RESUMO
Childhood absence epilepsy (CAE) is a common type of idiopathic generalized epilepsy, manifesting as daily multiple absence seizures. Although seizures in most patients can be adequately controlled with first-line antiseizure medication (ASM), approximately 25 % of patients respond poorly to first-line ASM. In addition, an accurate method for predicting first-line medication responsiveness is lacking. We used the quantitative electroencephalogram (QEEG) features of patients with CAE along with machine learning to predict the therapeutic effects of valproic acid in this population. We enrolled 25 patients with CAE from multiple medical centers. Twelve patients who required additional medication for seizure control or who were shifted to another ASM and 13 patients who achieved seizure freedom with valproic acid within 6 months served as the nonresponder and responder groups. Using machine learning, we analyzed the interictal background EEG data without epileptiform discharge before ASM. The following features were analyzed: EEG frequency bands, Hjorth parameters, detrended fluctuation analysis, Higuchi fractal dimension, Lempel-Ziv complexity (LZC), Petrosian fractal dimension, and sample entropy (SE). We applied leave-one-out cross-validation with support vector machine, K-nearest neighbor (KNN), random forest, decision tree, Ada boost, and extreme gradient boosting, and we tested the performance of these models. The responders had significantly higher alpha band power and lower delta band power than the nonresponders. The Hjorth mobility, LZC, and SE values in the temporal, parietal, and occipital lobes were higher in the responders than in the nonresponders. Hjorth complexity was higher in the nonresponders than in the responders in almost all the brain regions, except for the leads FP1 and FP2. Using KNN classification with theta band power in the temporal lobe yielded optimal performance, with sensitivity of 92.31 %, specificity of 76.92 %, accuracy of 84.62 %, and area under the curve of 88.46 %.We used various EEG features along with machine learning to accurately predict whether patients with CAE would respond to valproic acid. Our method could provide valuable assistance for pediatric neurologists in selecting suitable ASM.
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Epilepsia Tipo Ausência , Criança , Humanos , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/tratamento farmacológico , Ácido Valproico/uso terapêutico , Convulsões/tratamento farmacológico , Eletroencefalografia/métodos , Aprendizado de MáquinaRESUMO
INTRODUCTION: Guidelines for infant CPR recommend the two-thumb encircling hands technique (TTT) and the two-finger technique (TFT) for chest compression. Some devices have been designed to assist with infant CPR, but are often not readily available. Syringe plungers may serve as an alternative infant CPR assist device given their availability in most hospitals. In this study, we aimed to determine whether CPR using a syringe plunger could improve CPR quality measurements on the Resusci-Baby manikin compared with traditional methods of infant CPR. METHODS: Compression area with a diameter of 1 to 2 cm is recommended in previous infant CPR device researches. In this is a randomized crossover manikin study, we examined the efficacy of the Syringe Plunger Technique (SPT) which uses the plunger of the 20 ml syringe with a 2 cm diameter flat piston, commonly available in hospital, for infant External Chest Compressions (ECC). Participants performed TTT, TFT and SPT ECC on Resusci® Baby QCPR® according to 2020 BLS guidelines. RESULTS: Sixty healthcare providers participated in this project. The median (IQR) ECC depths in the TTT, TFT and SPT in the first minute were 41 mm (40-42), 40 mm (38-41) and 40 mm (39-41), respectively, with p < 0.001. The median (IQR) ECC recoil in the TTT, TFT and SPT groups in the first minute was 15% (1-93), 64% (18-96) and 53% (8-95), respectively, with p = 0.003. The result in the second minute had similar findings. The SPT had the best QCPR score and less fatigue. CONCLUSION: The performance of chest compression depth and re-rebound ratio was statistically different among the three groups. TTT has good ECC depth and depth accuracy but poor recoil. TFT is the complete opposite. SPT can achieve a depth close to TTT and has a good recoil performance as TFT. Regarding comprehensive performance, SPT obtains the highest QCPR score, and SPT is also less fatigued. SPT may be an effective alternative technique for infant CPR.
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Reanimação Cardiopulmonar , Lactente , Humanos , Reanimação Cardiopulmonar/métodos , Manequins , Polegar , Dedos , Tórax , Estudos Cross-Over , FadigaRESUMO
BACKGROUND: Protein phosphatase 2A (PP2A) is one of the major protein phosphatases in eukaryotic cells and is essential for cellular homeostasis. PP2A is a heterotrimer comprising the dimeric AC core enzyme and a highly variable regulatory B subunit. Distinct B subunits help the core enzyme gain full activity toward specific substrates and contribute to diverse cellular roles of PP2A. PP2A has been thought to play a tumor suppressor and the B56γ3 regulatory subunit was shown to play a key tumor suppressor regulatory subunit of PP2A. Nevertheless, we uncovered a molecular mechanism of how B56γ3 may act as an oncogene in colorectal cancer (CRC). METHODS: Polyclonal pools of CRC cells with stable B56γ3 overexpression or knockdown were generated by retroviral or lentiviral infection and subsequent drug selection. Co-immunoprecipitation(co-IP) and in vitro pull-down analysis were applied to analyze the protein-protein interaction. Transwell migration and invasion assays were applied to investigate the role of B56γ3 in affecting motility and invasive capability of CRC cells. The sensitivity of CRC cells to 5-fluorouracil (5-FU) was analyzed using the PrestoBlue reagent assay for cell viability. Immunohistochemistry (IHC) was applied to investigate the expression levels of phospho-AKT and B56γ3 in paired tumor and normal tissue specimens of CRC. DataSets of TCGA and GEO were analyzed to investigate the correlation of B56γ3 expression with overall survival rates of CRC patients. RESULTS: We showed that B56γ3 promoted epithelial-mesenchymal transition (EMT) and reduced the sensitivity of CRC cells to 5-FU through upregulating AKT activity. Mechanistically, B56γ3 upregulates AKT activity by targeting PP2A to attenuate the p70S6K-mediated negative feedback loop regulation on PI3K/AKT activation. B56γ3 was highly expressed and positively correlated with the level of phospho-AKT in tumor tissues of CRC. Moreover, high B56γ3 expression is associated with poor prognosis of a subset of patients with CRC. CONCLUSIONS: Our finding reveals that the B56γ3 regulatory subunit-containing PP2A plays an oncogenic role in CRC cells by sustaining AKT activation through suppressing p70S6K activity and suggests that the interaction between B56γ3 and p70S6K may serve as a therapeutic target for CRC. Video Abstract.
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Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Humanos , Proteína Fosfatase 2 , Proteínas Proto-Oncogênicas c-akt , Retroalimentação , Proteínas Quinases S6 Ribossômicas 70-kDa , Fosfatidilinositol 3-Quinases , FluoruracilaRESUMO
BACKGROUND: Even force distribution would generate efficient external chest compression (ECC). Little research has been done to compare force distribution between one-hand (OH) and two-handed (TH) during child ECC. Therefore, this study was to investigate force distribution, rescuer perceived fatigue and discomfort/pain when applying OH and TH ECC in children. METHODS: Crossover manikin study. Thirty-five emergency department registered nurses performed lone rescuer ECC using TH and OH techniques, each for 2 min at a rate of at least 100 compressions/min. A Resusci Junior Basic manikin equipped with a MatScan pressure measurement system was used to collect data. The perceived exertion scale (modified Borg scale) and numerical rating scale (NRS) was applied to evaluate the fatigue and physical pain of delivering chest compressions. RESULTS: The maximum compression force (kg) delivered was 56.58 ± 13.67 for TH and 45.12 ± 7.90 for OH ECC (p < 0.001). The maximum-minimum force difference force delivered by TH and OH ECC was 52.24 ± 13.43 and 41.36 ± 7.57, respectively (p < 0.001). The mean caudal force delivered by TH and OH ECC was 29.45 ± 16.70 and 34.03 ± 12.01, respectively (p = 0.198). The mean cranial force delivered by TH and OH ECC was 27.13 ± 11.30 and 11.09 ± 9.72, respectively (p < 0.001). The caudal-cranial pressure difference delivered by TH and OH ECC was 19.14 ± 15.96 and 26.94 ± 14.48, respectively (p = 0.016). The perceived exertion and NRS for OH ECC was higher than that of the TH method (p < 0.001, p = 0.004, respectively). CONCLUSIONS: The TH method produced greater compression force, had more efficient compression, and delivered a more even force distribution, and produced less fatigue and physical pain in the rescuer than the OH method. TRIAL REGISTRATION: The Cheng Kung University Institutional Review Board A-ER-103-387. http://nckuhirb.med.ncku.edu.tw/sitemap.php.
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Reanimação Cardiopulmonar , Reanimação Cardiopulmonar/métodos , Criança , Estudos Cross-Over , Fadiga , Humanos , Manequins , Dor , PressãoRESUMO
Carbamazepine (CBZ, Tegretol®) is an anticonvulsant used in the treatment of epilepsy and neuropathic pain; however, several unwanted effects of this drug have been noticed. Therefore, the regulatory actions of CBZ on ionic currents in electrically excitable cells need to be reappraised, although its efficacy in suppressing voltage-gated Na+ current (INa) has been disclosed. This study was undertaken to explore the modifications produced by CBZ on ionic currents (e.g., INa and erg-mediated K+ current [IK(erg)]) measured from Neuro-2a (N2a) cells. In these cells, we found that this drug differentially suppressed the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa in a concentration-dependent manner with effective IC50 of 56 and 18 µM, respectively. The overall current-voltage relationship of INa(T) with or without the addition of CBZ remained unchanged; however, the strength (i.e., ∆area) in the window component of INa (INa(W)) evoked by the short ascending ramp pulse (Vramp) was overly lessened in the CBZ presence. Tefluthrin (Tef), a synthetic pyrethroid, known to stimulate INa, augmented the strength of the voltage-dependent hysteresis (Hys(V)) of persistent INa (INa(P)) in response to the isosceles-triangular Vramp; moreover, further application of CBZ attenuated Tef-mediated accentuation of INa(P)'s Hys(V). With a two-step voltage protocol, the recovery of INa(T) inactivation seen in Neuro-2a cells became progressively slowed by adding CBZ; however, the cumulative inhibition of INa(T) evoked by pulse train stimulation was enhanced during exposure to this drug. Neuro-2a-cell exposure to CBZ (100 µM), the magnitude of erg-mediated K+ current measured throughout the entire voltage-clamp steps applied was mildly inhibited. The docking results regarding the interaction of CBZ and voltage-gate Na+ (NaV) channel predicted the ability of CBZ to bind to some amino-acid residues in NaV due to the existence of a hydrogen bond or hydrophobic contact. It is conceivable from the current investigations that the INa (INa(T), INa(L), INa(W), and INa(P)) residing in Neuro-2a cells are susceptible to being suppressed by CBZ, and that its block on INa(L) is larger than that on INa(T). Collectively, the magnitude and gating of NaV channels produced by the CBZ presence might have an impact on its anticonvulsant and analgesic effects occurring in vivo.
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Anticonvulsivantes , Crista Neural , Animais , Anticonvulsivantes/farmacologia , Benzodiazepinas , Carbamazepina/farmacologia , Linhagem Celular , Camundongos , SódioRESUMO
The effects of lacosamide (LCS, Vimpat®), an anti-convulsant and analgesic, on voltage-gated Na+ current (INa) were investigated. LCS suppressed both the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa with the IC50 values of 78 and 34 µM found in GH3 cells and of 112 and 26 µM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent INa (INa(P)) during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of INa(T) or INa(L) during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the INa block elicited by the preceding conditioning train can be fitted by two exponential processes, while the single exponential increase in current recovery without a conditioning train was adequately fitted. The fast and slow τ's of recovery from the INa block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window INa (INa(W)) during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of INa activated by pulse train stimulation, and veratridine reversed its decrease in the decaying τ value in current inactivation. The docking results predicted the capability of LCS binding to some amino-acid residues in sodium channels owing to the occurrence of hydrophobic contact. Overall, our findings unveiled that LCS can interact with the sodium channels to alter the magnitude, gating, voltage-dependent hysteresis behavior, and use dependence of INa in excitable cells.
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Canais de Sódio , Sódio , Íons/metabolismo , Lacosamida/farmacologia , Sódio/metabolismo , VeratridinaRESUMO
BACKGROUND/PURPOSE: Typhoon Morakot in August 2009 caused significant damages and health and socio-economic impacts in Taiwan. Therefore, we evaluated the mental health status of adult and patients who lived in the affected area after the disaster. METHODS: An observational, prospective population-based study was conducted. Adults living in the affected area were selected as the affected population in the National Health Insurance Database from January 2008 to December 2011. Prevalence and incidence of stress-associated illnesses, such as insomnia, anxiety, depressive, adjustment and mood disorders, post-traumatic stress disorder (PTSD) in the psychiatry department were analysed after the disaster. RESULTS: A total of 897,689 adult patients were studied. Of the affected population without pre-existing chronic mental health illness, the monthly visits for stress-associated illnesses, such as insomnia, anxiety, depressive disorders and PTSD increased about twice after the disaster in elderly and non-elderly groups. Comparing to the non-elderly group, the elderly group has more increased in the incidence of insomnia (356% vs. 318% increase) and depressive disorders (308% vs. 245%) but was affected to a lesser extent increase in the anxiety (269% vs. 307%), PTSD, episodic mood disorders (82% vs. 158%), and adjustment reaction (160% vs. 202%). CONCLUSION: The mental health statuses of patients who experienced a major natural disaster deteriorated in the elderly population after the disaster. However, we still need pay more attentions on the elderly of the affected population to decrease the risk for insomnia and depressive disorders after the disaster.
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Tempestades Ciclônicas , Desastres , Estresse Psicológico , Idoso , Humanos , Incidência , Estudos Prospectivos , Estresse Fisiológico , Taiwan/epidemiologiaRESUMO
Full genome analysis of a young girl with deafness, dystonia, central hypomyelination, refractory seizure, and fluctuating liver function impairment revealed a heterozygous, de novo variant in the BCAP31 gene on chromosome Xq28 (NM_001256447.2:c.92G>A), mutations of which caused the X-linked recessive severe neurologic disorder deafness, dystonia, and cerebral hypomyelination. Reverse transcription-polymerase chain reaction of the patient's white blood cells showed the absence of wild-type BCAP31 messenger RNA (mRNA) but the presence of two novel BCAP31 mRNAs. The major alternatively spliced mRNA is due to Exon 2 skipping and the utilization of a new initiation site in Exon 3 that leads to a frameshift and truncated transcript while the minor novel mRNA has a 110 nucleotide insertion to Exon 2. Phasing studies showed that the de novo variant arose in the paternal X chromosome. X chromosome inactivation assay was done and confirmed that the patient's maternal X chromosome was preferentially inactivated, providing evidence that the mutated BCAP31 gene was the one predominantly expressed. According to the American College of Medical Genetics and Genomics guideline, this variant is deemed "pathogenic" (PS2, PS3, PM2, PP3, and PP4) and deleterious. This is the first reported female patient in BCAP31-related syndrome resulted from skewed X-inactivation and a de novo mutation in the active X chromosome.
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Proteínas de Membrana , Inativação do Cromossomo X , Éxons/genética , Feminino , Heterozigoto , Humanos , Proteínas de Membrana/genética , Mutação , SíndromeRESUMO
Neonatal hypoxic-ischemic encephalopathy is the most common cause of neurological disability in infancy. Superimposed inflammation may further worsen neurological outcomes. Reliable biomarkers which are both sensitive to hypoxic-ischemia and inflammation are critically needed. We tested plasma osteopontin (OPN) and glial fibrillary astrocytic protein (GFAP) within the reported therapeutic window (90 min after hypoxic-ischemic (HI) injury) in neonatal rats with different HI severity and inflammation. Two different HI severity groups (mild-HI with 75 min hypoxia and severe-HI with 150 min hypoxia) were established. Inflammation-sensitized HI brain injury induced by lipopolysaccharide (LPS) further increased apoptotic neurons and infarct volumes. In HI alone groups, OPN was significantly decreased (p < 0.001) but GFAP was slightly increased (p < 0.05) at 90 min after HI either in mild-HI or severe-HI compared with naïve group. In LPS-sensitized HI groups, both OPN and GFAP were significantly increased either in LPS-mild-HI or LPS-severe-HI groups compared with the naïve group (all p < 0.05). Induced inflammation by LPS exaggerated neonatal HI brain injury. The plasma OPN and GFAP levels may be useful to differentiate HI alone groups from inflammation-sensitized HI groups or naïve group.
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Proteína Glial Fibrilar Ácida/sangue , Hipóxia-Isquemia Encefálica/diagnóstico , Inflamação/diagnóstico , Osteopontina/sangue , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Diagnóstico Diferencial , Ratos Sprague-DawleyRESUMO
OBJECTIVE: This study investigated the incidence of epilepsy and identified neonatal risk morbidities for epilepsy in children born extremely preterm. METHODS: Of the 806 very preterm infants (birth weight < 1500 g, gestational age < 32 weeks) who survived and were discharged from the four neonatal intensive care units in southern Taiwan between 2003 and 2012, 686 (85.1%) had longitudinal neurodevelopmental follow-up assessments up to 5 years of age. RESULTS: Among the 686 very preterm children, 19 (2.8%) exhibited epilepsy at a mean age of 19 ± 14 months. The incidence of epilepsy was highest among infants with neonatal seizure (33%), followed by cystic periventricular leukomalacia (cPVL, 27%), high-grade intraventricular hemorrhage (IVH, 21%), and necrotizing enterocolitis (NEC) stage III (20%). NEC stage III, neonatal seizure, high-grade IVH, and cPVL were also independent neonatal risk morbidities for epilepsy. Furthermore, the incidence of epilepsy was 21.6% in preterm children with significant neonatal brain injury (SNBI; ie, high-grade IVH and cPVL), but only 1% in preterm children without SNBI. Among preterm children with SNBI, neonatal seizure was higher in preterm children with epilepsy than in those without epilepsy (23.1% vs 2.1%, P = .03). Among preterm children without SNBI, NEC stage III was higher in preterm children with epilepsy than in those without epilepsy (33.3% vs 1.8%, P < .01). The preterm children with epilepsy were prone to have neurodevelopmental disability regardless of whether they had neonatal brain injury, and drug-resistant epilepsy (42%), particularly those with neonatal high-grade IVH. SIGNIFICANCE: There is an elevated incidence of epilepsy among very preterm children, and particularly those with significant brain injury and/or severe NEC during the neonatal period. Very preterm children with epilepsy are prone to have neurodevelopmental disability and drug-resistant epilepsy.
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Epilepsia/epidemiologia , Recém-Nascido Prematuro , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Doenças do Recém-Nascido , Masculino , Taiwan/epidemiologiaRESUMO
BACKGROUND: Helicobacter pylori infection is known to alter growth-related hormones and affect growth in young children. However, it is still unknown whether maternal H. pylori infection has an impact on the levels of cord blood growth-related hormones and whether this can predict intrauterine growth restriction and poor physical and neurodevelopmental outcomes in children. This study aimed to examine associations between maternal H. pylori infection and pregnancy-related adverse events, fetal growth and early childhood development. METHODS: In this prospective cohort study, we recruited singleton pregnant women without major medical illnesses from January 2014 to January 2015. Seropositivity for H. pylori was defined as > 12 U/ml of anti-H. pylori IgG in maternal serum. Demographic data and pregnancy-related medical issues of the cohort were documented. Cord blood levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), insulin, and ghrelin were determined using ELISA. The growth of the included neonates was monitored annually for up to 3 years, and cognitive development was assessed using the comprehensive developmental inventory for infants and toddlers (CDIIT) test 3 years after birth. RESULTS: Of the 106 enrolled women, 25 (23.6%) were H. pylori-seropositive. Maternal H. pylori seropositivity was correlated with a higher risk of developing gestational hypertension (GH) (12% vs. 1.2%, p = 0.04) and lower cord blood levels of IGF-1 (< 35 ng/ml, 70.0% vs. 40.7%, p = 0.02) and IGFBP-3 (< 1120 ng/ml, 100.0% vs. 76.3%, p = 0.02) compared with the seronegative women. No significant impacts on birth weight, childhood growth and cognitive development were found to be correlated with maternal H. pylori seropositivity during pregnancy. CONCLUSIONS: Maternal H. pylori infection during pregnancy was more likely to lead to the development of GH, but was not correlated with fetal and childhood growth and development. In addition to close monitoring of hypertension, H. pylori eradication can be considered for mothers with H. pylori infection.
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Anticorpos Antibacterianos/sangue , Desenvolvimento Infantil , Desenvolvimento Fetal , Infecções por Helicobacter/sangue , Helicobacter pylori , Hipertensão Induzida pela Gravidez/sangue , Complicações Infecciosas na Gravidez/sangue , Estudos de Coortes , Feminino , Infecções por Helicobacter/complicações , Helicobacter pylori/imunologia , Humanos , Recém-Nascido , Gravidez , Estudos ProspectivosRESUMO
Ischemic stroke is a leading cause of human death in present times. Two phases of pathological impact occur during an ischemic stroke, namely, ischemia and reperfusion. Both periods include individual characteristic effects on cell injury and apoptosis. Moreover, these conditions can cause severe cell defects and harm the blood-brain barrier (BBB). Also, the BBB components are the major targets in ischemia-reperfusion injury. The BBB owes its enhanced protective roles to capillary endothelial cells, which maintain BBB permeability. One of the nerve growth factor (NGF) receptors initiating cell signaling, once activated, is the p75 neurotrophin receptor (p75NTR). This receptor is involved in both the survival and apoptosis of neurons. Although many studies have attempted to explain the role of p75NTR in neurons, the mechanisms in endothelial cells remain unclear. Endothelial cells are the first cells to encounter p75NTR stimuli. In this study, we found the upregulated p75NTR expression and reductive expression of tight junction proteins after in vivo and in vitro ischemia-reperfusion injury. Moreover, astaxanthin (AXT), an antioxidant drug, was utilized and was found to reduce p75NTR expression and the number of apoptotic cells. This study verified that p75NTR plays a prominent role in endothelial cell death and provides a novel downstream target for AXT.
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Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Receptor de Fator de Crescimento Neural/metabolismo , Animais , Animais Recém-Nascidos , Antioxidantes/uso terapêutico , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Imunoquímica , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Xantofilas/uso terapêuticoRESUMO
BACKGROUND: In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood-brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. METHODS: Postpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity. RESULTS: On P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration. CONCLUSIONS: CXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain.
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Barreira Hematoencefálica/lesões , Barreira Hematoencefálica/patologia , Quimiocina CXCL5/metabolismo , Encefalite/complicações , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Leucoencefalopatias/etiologia , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Quimiocina CXCL5/farmacologia , Modelos Animais de Doenças , Ectodisplasinas/metabolismo , Encefalite/induzido quimicamente , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Injeções Intraventriculares , Interleucina-3/metabolismo , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Microglia/patologia , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-8B/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: Acute transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory, and autonomic dysfunction. In this study, we delineate the clinical manifestations, neuroimaging characteristics, and outcome-associated risk factors in children with idiopathic ATM. METHODS: We retrospectively reviewed the medical charts and neuroimages in nine children aged younger than 18 years diagnosed with ATM between January 2006 and August 2014. RESULTS: The mean onset age was 5 years and 9 months. Infectious prodromes were observed in six patients. Leg weakness was observed in all patients, autonomic sphincter dysfunction was observed in seven patients, and sensory deficits on admission were observed only in four patients. The diagnosis was delayed in patients younger than 5.5 years compared with older children. The adverse outcomes cannot be predicted by the course of the disease, the laboratory findings, nor the extent of magnetic resonance imaging-detected spinal lesions; however, these outcomes can be predicted by poor early response to corticosteroids and the requirement of additional treatments (p < 0.05). CONCLUSION: The diagnosis of ATM is challenging in young children. Children with ATM who responded early to corticosteroids had more favorable outcomes than those who required additional therapies.
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Mielite Transversa/epidemiologia , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mielite Transversa/patologia , Estudos Retrospectivos , Fatores de Risco , Medula Espinal/patologiaRESUMO
BACKGROUND: Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood-brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-α is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress-responsive kinases. OBJECTIVE: To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain. METHODS: Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-α expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining. RESULTS: The LPS + HI group had significantly greater up-regulation of activated microglia, TNF-α and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS + HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-α inhibitor) and AS601245 (a JNK inhibitor) protected against LPS-sensitized HI brain injury. The TNFR1-knockout but not TNFR2-knockout pups had significant reduction in JNK activation, attenuation of microglial activation, BBB breakdown and cleaved caspase-3 expression, and showed markedly less cortical and white matter injury than the wild-type pups after LPS-sensitized HI. CONCLUSION: TNFR1-JNK signaling is the shared pathway leading to neuroinflammation and neurovascular damage after LPS-sensitized HI in the immature brain.
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Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Receptores Tipo I de Fatores de Necrose Tumoral/biossíntese , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Hipóxia-Isquemia Encefálica/induzido quimicamente , Hipóxia-Isquemia Encefálica/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
This review aims to serve as a foundational resource for general radiologists, enhancing their understanding of the role of Magnetic Resonance Imaging (MRI) in early prognostication for newborns diagnosed with hypoxic ischaemic encephalopathy (HIE). The article explores the application of MRI as a predictive instrument for determining long-term outcomes in newborns affected by HIE. With HIE constituting a leading cause of neonatal mortality and severe long-term neurodevelopmental impairments, early identification of prognostic indicators is crucial for timely intervention and optimal clinical management. We examine current literature and recent advancements to provide an in-depth overview of MRI predictors, encompassing brain injury patterns, injury scoring systems, spectroscopy, and diffusion imaging. The potential of these MRI biomarkers in predicting long-term neurodevelopmental outcomes and the probability of epilepsy is also discussed.
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Hipóxia-Isquemia Encefálica , Imageamento por Ressonância Magnética , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Recém-Nascido , Imageamento por Ressonância Magnética/métodos , Prognóstico , Encéfalo/diagnóstico por imagemRESUMO
Objective: The acquisition of fine motor skills is considered to be a crucial developmental milestone throughout early childhood. This study aimed to investigate the fine motor performance of young children with different disability diagnoses. Methods: We enrolled a sample of 1,897 young children under the age of 6 years who were at risk of developmental delays and were identified by a transdisciplinary team. A series of standardized developmental assessments included the Bayley Scales of Infant Development-Third Edition, Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition, Peabody Developmental Motor Scale-Second Edition, and Movement Assessment Battery for Children-Second Edition were used. Retrospective chart reviews were conducted on all children to identify specific developmental disorders. The number of autism spectrum disorder (ASD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), comorbidity, motor dysfunction, and unspecified developmental delays (DD) were 363 (19.1%), 223 (11.8%), 234 (12.3%), 285 (15.0%), 128 (6.7%), and 590 (31.1%), respectively. Results: Young children with ID, comorbidity, and motor dysfunction demonstrated significant difficulty in performing manual dexterity and visual motor integration tasks and scored significantly lower in these areas than children with ASD, ADHD, and unspecified DD. In addition, fine motor performance was associated with cognitive ability in children with different disability diagnoses, indicating that young children showed better fine motor performance when they demonstrated better cognitive ability. Conclusion: Our findings support that differences in fine motor performance differ by disability type. Close links between fine motor performance and cognitive ability in children under the age of 6 years were seen in all disability types.
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PURPOSES: Although electrolyte abnormalities have been generally considered the major cause of out-of-hospital cardiac arrest (OHCA) in patients with kidney disease (KD), this association has never been prospectively validated. METHODS: A prospective, observational study was conducted in a tertiary university hospital between January 2008 and December 2009. The study sample consisted of consecutively admitted patients with nontraumatic OHCA. Based on the estimated glomerular filtration rate (eGFR, unit: milliliters per minute per 1.73 m(2)), the enrollees were divided into 3 groups: group A (normal kidney function or mild KD; eGFR, 60.0), group B (moderate KD; eGFR between 15.0 and 59.9), and group C (severe KD; eGFR<15.0 or on dialysis). The laboratory findings of the groups were compared. Two-tailed P values less than .005 were considered significant. RESULTS: Two hundred thirty-four enrollees (137 were male) were divided into 3 groups: group A (n = 51; 21.8%), group B (n = 128; 54.7%), and group C (n = 55; 23.5%). Compared with the other 2 groups, group C presented significantly higher serum potassium and magnesium and lower pH and hemoglobin level (all P < .005). After stratifications of the significant variables, a post hoc analysis revealed that group C presented significantly higher incidences of hypermagnesemia (Mg >2.5 mmol/L) and severe hyperkalemia (K >6.5 mmol/L) (both P < .005) than the other 2 groups. The odds ratios of the incidence of severe hyperkalemia in group C was 3.37 (95% confidence intervals, 1.46-7.77) compared with group A (50.9% vs 23.5%, P < .005). CONCLUSIONS: Severe hyperkalemia is common in patients with OHCA who have severe KD and should be considered during resuscitation for these patients.
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Nefropatias/complicações , Parada Cardíaca Extra-Hospitalar/etiologia , Desequilíbrio Hidroeletrolítico/complicações , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Hemoglobinas/metabolismo , Humanos , Hiperpotassemia/complicações , Hiperpotassemia/diagnóstico , Hiperpotassemia/epidemiologia , Incidência , Nefropatias/sangue , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Parada Cardíaca Extra-Hospitalar/sangue , Estudos Prospectivos , Índice de Gravidade de Doença , Desequilíbrio Hidroeletrolítico/sangue , Desequilíbrio Hidroeletrolítico/diagnóstico , Desequilíbrio Hidroeletrolítico/epidemiologiaRESUMO
INTRODUCTION: Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics. METHODS: This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5. RESULTS: A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8-38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age. DISCUSSION/CONCLUSION: Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.