelination was not observed in either the CNS or PNS. In contrast to the PNS, signs of axonal degeneration were not observed in the CNS of these animals. We induced a Dicer deletion in oligodendroglia at postnatal day 5 in NG2-CreERT; Dicer fl/fl mice to evaluate whether Dicer expression in OLs is essential for axonal survival. Dicer deletion in oligodendroglia did not cause motor dysfunction at the age of 7 months. Neither axonal atrophy nor demyelination was observed in the CNS. Based on our results, Dicer expression in SCs is required to maintain axon integrity in adult PNS, and Dicer is dispensable for maintaining myelin sheaths in MGCs.


Assuntos
Axônios/enzimologia , RNA Helicases DEAD-box/deficiência , Bainha de Mielina/enzimologia , Degeneração Neural/enzimologia , Ribonuclease III/deficiência , Animais , Ataxia/enzimologia , Ataxia/patologia , Atrofia , Axônios/patologia , RNA Helicases DEAD-box/genética , Progressão da Doença , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Bainha de Mielina/patologia , Degeneração Neural/patologia , Nervo Óptico/enzimologia , Nervo Óptico/patologia , Paralisia/enzimologia , Paralisia/patologia , Ribonuclease III/genética , Nervo Isquiático/enzimologia , Nervo Isquiático/patologia , Medula Espinal/enzimologia , Medula Espinal/patologia , Substância Branca/enzimologia , Substância Branca/patologia
14.
Spinal Cord ; 56(10): 964-970, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29795171

RESUMO

STUDY DESIGN: This was an animal study. OBJECTIVES: Local inflammation is attenuated below high thoracic SCI, where innervation of major lymphoid organs is involved. However, whether inflammatory responses are affected after low thoracic SCI, remains undetermined. The aim of this study was to characterize the influence of low thoracic SCI on carrageenan-induced paw swelling in intact and paralyzed limbs, at acute and subacute stages. SETTING: University and hospital-based research center, Mexico City, Mexico. METHODS: Rats received a severe contusive SCI at T9 spinal level or sham injury. Then, 1 and 15 days after lesion, carrageenan or vehicle was subcutaneously injected in forelimb and hindlimb paws. Paw swelling was measured over a 6-h period using a plethysmometer. RESULTS: Swelling increased progressively reaching the maximum 6 h post-carrageenan injection. Swelling increase in sham-injured rats was approximately 130% and 70% compared with baseline values of forelimbs and hindlimbs, respectively. Paws injected with saline exhibited no measurable swelling. Carrageenan-induced paw swelling 1-day post-SCI was suppressed in both intact and paralyzed limbs. Fifteen days post-injury, the swelling response to carrageenan was completely reestablished in forelimbs, whereas in hindlimbs it remained significantly attenuated compared with sham-injured rats. CONCLUSIONS: SCI at low spinal level affects the induced swelling response in a different way depending on both, the neurological status of challenged regions and the stage of injury. These findings suggest that neurological compromise of the main immunological organs is not a prerequisite for the local swelling response to be affected after injury.


Assuntos
Inflamação/fisiopatologia , Traumatismos da Medula Espinal/imunologia , Doença Aguda , Animais , Carragenina , Modelos Animais de Doenças , Progressão da Doença , Feminino , Membro Anterior , Membro Posterior , Inflamação/patologia , Paralisia/imunologia , Paralisia/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/patologia , Vértebras Torácicas , Fatores de Tempo
15.
Aquat Toxicol ; 200: 233-240, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29778932

RESUMO

New C-11 hydroxyl metabolites of paralytic shellfish toxins (PSTs) have been reported in shellfish. To gain further information on these metabolites, as well as the potential for formation of phase-II metabolites and acyl esters of PSTs, bivalves were fed with the PSTs-producing dinoflagellate Alexandrium pacificum (strain ATHK). Through independent experiments, scallops (Chlamys farreri) were fed for 9 days and mussels (Mytilus galloprovincialis) for 5 days plus an additional 5 days of depuration, with representative samples taken throughout. Several common PSTs (C1-4, GTX1-6 and NEO) and metabolites including M1, M3, M5, M7, M9, M2 and M8 were detected in the hepatopancreas of scallops during toxin accumulation and in the hepatopancreas of mussels during both toxin accumulation and elimination periods. The relative molar ratio of metabolites to precursor molecules was used to estimate relative metabolic conversion rates. Conversion rates of C1/2 and GTX2/3 were higher than those of C3/4 and GTX1/4, in scallops and mussels. The first metabolites observed in both bivalve species investigated were M1/3, which are formed from C1/2. However, the conversion of GTX2/3 to M2 was more complete than other biotransformation reactions in both mussels and scallops. In general, metabolic conversion of PSTs was observed after a shorter time and to a greater extent in mussels than in scallops in the exposure period. No acyl esters or conjugation products of PSTs with glucuronic acid, glutathione, cysteine and taurine were detected by liquid chromatography with high resolution tandem mass spectrometry in the samples investigated. Additionally, only GTX1/4 and GTX2/3 were detected in the kidney of scallops, which demonstrates that PSTs are mainly metabolized through the hepatic metabolism pathway in bivalves. This work improves the understanding of PST metabolism during toxin accumulation and depuration in commercially harvested shellfish.


Assuntos
Bivalves/fisiologia , Exposição Ambiental , Toxinas Marinhas/metabolismo , Toxinas Marinhas/toxicidade , Mytilus/fisiologia , Paralisia/patologia , Pectinidae/metabolismo , Intoxicação por Frutos do Mar/patologia , Animais , Bivalves/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Toxinas Marinhas/química , Metaboloma , Mytilus/efeitos dos fármacos , Espectrometria de Massas em Tandem , Fatores de Tempo , Poluentes Químicos da Água/toxicidade
17.
J Neurosci ; 38(10): 2615-2630, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29437892

RESUMO

Members of the SCY1-like (SCYL) family of protein kinases are evolutionarily conserved and ubiquitously expressed proteins characterized by an N-terminal pseudokinase domain, centrally located Huntingtin, elongation factor 3, protein phosphatase 2A, yeast kinase TOR1 repeats, and an overall disorganized C-terminal segment. In mammals, three family members encoded by genes Scyl1, Scyl2, and Scyl3 have been described. Studies have pointed to a role for SCYL1 and SCYL2 in regulating neuronal function and viability in mice and humans, but little is known about the biological function of SCYL3. Here, we show that the biochemical and cell biological properties of SCYL3 are similar to those of SCYL1 and both proteins work in conjunction to maintain motor neuron viability. Specifically, although lack of Scyl3 in mice has no apparent effect on embryogenesis and postnatal life, it accelerates the onset of the motor neuron disorder caused by Scyl1 deficiency. Growth abnormalities, motor dysfunction, hindlimb paralysis, muscle wasting, neurogenic atrophy, motor neuron degeneration, and loss of large-caliber axons in peripheral nerves occurred at an earlier age in Scyl1/Scyl3 double-deficient mice than in Scyl1-deficient mice. Disease onset also correlated with the mislocalization of TDP-43 in spinal motor neurons, suggesting that SCYL1 and SCYL3 regulate TDP-43 proteostasis. Together, our results demonstrate an overlapping role for SCYL1 and SCYL3 in vivo and highlight the importance the SCYL family of proteins in regulating neuronal function and survival. Only male mice were used in this study.SIGNIFICANCE STATEMENT SCYL1 and SCYL2, members of the SCY1-like family of pseudokinases, have well established roles in neuronal function. Herein, we uncover the role of SCYL3 in maintaining motor neuron viability. Although targeted disruption of Scyl3 in mice had little or no effect on embryonic development and postnatal life, it accelerated disease onset associated with the loss of Scyl1, a novel motor neuron disease gene in humans. Scyl1 and Scyl3 double-deficient mice had neuronal defects characteristic of amyotrophic lateral sclerosis, including TDP-43 pathology, at an earlier age than did Scyl1-deficient mice. Thus, we show that SCYL1 and SCYL3 play overlapping roles in maintaining motor neuronal viability in vivo and confirm that SCYL family members are critical regulators of neuronal function and survival.


Assuntos
Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Proteínas de Membrana/fisiologia , Neurônios Motores/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Proteínas Quinases/genética , Animais , Atrofia , Axônios/patologia , Caspases/metabolismo , Proteínas de Ligação a DNA/genética , Fibroblastos/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Músculo Esquelético/patologia , Degeneração Neural/genética , Proteínas do Tecido Nervoso/genética , Paralisia/genética , Paralisia/patologia
18.
J Neurovirol ; 24(3): 372-375, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29322435

RESUMO

We report a case of vaccine-associated paralytic poliomyelitis (VAPP) in an immunocompromised patient with acute lymphocytic leukemia who was initially diagnosed with aseptic meningitis. Isolation of Sabin-like type 1 poliovirus from the patient's cerebrospinal fluid made this a case of vaccine-related poliovirus (VRPV) infection. The patient developed paralysis and respiratory distress and deceased a few months after onset of paralysis with respiratory failure. This tragic case report highlights the emergence of VAPP and indicates the importance of timely diagnosis of VRPV infections to improve clinical management of VRPV-infected patients and to prevent the devastating consequences of silent introduction of VRPVs in treatment wards and eventually in the society.


Assuntos
Hospedeiro Imunocomprometido , Meningite Asséptica/diagnóstico , Poliomielite/diagnóstico , Vacina Antipólio Oral/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adulto , Erros de Diagnóstico , Evolução Fatal , Humanos , Masculino , Meningite Asséptica/imunologia , Meningite Asséptica/patologia , Meningite Asséptica/virologia , Paralisia/diagnóstico , Paralisia/imunologia , Paralisia/patologia , Paralisia/virologia , Poliomielite/etiologia , Poliomielite/imunologia , Poliomielite/virologia , Vacina Antipólio Oral/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/virologia
20.
PLoS One ; 12(12): e0189151, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29244816

RESUMO

Sensorimotor dysfunction following incomplete spinal cord injury (SCI) is often characterized by paralysis, spasticity and pain. Previously, we showed that intrathecal (i.t.) administration of the albumin-oleic acid (A-OA) complex in rats with SCI produced partial improvement of these symptoms and that oral 2-hydroxyoleic acid (HOA, a non-hydrolyzable OA analogue), was efficacious in the modulation and treatment of nociception and pain-related anxiety, respectively. Here we observed that intrathecal treatment with the complex albumin-HOA (A-HOA) every 3 days following T9 spinal contusion injury improved locomotor function assessed with the Rotarod and inhibited TA noxious reflex activity in Wistar rats. To investigate the mechanism of action of A-HOA, microarray analysis was carried out in the spinal cord lesion area. Representative genes involved in pain and neuroregeneration were selected to validate the changes observed in the microarray analysis by quantitative real-time RT-PCR. Comparison of the expression between healthy rats, SCI rats, and SCI treated with A-HOA rats revealed relevant changes in the expression of genes associated with neuronal morphogenesis and growth, neuronal survival, pain and inflammation. Thus, treatment with A-HOA not only induced a significant overexpression of growth and differentiation factor 10 (GDF10), tenascin C (TNC), aspirin (ASPN) and sushi-repeat-containing X-linked 2 (SRPX2), but also a significant reduction in the expression of prostaglandin E synthase (PTGES) and phospholipases A1 and A2 (PLA1/2). Currently, SCI has very important unmet clinical needs. A-HOA downregulated genes involved with inflammation and upregulated genes involved in neuronal growth, and may serve to promote recovery of function after experimental SCI.


Assuntos
Albuminas/farmacologia , Ácidos Oleicos/farmacologia , Dor/prevenção & controle , Paralisia/tratamento farmacológico , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Albuminas/química , Animais , Esquema de Medicação , Proteínas da Matriz Extracelular/agonistas , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Fator 10 de Diferenciação de Crescimento/agonistas , Fator 10 de Diferenciação de Crescimento/genética , Fator 10 de Diferenciação de Crescimento/metabolismo , Injeções Espinhais , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nociceptividade/efeitos dos fármacos , Ácidos Oleicos/química , Dor/genética , Dor/metabolismo , Dor/patologia , Paralisia/genética , Paralisia/metabolismo , Paralisia/patologia , Fosfolipases/antagonistas & inibidores , Fosfolipases/genética , Fosfolipases/metabolismo , Prostaglandina-E Sintases/antagonistas & inibidores , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia , Teste de Desempenho do Rota-Rod , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Tenascina/agonistas , Tenascina/genética , Tenascina/metabolismo , Resultado do Tratamento
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