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1.
Neurosci Res ; 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34838904

RESUMO

Oxidative stress is a major risk factor for Alzheimer's disease (AD). Among various oxidized molecules, the marked accumulation of an oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is observed in the AD brain. 8-oxo-2´-deoxyguanosine triphosphatase (MTH1) and 8-oxoG DNA glycosylase (OGG1) minimize the 8-oxoG accumulation in DNA, and their expression is decreased in the AD brain. MTH1 and/or OGG1 may suppress the pathogenesis of AD; however, their exact roles remain unclear. We evaluated the roles of MTH1 and OGG1 during the pathogenesis of AD using AppNL-G-F/NL-G-F knock-in mice (a preclinical AD model). Six-month-old female AppNL-G-F/NL-G-F mice with MTH1 and/or OGG1 deficiency exhibited reduced anxiety-related behavior, but their cognitive and locomotive functions were unchanged; the alteration was less evident in 12-month-old mice. MTH1 and/or OGG1 deficiency accelerated the 8-oxoG accumulation and microgliosis in the amygdala and cortex of six-month-old mice; the alteration was less evident in 12-month-old mice. Astrocytes and neurons were not influenced. We showed that MTH1 and OGG1 are essential for minimizing oxidative DNA damage in the AppNL-G-F/NL-G-F brain, and the effects are age-dependent. MTH1 and/or OGG1 deficiency reduced anxiety-related behavior in AppNL-G-F/NL-G-F mice with a significant acceleration of the 8-oxoG burden and microgliosis, especially in the cortex and amygdala.

2.
Lung Cancer ; 162: 135-139, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34798590

RESUMO

OBJECTIVES: This study aimed to assess the effect of home-based preoperative pulmonary rehabilitation (HBPPR) on the incidence of postoperative complications, length of stay (LOS), and duration of intercostal catheterization in non-small cell lung cancer (NSCLC) patients who underwent lung resection. MATERIALS AND METHODS: In this retrospective cohort study, 144 patients who underwent lung resection were recruited, 51 of whom received HBPPR, comprising respiratory muscle training and was supervised (for patients undergoing it for the first time). Patients continued these programs for 2-4 weeks during the preoperative waiting period, in their homes. Data on postoperative complications graded according to the Clavien-Dindo classification, LOS, and intercostal catheterization duration were collected from medical records. These outcomes were compared between the HBPPR and non-HBPPR groups using Fisher's exact test and Wilcoxon rank sum test, after 1:1 propensity score matching to avoid selection bias. RESULTS: Forty-nine matched pairs were extracted using propensity score matching. HBPPR reduced the onset of postoperative complications (p = 0.04), with the relative ratio (RR) for Clavien-Dindo Class I postoperative complications showing a significant difference (RR 0.55, 95% CI 0.30-1.02; p = 0.05), whereas RRs for the other Clavien-Dindo classes were not statistically significant. There was no significant difference in LOS or the duration of intercostal catheterization. CONCLUSION: HBPPR reduced the incidence of Clavien-Dindo Class I postoperative complications after lung resection. Implementing HBPPR practices in a clinical setting would benefit patients unable to receive supervised preoperative pulmonary rehabilitation due to access barriers, time, and financial constraints.

3.
Mol Psychiatry ; 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34737456

RESUMO

Alzheimer's disease (AD) is characterized by the deposition of amyloid ß peptide (Aß) in the brain. The neuropeptide somatostatin (SST) regulates Aß catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here, we identified α-endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (KATP) channel, as a negative regulator of NEP downstream of SST signaling. The expression of ENSA is significantly increased in AD mouse models and in patients with AD. In addition, NEP directly contributes to the degradation of ENSA, suggesting a substrate-dependent feedback loop regulating NEP activity. We also discovered the specific KATP channel subtype that modulates NEP activity, resulting in the Aß levels altered in the brain. Pharmacological intervention targeting the particular KATP channel attenuated Aß deposition, with impaired memory function rescued via the NEP activation in our AD mouse model. Our findings provide a mechanism explaining the molecular link between KATP channel and NEP activation, and give new insights into alternative strategies to prevent AD.

4.
Inorg Chem ; 60(22): 16977-16985, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34730983

RESUMO

Recently, there has been an increased interest in quaternary clathrate systems as promising thermoelectric materials. Because of their increased complexity, however, the chemical ordering in the host framework of quaternary clathrates has not yet been comprehensively analyzed. Here, we have synthesized a prototypical quaternary type-I clathrate Ba8AlxGa16-xGe30 by Czochralski and flux methods, and we employed a combination of X-ray and neutron diffraction along with atomic scale simulations to investigate chemical ordering in this material. We show that the site occupancy factors of trivalent elements at the 6c site differ, depending on the synthesis method, which can be attributed to the level of equilibration. The flux-grown samples are consistent with the simulated high-temperature disordered configuration, while the degree of ordering for the Czochralski sample lies between the ground state and the high-temperature state. Moreover, we demonstrate that the atomic displacement parameters of the Ba atoms in the larger tetrakaidecahedral cages are related to chemical ordering. Specifically, Ba atoms are either displaced toward the periphery or localized at the cage centers. Consequently, this study reveals key relationships between the chemical ordering in the quaternary clathrates Ba8AlxGa16-xGe30 and the structural properties, thereby offering new perspectives on designing these materials and optimizing their thermoelectric properties.

5.
Anticancer Res ; 41(11): 5635-5642, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732436

RESUMO

BACKGROUND/AIM: To evaluate the outcomes of proton beam therapy (PBT) for early-stage non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD). PATIENTS AND METHODS: Between 2002 and 2017, 110 patients receiving hypofractionated PBT for cT1-2N0M0 NSCLC were reviewed. RESULTS: Of the 110 patients, 17 were diagnosed with ILD. The median follow-up period was 37.8 months. No significant difference in the 1-year cumulative rate of grade ≥2 pneumonitis was observed between patients with and those without ILD (17.6% vs. 14.1%, p=0.708). The lung doses were significantly lower in patients with than in those without ILD among patients without grade ≥2 pneumonitis. There were no significant differences in overall survival or local recurrence-free rates according to the presence of ILD. CONCLUSION: PBT appears to be a feasible and effective treatment for cT1-2N0M0 NSCLC in patients with ILD, but the lung dose should be strictly reduced.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Doenças Pulmonares Intersticiais/complicações , Neoplasias Pulmonares/radioterapia , Terapia com Prótons , Hipofracionamento da Dose de Radiação , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/mortalidade , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Terapia com Prótons/efeitos adversos , Pneumonite por Radiação/etiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
6.
Cells ; 10(11)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34831483

RESUMO

Alzheimer's disease (AD), the most common form of dementia, is characterized by amyloid-ß (Aß) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-ß deposition, synaptic dysfunction, neuroinflammation, and dysregulation of ß-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

7.
Inorg Chem ; 60(20): 15667-15674, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34596398

RESUMO

Layered oxyhalides containing double or triple fluorite layers are promising visible-light-responsive water-splitting photocatalysts with unique band structures. Herein, we report on the synthesis, structure, and photocatalytic property of Bi4BaO6Cl2 (I4/mmm) with alternating double (Bi2O2) and triple (Bi2BaO4) fluorite layers, which was extracted from the crystallographic database on the basis of Madelung potential calculations. Rietveld refinements from powder X-ray and neutron diffraction data revealed the presence of cationic disorder between Bi2O2 and Bi2BaO4 layers, leading to electrostatic stabilization. DFT calculations suggested that photogenerated electrons and holes flow through the double and triple layers, respectively, which may suppress electron-hole recombination. We expanded this double-triple system to include Bi4CaO6Cl2 and Bi4SrO6Cl2 with orthorhombic distortions and different degrees of cationic disorder, which allow band gap tuning. All the double-triple compounds Bi4AO6Cl2 showed stable water-splitting photocatalysis in the presence of a sacrificial reagent.

8.
Inorg Chem ; 60(20): 15751-15758, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34613695

RESUMO

Crystallographic order-disorder phenomena in solid state compounds are of fundamental interest due to intimate relationship between the structure and properties. Here, by using high-pressure and high-temperature synthesis, we obtained vanadium perovskite oxyhydrides Sr1-xNaxVO3-yHy (x = 0, 0.05, 0.1, 0.2) with an anion-disordered structure, which is different from anion-ordered SrVO2H synthesized by topochemical reduction. High-pressure and high-temperature synthesis from nominal composition SrVO2H yielded the anion-disordered perovskite SrVO3-yHy (y ∼ 0.4) with a significant amount of byproducts, while Na substitution resulted in the almost pure anion-disordered perovskite Sr1-xNaxVO3-yHy with an increased amount of hydride anion (y ∼ 0.7 for x = 0.2). The obtained disordered phases for x = 0.1 and 0.2 are paramagnetic with almost temperature-independent electronic conductivity, whereas anion-ordered SrVO2H is an antiferromagnetic insulator. Although we obtained the anion-disordered perovskite under high pressure, a first-principles calculation revealed that the application of pressure stabilizes the ordered phase due to a reduced volume in the ordered structure, suggesting that a further increase of the pressure or reduction of the reaction temperature leads to the anion ordering. This study shows that anion ordering in oxyhydrides can be controlled by changing synthetic pressure and temperature.

9.
Commun Biol ; 4(1): 1175, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635772

RESUMO

DNA damage is increased in Alzheimer's disease (AD), while the underlying mechanisms are unknown. Here, we employ comprehensive phosphoproteome analysis, and identify abnormal phosphorylation of 70 kDa subunit of Ku antigen (Ku70) at Ser77/78, which prevents Ku70-DNA interaction, in human AD postmortem brains. The abnormal phosphorylation inhibits accumulation of Ku70 to the foci of DNA double strand break (DSB), impairs DNA damage repair and eventually causes transcriptional repression-induced atypical cell death (TRIAD). Cells under TRIAD necrosis reveal senescence phenotypes. Extracellular high mobility group box 1 (HMGB1) protein, which is released from necrotic or hyper-activated neurons in AD, binds to toll-like receptor 4 (TLR4) of neighboring neurons, and activates protein kinase C alpha (PKCα) that executes Ku70 phosphorylation at Ser77/78. Administration of human monoclonal anti-HMGB1 antibody to post-symptomatic AD model mice decreases neuronal DSBs, suppresses secondary TRIAD necrosis of neurons, prevents escalation of neurodegeneration, and ameliorates cognitive symptoms. TRIAD shares multiple features with senescence. These results discover the HMGB1-Ku70 axis that accounts for the increase of neuronal DNA damage and secondary enhancement of TRIAD, the cell death phenotype of senescence, in AD.

10.
Genome Med ; 13(1): 168, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702310

RESUMO

BACKGROUND: In spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., ß-secretase) has proven to be insufficient to significantly alter the physiopathology of the disease, and we should therefore move from gene-centric to systemic therapeutic strategies, where AD-related changes are modulated globally. METHODS: Here we present the complete characterization of three murine models of AD at different stages of the disease (i.e., onset, progression and advanced). We combined the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Additionally, we derived specific Aß-related molecular AD signatures and looked for drugs able to globally revert them. RESULTS: We found that AD models show accelerated aging and that factors specifically associated with Aß pathology are involved. We discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable, and showed that at least two of them (i.e., lfit3 and Syt11) co-localize with Aß plaques in the brain. Finally, we found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aß plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels. CONCLUSIONS: The characterization of three AD mouse models at different disease stages provides an unprecedented view of AD pathology and how this differs from physiological aging. Moreover, our computational strategy to chemically revert AD signatures has shown that NSAID and anti-hypertensive drugs may still have an opportunity as anti-AD agents, challenging previous reports.

11.
Elife ; 102021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609281

RESUMO

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for activated CD11c+ microglia and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimer's disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow (BM) cells to the pool of fetal-derived brain macrophages during the development of AD. We demonstrated that microglia remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor is replenished by, BM-derived cells. At the border-associated brain regions, bona fide CD206+ BAMs are minimally replaced by BM-derived cells, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by BM progenitors. This information further elucidates the turnover kinetics of these cells not only at steady state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.


Assuntos
Doença de Alzheimer/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Lectinas de Ligação a Manose/metabolismo , Microglia/metabolismo , Receptores de Superfície Celular/metabolismo , Doença de Alzheimer/embriologia , Animais , Modelos Animais de Doenças , Camundongos
13.
Metabolites ; 11(9)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34564432

RESUMO

Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer's disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed by ultra-performance liquid chromatography followed by mass spectrometry. We found that a unique mannosylated-glycan is carried by a Tf isoform in CSF (Man-Tf). The cerebral cortex contained Man-Tf as a major isofom, suggesting that CSF Man-Tf is, at least partly, derived from the cortex. Man-Tf levels were analyzed in CSF of patients with neurological diseases. Concentrations of Man-Tf were significantly increased in AD and mild cognitive impairment (MCI) comparing with other neurological diseases, and the levels correlated well with those of phosphorylated-tau (p-tau), a representative AD marker. Consistent with the observation, p-tau and Tf were co-expressed in hippocampal neurons of AD, leading to the notion that a combined p-tau and Man-Tf measure could be a biomarker for AD. Indeed, levels of p-tau x Man-Tf showed high diagnostic accuracy for MCI and AD; 84% sensitivities and 90% specificities for MCI and 94% sensitivities and 89% specificities for AD. Thus Man-Tf could be a new biomarker for AD.

14.
Immun Inflamm Dis ; 9(4): 1740-1748, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34533288

RESUMO

BACKGROUND: The efficacy assessment of human anti-IgE monoclonal antibodies (mAbs) in animal models before clinical trials is hampered due to the lack of cross-reactivity of anti-IgE mAbs between species. OBJECTIVE: We developed CRE-DR (an anti-dog IgE monoclonal antibody), an anti-IgE mouse mAb that recognizes canine and human IgE, and then examined its IgE specificity and cross-reactivity between three animal and human species. METHODS: After mouse immunization with a synthetic peptide derived from canine IgE (282 NTNDWIEGETYYC294 ), we generated a hybridoma producing CRE-DR. The CRE-DR purified from the ascites of hybridoma-inoculated mice was used for ELISA and Western blot analysis to examine reactivity to dog, human, and rodent IgEs as well as recombinant bovine serum albumin (BSA)-conjugated to canine, human, and rodent IgE amino acid peptides corresponding to the immunizing sequence. We then performed enzyme-linked immunosorbent assays (ELISAs) for dog IgE using sera from dogs with atopic dermatitis (AD) after inhibition with canine IgE and IgG. The amino acid sequence recognized by CRE-DR was identified by ELISA using synthetic peptides. RESULTS: CRE-DR is a monoclonal mouse IgG1κ specific for dog IgE, and the ELISA values in atopic dog sera were inhibited by dog IgE, but not dog IgG. The binding of CRE-DR to human IgE was relatively maintained, but not to rodent IgEs, which results were confirmed with the BSA-conjugated IgE peptides of the various species. The CRE-DR reactivity was supported by the comparison of amino acid sequence of CRE-DR epitope, DWIEGETYYC, in dog IgE; one, two, and three amino acids were substituted in the human, rat, and mouse IgE epitopes, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: CRE-DR is a mAb cross-reactive to dog and human IgEs, which can allow the use of a dog model of allergy to test the efficacy of a CRE-DR-derived anti-IgE therapeutic mAb before human clinical trials.

15.
Esophagus ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34383155

RESUMO

BACKGROUND: The 6-minute walk distance (6MWD) is a simple way of assessing exercise capacity. The purpose of this study was to investigate the relationship between preoperative 6MWD and long-term prognosis after esophagectomy. METHODS: This retrospective cohort study involved 108 patients who underwent radical esophagectomy for esophageal cancer between 2013 and 2020. The patients were classified into the short group (SG: 6MWD < 480 m) or the long group (LG: 6MWD ≥ 480 m). To adjust for the background characteristics of both groups, propensity score matching (PSM) analysis was performed and 32 patients were matched from each group. Five-year overall survival (OS) and relapse-free survival (RFS) were analyzed by the Kaplan-Meier method. The log-rank test was used to evaluate differences in survival between the groups. After adjusting for other prognostic factors, the Cox proportional hazards model was used to investigate the impact of preoperative 6MWD on long-term prognosis. RESULTS: The median follow-up period was 923 days. Thirty-three deaths were recorded during the study period. After PSM, 5-year OS following surgery was 29.2 and 66.1% (p = 0.003) and 5-year RFS was 27.9 and 58.6% (p = 0.021) in the SG and LG, respectively. In Cox proportional hazards analysis, the SG was a significant independent risk factor for OS (hazard ratio 3.33; 95% confidence interval 1.37-8.11, p = 0.008) and RFS (hazard ratio 2.30; 95% confidence interval 1.08-4.88, p = 0.030). CONCLUSION: The preoperative 6MWD is useful for evaluating exercise capacity and predicting the long-term outcome in patients undergoing esophagectomy.

16.
Cell Death Dis ; 12(8): 769, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349120

RESUMO

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Increased Aß production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aß generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

17.
J Neurosurg Pediatr ; 28(4): 395-403, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34388720

RESUMO

OBJECTIVE: Pediatric epilepsy surgery is known to be effective, but early surgery in infancy is not well characterized. Extensive cortical dysplasia, such as hemimegalencephaly, can cause refractory epilepsy shortly after birth, and early surgical intervention is indicated. However, the complication rate of early pediatric surgery is significant. In this study, the authors assessed the risk-benefit balance of early pediatric epilepsy surgery as relates to developmental outcomes. METHODS: This is a retrospective descriptive study of 75 patients who underwent their first curative epilepsy surgery at an age under 3 years at the authors' institution between 2006 and 2019 and had a minimum 1-year follow-up of seizure and developmental outcomes. Clinical information including surgical complications, seizure outcomes, and developmental quotient (DQ) was collected from medical records. The effects of clinical factors on DQ at 1 year after surgery were evaluated. RESULTS: The median age at surgery was 6 months, peaking at between 3 and 4 months. Operative procedures included 27 cases of hemispherotomy, 19 cases of multilobar surgery, and 29 cases of unilobar surgery. Seizure freedom was achieved in 82.7% of patients at 1 year and in 71.0% of patients at a mean follow-up of 62.8 months. The number of antiseizure medications (ASMs) decreased significantly after surgery, and 19 patients (30.6%) had discontinued their ASMs by the last follow-up. Postoperative complications requiring cerebrospinal fluid (CSF) diversion surgery, such as hydrocephalus and cyst formation, were observed in 13 patients (17.3%). The mean DQ values were 74.2 ± 34.3 preoperatively, 60.3 ± 23.3 at 1 year after surgery, and 53.4 ± 25.1 at the last follow-up. Multiple regression analysis revealed that the 1-year postoperative DQ was significantly influenced by preoperative DQ and postoperative seizure freedom but not by the occurrence of any surgical complication requiring CSF diversion surgery. CONCLUSIONS: Early pediatric epilepsy surgery has an acceptable risk-benefit balance. Seizure control after surgery is important for postoperative development.


Assuntos
Desenvolvimento Infantil , Epilepsia Resistente a Medicamentos/cirurgia , Procedimentos Neurocirúrgicos/métodos , Fatores Etários , Derivações do Líquido Cefalorraquidiano , Pré-Escolar , Feminino , Seguimentos , Hemisferectomia , Humanos , Lactente , Masculino , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Medição de Risco , Convulsões/epidemiologia , Convulsões/cirurgia , Resultado do Tratamento
18.
J Neurochem ; 159(3): 603-617, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379812

RESUMO

Two common conjugated linoleic acids (LAs), cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid-ß (Aß) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of Aß in mouse neurons. CLA treatment did not affect the level of ß-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment, or Aß protein precursor (APP) in cultured neurons. BACE1 and γ-secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA-containing phosphatidylcholine (CLA-PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane-associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent Aß generation. Our findings suggest that the accumulation of c9,t11 CLA-PC/LPC in neuronal membranes suppresses the production of neurotoxic Aß in neurons.


Assuntos
Peptídeos beta-Amiloides/biossíntese , Ácido Linoleico/farmacologia , Ácidos Linoleicos Conjugados/farmacologia , Neurônios/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Suplementos Nutricionais , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Fosfatidilcolinas/metabolismo
19.
Epilepsy Behav Rep ; 16: 100463, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195590

RESUMO

Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is often refractory to medical treatment and leads to poor cognitive outcomes. Corpus callosotomy may be an effective treatment option for drug-resistant ESES with no focal etiology. We retrospectively identified three patients who underwent corpus callosotomy for drug-resistant ESES in our institution. Electroencephalography (EEG) findings and cognitive functions were evaluated before surgery, at 3 months, 6 months, 1 year, and 2 years after surgery. Age at surgery was 6 years 10 months, 7 years 9 months, and 8 years 4 months, respectively. Period between the diagnosis of ESES and surgery ranged from 7 to 25 months. All patients had no obvious structural abnormalities and presented with cognitive decline despite multiple antiseizure medications and steroid therapies. One patient showed complete resolution of ESES and an improvement of intelligence quotient after surgery. Epileptiform EEG was lateralized to one hemisphere after surgery and spike wave index (SWI) was decreased with moderate improvement in development and seizures in the other 2 patients. SWI re-exacerbated from 6 months after surgery, but without subsequent developmental regression in these 2 patients. Corpus callosotomy may become an important treatment option for drug-resistant ESES in patients with no structural abnormalities.

20.
Mol Neurodegener ; 16(1): 47, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266459

RESUMO

BACKGROUND: Microglia are active modulators of Alzheimer's disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. METHODS: AppNL-F and AppNL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer's disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. RESULTS: Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in AppNL-F mice but was not evident in AppNL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. CONCLUSIONS: Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer's disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer's disease.

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