Surgery for Drug-Resistant Epilepsy in Children Dwivedi, Rekha; Ramanujam, Bhargavi; Chandra, P Sarat ...
The New England journal of medicine,
10/2017, Volume:
377, Issue:
17
Journal Article
Peer reviewed
Open access
Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials.
In this single-center trial, we randomly ...assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet-Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory.
At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (P<0.001). Between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the score on the Hague Seizure Severity scale (difference, 19.4; 95% confidence interval CI, 15.8 to 23.1; P<0.001), on the Child Behavior Checklist (difference, 13.1; 95% CI, 10.7 to 15.6; P<0.001), on the Pediatric Quality of Life Inventory (difference, 21.9; 95% CI, 16.4 to 27.6; P<0.001), and on the Vineland Social Maturity Scale (difference, 4.7; 95% CI, 0.4 to 9.1; P=0.03), but not on the Binet-Kamat intelligence quotient (difference, 2.5; 95% CI, -0.1 to 5.1; P=0.06). Serious adverse events occurred in 19 patients (33%) in the surgery group, including hemiparesis in 15 (26%).
In this single-center trial, children and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection. (Funded by the Indian Council of Medical Research and others; Clinical Trial Registry-India number, CTRI/2010/091/000525 .).
Angiotensin-converting enzyme 2 (ACE2) is a key host protein by which severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters and multiplies within cells. The level of ACE2 expression in ...the lung is hypothesised to correlate with an increased risk of severe infection and complications in COrona VIrus Disease 2019 (COVID-19). To test this hypothesis, we compared the protein expression status of ACE2 by immunohistochemistry (IHC) in post-mortem lung samples of patients who died of severe COVID-19 and lung samples obtained from non-COVID-19 patients for other indications. IHC for CD61 and CD163 was performed for the assessment of platelet-rich microthrombi and macrophages, respectively. IHC for SARS-CoV-2 viral antigen was also performed. In a total of 55, 44 COVID-19 post-mortem lung samples were tested for ACE2, 36 for CD163, and 26 for CD61, compared to 15 non-covid 19 control lung sections. Quantification of immunostaining, random sampling, and correlation analysis were used to substantiate the morphologic findings. Our results show that ACE2 protein expression was significantly higher in COVID-19 post-mortem lung tissues than in controls, regardless of sample size. Histomorphology in COVID-19 lungs showed diffuse alveolar damage (DAD), acute bronchopneumonia, and acute lung injury with SARS-CoV-2 viral protein detected in a subset of cases. ACE2 expression levels were positively correlated with increased expression levels of CD61 and CD163. In conclusion, our results show significantly higher ACE2 protein expression in severe COVID-19 disease, correlating with increased macrophage infiltration and microthrombi, suggesting a pathobiological role in disease severity.
In this study, graphene nanosheet-supported ultrafine Cu nanoparticles (NPs) encapsulated with thin mesoporous silica (Cu–GO@m-SiO2) materials are fabricated with particle sizes ranging from 60 to ...7.8 nm and are systematically investigated for the oxidative coupling of amines to produce biologically and pharmaceutically important imine derivatives. Catalytic activity remarkably increased from 76.5% conversion of benzyl amine for 60 nm NPs to 99.3% conversion and exclusive selectivity of N-benzylidene-1-phenylmethanamine for 7.8 nm NPs. The superior catalytic performance along with the outstanding catalyst stability of newly designed catalysts are attributed to the easy diffusion of organic molecules through the porous channel of mesoporous SiO2 layers, which not only restricts the restacking of the graphene nanosheets but also prevents the sintering and leaching of metal NPs to an extreme extent through the nanoconfinement effect. Density functional theory calculations were performed to shed light on the reaction mechanism and to give insight into the trend of catalytic activity observed. The computed activation barriers of all elementary steps are very high on terrace Cu(111) sites, which dominate the large-sized Cu NPs, but are significantly lower on step sites, which are presented in higher density on smaller-sized Cu NPs and could explain the higher activity of smaller Cu–GO@m-SiO2 samples. In particular, the activation barrier for the elementary coupling reaction is reduced from 139 kJ/mol on flat terrace Cu(111) sites to the feasible value of 94 kJ/mol at step sites, demonstrating the crucial role of the step site in facilitating the formation of secondary imine products.
Glioblastoma is the most life-threatening tumor of the central nervous system. Despite recent therapeutic advancements, maximum survival of glioblastoma patients remains dismal. The mediator complex ...is a set of proteins, essential for eukaryotic gene expression. Abnormal expression/mutations of specific mediator genes have been associated with progression of various cancers, however, its role and status in glioblastoma remains largely unknown. Our work shows overexpression of a subunit of kinase assembly of mediator complex, MED12, in various glioblastoma patient cohorts including Indian glioblastoma patients and cell lines. Functional characterization of MED12 using both overexpression and knockdown approach revealed that it promotes glioblastoma cell proliferation, migration and inhibits apoptosis. Transcriptome analysis post MED12 knockdown revealed Vitamin D receptor (VDR) pathway to be one of the key pathways affected by MED12 in glioblastoma. We studied direct interaction of MED12 with VDR protein using docking studies and co-immunoprecipitation assay. We identify BCL6, a secondary regulator of VDR signaling, to be directly regulated by MED12 through a combination of chromatin immunoprecipitation, qRT-PCR and western analyses. We further show that MED12 brings about the inhibition of p53 levels and apoptosis partly through induction of BCL6 in glioblastoma. Overall, this stands as the first report of MED12 over-expression and involvement in glioblastoma pathogenesis and identifies MED12 as an important mediator of VDR signaling and an attractive molecule for development of new therapeutic interventions.
Selective formation of 2,5-dimethylfuran (DMF) by hydrogenolysis of lignocellulosic biomass-derived 5-hydroxymethylfurfural (HMF) is highly desirable for renewable liquid biofuel production. Here we ...have synthesized Cu–Pd bimetallic nanoparticles embedded in carbon matrix (Cu–Pd@C) by simple pyrolysis of Pd-impregnated Cu-based metal–organic frameworks (MOFs) followed by conventional hydrogenation route. It was found that Cu–Pd@C-B (solid–gas-phase hydrogenation route) with Cu–Pd bimetallic alloying exhibited brilliant catalytic performance at 120 °C under 15 bar H2 pressure to produce liquid DMF biofuel with 96.5% yield from HMF as compared with the Cu–Pd@C-A catalyst (liquid phase hydrogenation route), which gave 46.4% yield under the same conditions. X-ray photoelectron spectroscopy (XPS) and X-ray absorption near-edge structure (XANES) studies reveal that Pd in Cu–Pd@C-B catalyst is electronically promoted by Cu with the unique intrinsic synergy of increased Pd–Pd bond distance and decreased Cu–Cu bond length, which eventually modulate the local atomic structural environment and result in enhanced catalytic activity. Moreover, the entrapped bimetallic nanoparticles with carbon shells in Cu–Pd@C-B catalyst further protect the active catalytic site from migration, aggregation, and leaching during hydrogenolysis reaction and improve the stability of the catalyst.
Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the ...known involvement of TERT and EZH2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia‐telangiectasia‐mutated (ATM) phosphorylation levels. Conversely, diminished TERT and FASN levels upon siRNA‐mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition‐mediated decrease in FASN and EZH2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT‐EZH2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non‐canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma.
Mutation in telomerase reverse transcriptase (TERT) promoter correlates with poor prognosis in glioblastoma (GBM). As elevated enhancer of zeste homolog 2 (EZH2) and fatty acid synthase (FASN) levels were accompanied by heightened microsatellite instability in TERT‐mutant GBMs, their correlations were investigated. Genetic and pharmacological manipulation of TERT indicated the importance of TERT–EZH2 axis in regulating lipid metabolism and ataxia‐telangiectasia‐mutated (ATM) activation. This study provides better understanding of aberrant metabolic programming in GBM based on distinctive genetic alterations.
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