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BACKGROUND: It is unknown how accurately the current Japanese classification system for neurodevelopmental delay based on the assessment with the Kyoto Scale of Psychological Development (KSPD) at toddlerhood and pre-school periods predicts cognitive impairment at school age. METHODS: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age. At 18-24 months of corrected age and 3 years of age, the patients were categorized according to the current Japanese criteria for neurodevelopmental delay based on their overall developmental quotient calculated using the KSPD-2001. Cognitive impairment at 6 years of age was classified according to the calculated or estimated full-scale intelligence quotient. The predictability of the current Japanese classification of neurodevelopmental delay for cognitive impairment at 6 years of age was investigated. RESULTS: Of 566 eligible patients, 364 (64 %) completed the protocol. The current classification for the neurodevelopmental delay showed significant agreement with the severity of cognitive impairment at 6 years of age. The sensitivity and specificity of the KSPD-2001-based assessment for any cognitive impairment at 6 years of age were 0.64 and 0.74 at 18-24 months of corrected age and 0.83 and 0.70 at 3 years of age. The corresponding sensitivity and specificity for moderate/severe cognitive impairment were 0.51 and 0.96 at 18-24 months of corrected age and 0.68 and 0.95 at 3 years of age. CONCLUSION: The KSPD-2001 is a useful tool to predict the severity of cognitive impairment at school age.
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Disfunção Cognitiva , Humanos , Masculino , Feminino , Pré-Escolar , Recém-Nascido , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Lactente , Japão , Estudos Retrospectivos , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Criança , Desenvolvimento InfantilRESUMO
We present a case of an infant male born at 23 weeks' gestation with an interrupted aortic arch (IAA) complex. We treated the patient with hypoxic gas ventilation to address developing systemic undercirculation in the acute postnatal phase. As the symptoms of bronchopulmonary dysplasia evolved, hypoxic gas ventilation was no longer required to stabilize the hemodynamics. The patient was discharged home after undergoing the palliative surgical procedure of bilateral pulmonary artery banding and ductus arteriosus stent implantation. Although he suffered from pulmonary hypertension, it was controllable with oxygen supplementation and pulmonary vasodilators. There are limited therapeutic options available for extremely preterm infants with critical congenital heart defects (CHDs). Hypoxic gas ventilation might be considered as one of the options, with its risks taken into account, to manage extremely preterm infants with CHDs with pulmonary overcirculation before performing surgical interventions.
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OBJECTIVES: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation. STUDY DESIGN: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models. RESULTS: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively. CONCLUSION: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.
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População do Leste Asiático , Lactente Extremamente Prematuro , Transtornos do Neurodesenvolvimento , Humanos , Lactente , Recém-Nascido , Gravidez , Idade Gestacional , Mortalidade Hospitalar/tendências , Hospitais/normas , Hospitais/estatística & dados numéricos , Hospitais/tendências , Transtornos do Neurodesenvolvimento/epidemiologia , Estudos Retrospectivos , Centros de Atenção Terciária/normas , Centros de Atenção Terciária/estatística & dados numéricos , Centros de Atenção Terciária/tendências , Pré-Escolar , CriançaRESUMO
Recent studies have shown favorable outcomes for intra-abdominal umbilical vein varices (IUVVs) in term neonates who have no other complications. Little is known, however, about the prognosis of IUVVs in preterm neonates. We encountered a case of IUVV in an extremely low-birth-weight infant who developed severe consumptive coagulopathy after birth. The patient's coagulation test normalized as the varix spontaneously obstructed. Although life-threatening hemorrhagic complications were avoided, a cerebellum hemorrhage was found in the brain magnetic resonance imaging at the term-equivalent age. In a literature survey, coagulopathy was reported in 4 out of 15 infants with IUVVs born before 34 weeks of gestation, including our present case. Preterm infants with IUVVs may develop coagulopathy because of the prematurity of their coagulation-fibrinolysis systems. Attention should be given to the coagulation status of preterm neonates with IUVVs.
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During development or after brain injury, oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes to supplement the number of oligodendrocytes. Although mechanisms of OPC differentiation have been extensively examined, the role of epigenetic regulators, such as histone deacetylases (HDACs) and DNA methyltransferase enzymes (DNMTs), in this process is still mostly unknown. Here, we report the differential roles of epigenetic regulators in OPC differentiation. We prepared primary OPC cultures from neonatal rat cortex. Our cultured OPCs expressed substantial amounts of mRNA for HDAC1, HDAC2, DNMT1, and DNMT3a. mRNA levels of HDAC1 and HDAC2 were both decreased by the time OPCs differentiated into myelin-basic-protein expressing oligodendrocytes. However, DNMT1 or DNMT3a mRNA level gradually decreased or increased during the differentiation step, respectively. We then knocked down those regulators in cultured OPCs with siRNA technique before starting OPC differentiation. While HDAC1 knockdown suppressed OPC differentiation, HDAC2 knockdown promoted OPC differentiation. DNMT1 knockdown also suppressed OPC differentiation, but unlike HDAC1/2, DNMT1-deficient cells showed cell damage during the later phase of OPC differentiation. On the other hand, when OPCs were transfected with siRNA for DNMT3a, the number of OPCs was decreased, indicating that DNMT3a may participate in OPC survival/proliferation. Taken together, these data demonstrate that each epigenetic regulator has different phase-specific roles in OPC survival and differentiation.
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Epigênese Genética/fisiologia , Células Precursoras de Oligodendrócitos/fisiologia , Animais , Animais Recém-Nascidos , Diferenciação Celular , Córtex Cerebral/citologia , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , DNA Metiltransferase 3A , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , TransfecçãoRESUMO
Oligodendrocyte precursor cells (OPCs) give rise to oligodendrocytes in cerebral white matter. However, the underlying mechanisms that regulate this process remain to be fully defined, especially in adult brains. Recently, it has been suggested that signaling via A-kinase anchor protein 12 (AKAP12), a scaffolding protein that associates with intracellular molecules such as protein kinase A, may be involved in Schwann cell homeostasis and peripheral myelination. Here, we asked whether AKAP12 also regulates the mechanisms of myelination in the CNS. AKAP12 knockout mice were compared against wild-type (WT) mice in a series of neurochemical and behavioral assays. Compared with WTs, 2-months old AKAP12 knockout mice exhibited loss of myelin in white matter of the corpus callosum, along with perturbations in working memory as measured by a standard Y-maze test. Unexpectedly, very few OPCs expressed AKAP12 in the corpus callosum region. Instead, pericytes appeared to be one of the major AKAP12-expressing cells. In a cell culture model system, conditioned culture media from normal pericytes promoted in-vitro OPC maturation. However, conditioned media from AKAP12-deficient pericytes did not support the OPC function. These findings suggest that AKAP12 signaling in pericytes may be required for OPC-to-oligodendrocyte renewal to maintain the white matter homeostasis in adult brain. Stem Cells 2018;36:751-760.
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Proteínas de Ancoragem à Quinase A/metabolismo , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/fisiologia , Células-Tronco Neurais/citologia , Oligodendroglia/metabolismo , Substância Branca/metabolismo , Proteínas de Ancoragem à Quinase A/genética , Envelhecimento , Animais , Proteínas de Ciclo Celular/genética , Proliferação de Células/fisiologia , Células Cultivadas , Meios de Cultivo Condicionados , Camundongos Knockout , Bainha de Mielina/metabolismo , Neurogênese/fisiologia , Oligodendroglia/citologia , Substância Branca/citologiaRESUMO
Osteoporotic vertebral fractures are well-known complications of rheumatoid arthritis. The management of multiple vertebral fractures with kyphotic deformity is controversial. We present a case of a patient with mutilating rheumatoid arthritis who had multiple vertebral fractures with kyphotic deformity after occipitothoracic fusion for rheumatoid cervical disorder. Occipitosacral fusion was effective to create stable spine with better sagittal alignment in this case, but careful clinical assessment for early detection and management of postoperative insufficient pelvic fracture were required.
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Oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs). Mechanisms of OPC differentiation have been extensively examined with two-dimensional cell culture systems. However, these cellular events may be more accurately represented using a three-dimensional (3D) model. In this study, we report the development of a novel 3D OPC culture system using gels composed of a mixture of collagen and hyaluronan, wherein cultured rat primary OPCs can proliferate and differentiate into oligodendrocytes. Our data show that the gel concentration and cell-seeding density are critical factors for the numbers of OPCs and oligodendrocytes in our 3D culture system. In addition, Notch signaling, which supports cell-to-cell communication, may also be important for OPC function in our system because a Notch inhibitor DAPT suppressed OPC proliferation and differentiation. Taken together, cultured rat OPCs can grow in collagen-/hyaluronan-based gels, and our novel 3D OPC culture system may offer a useful platform for examining the mechanisms of OPC function in vitro.
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Técnicas de Cultura de Células/métodos , Células Precursoras de Oligodendrócitos/citologia , Animais , Astrócitos/citologia , Contagem de Células , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Células Cultivadas , Géis , Células Precursoras de Oligodendrócitos/metabolismo , Porosidade , Ratos Sprague-Dawley , Receptores Notch/metabolismo , Transdução de SinaisRESUMO
BACKGROUND AND PURPOSE: Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood-brain barrier dysfunction during the acute phase of ischemic stroke. METHODS: In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood-brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor-mediated endothelial permeability. RESULTS: During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor-induced endothelial permeability. CONCLUSIONS: Astrocytes in peri-infarct areas upregulate PTX3, which may support blood-brain barrier integrity by regulating vascular endothelial growth factor-related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood-brain barrier function after ischemic stroke.
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Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Proteína C-Reativa/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Componente Amiloide P Sérico/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Barreira Hematoencefálica/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Morte Celular , Meios de Cultivo Condicionados , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Ratos , Ratos Endogâmicos SHR , Acidente Vascular Cerebral/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Aging and vascular comorbidities such as hypertension comprise critical cofactors that influence how the brain responds to stroke. Ischemic stress induces neurogenesis and oligodendrogenesis in younger brains. However, it remains unclear whether these compensatory mechanisms can be maintained even under pathologically hypertensive and aged states. To clarify the age-related remodeling capacity after stroke under hypertensive conditions, we assessed infarct volume, behavioral outcomes, and surrogate markers of neurogenesis and oligodendrogenesis in acute and subacute phases after transient focal cerebral ischemia in 3- and 12-month-old spontaneously hypertensive rats (SHRs). Hematoxylin and eosin staining showed that 3- and 12-month-old SHRs exhibited similar infarction volumes at both 3 and 14 days after focal cerebral ischemia. However, recovery of behavioral deficits (neurological score assessment and adhesive removal test) was significantly less in 12-month-old SHRs compared to 3-month-old SHRs. Concomitantly, numbers of nestin(+) neural stem/progenitor cells (NSPCs) near the infarct border area or subventricular zone in 12-month-old SHRs were lower than 3-month-old SHRs at day 3. Similarly, numbers of PDGFR-α(+) oligodendrocyte precursor cells (OPCs) in the corpus callosum were lower in 12-month-old SHRs at day 3. Lower levels of NSPC and OPC numbers were accompanied by lower expression levels of phosphorylated CREB. By day 14 postischemia, NSPC and OPC numbers in 12-month-old SHRs recovered to similar levels as in 3-month-old SHRs, but the numbers of proliferating NSPCs (Ki-67(+)nestin(+) cells) and proliferating OPCs (Ki-67(+)PDGFR-α(+) cells) remained lower in the older brains even at day 14. Taken together, these findings suggest that aging may also decrease poststroke compensatory responses for neurogenesis and oligodendrogenesis even under hypertensive conditions.
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Envelhecimento/metabolismo , Infarto Encefálico/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese , Oligodendroglia/metabolismo , Envelhecimento/patologia , Animais , Infarto Encefálico/patologia , Masculino , Células-Tronco Neurais/patologia , Oligodendroglia/patologia , Ratos , Ratos Endogâmicos SHRRESUMO
Neuregulin-1 (NRG1) is an endogenous growth factor with multiple functions in the embryonic and postnatal brain. The NRG1 gene is large and complex, transcribing more than twenty transmembrane proteins and generating a large number of isoforms in tissue and cell type-specific patterns. Within the brain, NRG1 functions have been studied most extensively in neurons and glia, as well as in the peripheral vasculature. Recently, NRG1 signaling has been found to be important in the function of brain microvascular endothelial cells, decreasing IL-1ß-induced increases in endothelial permeability. In the current experiments, we have investigated the pathways through which the NRG1-ß isoform acts on IL-1ß-induced endothelial permeability. Our data show that NRG1-ß increases barrier function, measured by transendothelial electrical resistance, and decreases IL-1ß-induced hyperpermeability, measured by dextran-40 extravasation through a monolayer of brain microvascular endothelial cells plated on transwells. An investigation of key signaling proteins suggests that the effect of NRG1-ß on endothelial permeability is mediated through RhoA activation and myosin light chain phosphorylation, events which affect filamentous actin morphology. In addition, AG825, an inhibitor of the erbB2-associated tyrosine kinase, reduces the effect of NRG1-ß on IL-1ß-induced RhoA activation and myosin light chain phosphorylation. These data add to the evidence that NRG1-ß signaling affects changes in the brain microvasculature in the setting of neuroinflammation. We propose the following events for neuregulin-1-mediated effects on Interleukin-1 ß (IL-1ß)-induced endothelial hyperpermeability: IL-1ß leads to RhoA activation, resulting in an increase in phosphorylation of myosin light chain (MLC). Phosphorylation of MLC is known to result in actin contraction and alterations in the f-actin cytoskeletal structure. These changes are associated with increased endothelial permeability. Neuregulin-1ß acts through its transmembrane receptors to activate intracellular signaling pathways which inhibit IL-1ß-induced RhoA activation and MLC phosphorylation, thereby preserving the f-actin cytoskeletal structure and endothelial barrier function.
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Células Endoteliais/efeitos dos fármacos , Interleucina-1beta/farmacologia , Cadeias Leves de Miosina/metabolismo , Neuregulina-1/farmacologia , Transdução de Sinais/fisiologia , Quinases Associadas a rho/metabolismo , Adolescente , Benzotiazóis/farmacologia , Encéfalo , Células Cultivadas , Impedância Elétrica , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Inibidores Enzimáticos/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neuregulina-1/metabolismo , Permeabilidade/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tirfostinas/farmacologia , Adulto JovemRESUMO
Hypoxic-ischemic (HI) brain injury in newborns results in serious damage. Magnesium sulfate has been clinically used as a cyto-protective agent against HI brain injury in newborns in some countries, including Japan. However, it is not clear how magnesium exerts this effect and how it acts on the individual types of cells within the newborn brain. In this study, we exposed cultured rat oligodendrocyte precursor cells to magnesium sulfate during the period when they differentiate into oligodendrocytes, and showed that magnesium-exposed oligodendrocytes exhibited more resistance to HI injury. Our data may support the use of magnesium sulfate in the clinical setting.
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Hipóxia-Isquemia Encefálica/patologia , Sulfato de Magnésio/farmacologia , Oligodendroglia/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Diferenciação Celular , Linhagem da Célula , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Hipóxia-Isquemia Encefálica/prevenção & controle , Oligodendroglia/patologia , RatosRESUMO
Study Design Retrospective radiographic study. Objective We have performed occipitothoracic (OT) fusion for severe rheumatoid cervical disorders since 1991. In our previous study, we reported that the distal junctional disease occurred in patients with fusion of O-T4 or longer due to increased mechanical stress. The present study further evaluated the association between the distal junctional disease and the cervical spine sagittal alignment. Methods Among 60 consecutive OT fusion cases between 1991 and 2010, 24 patients who underwent O-T5 fusion were enrolled in this study. The patients were grouped based on whether they developed postoperative distal junctional disease (group F) or not (group N). We measured pre- and postoperative O-C2, C2-C7, and O-C7 angles and evaluated the association between these values and the occurrence of distal junctional disease. Results Seven (29%) of 24 patients developed adjacent-level vertebral fractures as distal junctional disease. In group F, the mean pre- and postoperative O-C2, C2-C7, and O-C7 angles were 12.1 and 16.8, 7.2 and 11.2, and 19.4 and 27.9 degrees, respectively. In group N, the mean pre- and postoperative O-C2, C2-C7, and O-C7 angles were 15.9 and 15.0, 4.9 and 5.8, and 21.0 and 20.9 degrees, respectively. There were no significant differences between the two groups. The difference in the O-C7 angle (postoperative angle - preoperative angle) in group F was significantly larger than that in group N (p = 0.04). Conclusion Excessive correction of the O-C7 angle (hyperlordotic alignment) is likely to cause postoperative distal junctional disease following the OT fusion.
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Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAP(cre)/BDNF(wt/fl)) in which BDNF expression is downregulated specifically in GFAP(+) astrocytes. Both wild-type (GFAP(wt)/BDNF(wt/fl) mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF. SIGNIFICANCE STATEMENT: The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However, the underlying mechanisms are still mostly unknown. Here, we use a combination of cell biology and an animal model to report a new pathway in which astrocyte-derived BDNF supports oligodendrogenesis and regeneration after white matter damage. These findings provide new mechanistic insight into white matter physiology and pathophysiology, which would be broadly and clinically applicable to CNS disease.
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Astrócitos/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Leucoencefalopatias/patologia , Animais , Antimutagênicos/farmacologia , Astrócitos/química , Astrócitos/metabolismo , Isquemia Encefálica/complicações , Fator Neurotrófico Derivado do Encéfalo/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Cromonas/farmacologia , Cobalto/farmacologia , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa S-Transferase pi/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leucoencefalopatias/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Morfolinas/farmacologia , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fosfopiruvato Hidratase/metabolismo , Células-Tronco/fisiologiaRESUMO
White matter damage is a clinically important aspect of several central nervous system diseases, including stroke. Cerebral white matter primarily consists of axonal bundles ensheathed with myelin secreted by mature oligodendrocytes, which play an important role in neurotransmission between different areas of gray matter. During the acute phase of stroke, damage to oligodendrocytes leads to white matter dysfunction through the loss of myelin. On the contrary, during the chronic phase, white matter components promote an environment, which is favorable for neural repair, vascular remodeling, and remyelination. For effective remyelination to take place, oligodendrocyte precursor cells (OPCs) play critical roles by proliferating and differentiating into mature oligodendrocytes, which help to decrease the burden of axonal injury. Notably, other types of cells contribute to these OPC responses under the ischemic conditions. This mini-review summarizes the non-cell autonomous mechanisms in oligodendrogenesis and remyelination after white matter damage, focusing on how OPCs receive support from their neighboring cells. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.
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Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Oligodendroglia/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Humanos , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/fisiologiaRESUMO
A prospective radiographic study.The purpose of this study was to analyze whether a novel skull clamp positioning system and technique is useful for obtaining good, quantitative cervical sagittal alignment during posterior cervical surgery.Different surgical procedures depend on cervical spine positioning. However, maneuver of the device and cervical position depends on the skill of the operator.This study included 21 male and 10 female patients with cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament of the cervical spine, undergoing posterior cervical surgery using the novel skull clamp positioning system. The average patient age was 68.6 years (range: 56-87 years). The novel system has a scale to adjust the neck position and to enable intended cervical sagittal alignment. First, the patient was placed on the operating table in the prone position with preplanned head-neck sagittal alignment (neutral position in general). The head was rotated sagittally, and the head was positioned in the military tuck position with the novel device that was used to widen the interlaminar space. After completing the decompression procedure, the head was rotated again back to the initial preplanned position. During this position change, the scale equipped with the device was useful in determining accurate positions. The C0-C1, C0-C2, C1-C2, C2-C7, and C0-C7 angles were measured on lateral radiographs taken pre-, intra-, and postoperatively.This novel system allowed us to obtain adequate, quantitative cervical sagittal alignment during posterior cervical surgery. There were no clinically significant differences observed between the pre- and postoperative angles for C1-C2 and C2-C7.Sagittal neck position was quantitatively changed during posterior cervical surgery using a novel skull clamp positioning system, enabling adequate final cervical sagittal alignment identical to the preplanned neck position.
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Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Ossificação do Ligamento Longitudinal Posterior/cirurgia , Restrição Física/instrumentação , Espondilose/cirurgia , Idoso , Idoso de 80 Anos ou mais , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Posicionamento do Paciente , Estudos Prospectivos , RadiografiaRESUMO
Pericytes are vascular mural cells embedded within the basal lamina of blood micro-vessels. Within the neurovascular unit, pericytes play important roles in regulating neurovascular homeostasis by secreting soluble factors, such as matrix metalloproteinases (MMPs). However, little is known about the regulatory signaling pathways in brain pericytes. Here we show that transforming growth factor-ß1 (TGF-ß1) induces MMP-9 upregulation in pericytes via p38 mitogen-activated protein (MAP) kinase signaling. Cultured human brain vascular pericytes were used in this study. When the brain pericytes were treated with purified human TGF-ß1 (0.1-10ng/mL for 24h), the levels of MMP-2 and MMP-9 in culture media were significantly increased in a concentration dependent manner as measured by gelatin zymography. WST assay confirmed that TGF-ß1 did not affect cell survival of the brain pericytes. A TGF-ß-receptor inhibitor SB431542 (0.5-5µM) decreased the TGF-ß1-induced upregulation of MMP-2 and MMP-9. To assess the underlying intracellular mechanisms, we focused on p38 MAP kinase signaling, which is one of the major downstream kinases for TGF-ß1. A well-validated p38 MAP kinase inhibitor SB203580 (0.5-5µM) cancelled the effect of TGF-ß1 in upregulation of MMP-9 but not MMP-2. Western blotting confirmed that TGF-ß1 treatment increased the level of p38 MAP kinase phosphorylation in pericytes, and again, the TGF-ß-receptor inhibitor SB431542 (0.5-5µM) blocked the TGF-ß1-induced phosphorylation of p38 MAP kinase. Both TGF-ß1 and MMP-9 are major neurovascular mediators, and therefore, our current finding may suggest a novel mechanism for how pericytes regulate neurovascular homeostasis.
Assuntos
Encéfalo/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pericitos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Benzamidas/farmacologia , Encéfalo/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Fármacos do Sistema Nervoso Central/farmacologia , Dioxóis/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases , Pericitos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Recombinantes/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
BACKGROUND: Cardiovascular instability immediately after birth is associated with intraventricular hemorrhage (IVH) in very-low-birth-weight (VLBW) infants. For circulatory management, evaluation of organ blood flow is important. In this study, the relationship between peripheral perfusion within 48 h after birth and IVH was evaluated in VLBW infants. METHODS: In this prospective observational study involving 83 VLBW infants, forehead blood flow (FBF) and lower-limb blood flow (LBF) were measured for 48 h after birth using a laser Doppler flowmeter. Blood flow was compared between infants with and without IVH. Multivariate logistic regression analysis was performed to identify the risk factors for IVH. RESULTS: IVH developed in nine infants. In eight of these patients, IVH occurred after 24 h. LBF was lower in infants with IVH at 18 and 24 h and increased to the same level as that of infants without IVH at 48 h. Multivariate logistic regression analysis identified a correlation only between LBF and IVH at 18 h. CONCLUSION: These findings were consistent with the hypoperfusion-reperfusion theory, which states that IVH develops after reperfusion subsequent to hypoperfusion. We speculate that measurement of skin blood flow in addition to systemic and cerebral circulation may be helpful in predicting IVH.
Assuntos
Hemorragia Cerebral/sangue , Recém-Nascido de muito Baixo Peso , Pele/irrigação sanguínea , Pressão Sanguínea , Feminino , Testa/irrigação sanguínea , Humanos , Recém-Nascido , Fluxometria por Laser-Doppler , Masculino , Análise Multivariada , Perfusão , Estudos Prospectivos , Fluxo Sanguíneo Regional , Fatores de Risco , Fatores de Tempo , UltrassonografiaRESUMO
Innate immune responses play a central role in neuroprotection and neurotoxicity during inflammatory processes that are triggered by pathogen-associated molecular pattern-exhibiting agents such as bacterial lipopolysaccharide (LPS) and that are modulated by inflammatory cytokines such as interferon γ (IFNγ). Recent findings describing the unexpected complexity of mammalian genomes and transcriptomes have stimulated further identification of novel transcripts involved in specific physiological and pathological processes, such as the neural innate immune response that alters the expression of many genes. We developed a system for efficient subtractive cloning that employs both sense and antisense cRNA drivers, and coupled it with in-house cDNA microarray analysis. This system enabled effective direct cloning of differentially expressed transcripts, from a small amount (0.5 µg) of total RNA. We applied this system to isolation of genes activated by LPS and IFNγ in primary-cultured cortical cells that were derived from newborn mice, to investigate the mechanisms involved in neuroprotection and neurotoxicity in maternal/perinatal infections that cause various brain injuries including periventricular leukomalacia. A number of genes involved in the immune and inflammatory response were identified, showing that neonatal neuronal/glial cells are highly responsive to LPS and IFNγ. Subsequent RNA blot analysis revealed that the identified genes were activated by LPS and IFNγ in a cooperative or distinctive manner, thereby supporting the notion that these bacterial and cellular inflammatory mediators can affect the brain through direct but complicated pathways. We also identified several novel clones of apparently non-coding RNAs that potentially harbor various regulatory functions. Characterization of the presently identified genes will give insights into mechanisms and interventions not only for perinatal infection-induced brain damage, but also for many other innate immunity-related brain disorders.
Assuntos
Antivirais/farmacologia , Córtex Cerebral , Clonagem Molecular/métodos , DNA Complementar/genética , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Animais , Encefalopatias/genética , Encefalopatias/imunologia , Células Cultivadas , Imunidade Inata/genética , CamundongosRESUMO
INTRODUCTION: Dopamine is one of the most frequently used inotropic drugs in neonatal intensive care units (NICUs); however, it does not seem to improve outcomes in premature infants. Given that the ultimate aim of cardiovascular management is to stabilize and maintain organ perfusion, an understanding of dopamine's effects on organ blood flow will help in judging when to use dopamine and how to titrate the dosage. Such an approach can lead to improved outcomes. This study aimed to evaluate the effects of dopamine on peripheral perfusion in very-low-birth-weight (VLBW) infants within 72 h of birth. METHODS: This prospective observational study identified and sampled 44 instances of initiation of dopamine treatment or increase in dopamine dose in 29 VLBW infants. Blood pressure, heart rate, and skin and subcutaneous blood flow were measured and compared before and after each instance. RESULTS: Blood pressure and skin and subcutaneous blood flow in the lower limbs increased after initiation of dopamine treatment or after dose increase. DISCUSSION: Dopamine increases blood pressure as well as skin and subcutaneous blood flow in VLBW infants despite its supposed vasoconstrictive action, indicating that it increases both perfusion pressure and blood flow and is devoid of overwhelming peripheral vasoconstrictive effects.