Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.

APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

The complete chloroplast genome of Dianella ensifolia (Asphodelaceae).

Dianella ensifolia (L.) Redouté 1802 is a plant known for its significant medicinal values. In this study, we presented its chloroplast genome. The length of the chloroplast genome was found to be 156,571 bp, with a GC content of 37.86%. It consisted of a large single-copy (LSC) of 85,318 bp and a small single-copy (SSC) of 18,307 bp, a pair of inverted repeats (IRs) of 26,473 bp each that separated the LSC and SSC regions. The chloroplast genome of D. ensifolia consisted of 114 unique genes, including 80 protein-coding genes, four rRNA genes, and 30 tRNA genes. Through phylogenetic analysis, we identified a close relationship between D. ensifolia and D. nigra. This newly sequenced chloroplast genome not only enhances our understanding of the genome of Dianella, but also provides valuable insights for the evolutionary study of the family Asphodelaceae.

APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia.

Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aß (fAß) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.

Effects of NSC in different organs and at different growth stages on the yield of oil peony Fengdan with different ages.

Non-structural carbohydrates (NSC) as resource reserves of plants play important roles in energy supply for normal growth and reproduction under environmental stress. The yield of perennial crops is mainly determined by the carbohydrate production and allocation in the current growth season, as well as the re-allocation of NSC reserves. However, the contribution of NSC to crop yield has not been fully determined. Fengdan (Paeonia ostii) is a variety of oil Peony that is newly developed in China. The effects of tree age and NSC on yield were examined by investigated the variations of biomass, soluble sugars, starch, and NSC in the organ and whole tree levels in the dormant and ripening stages of Fengdan populations with 4-, 6-, and 8-year-old in 2020 and 5-, 7-, and 9- year old in 2021. Results showed that the biomass, yield (seed biomass), soluble sugars, starch, and NSC reserve of Fengdan at the whole tree level increased with the increase in age. Although consistent correlations were observed between soluble sugars, starch and NSC storage, and yield among the plants with different ages, Fengdan showed allometric growth relationships between the accumulation of soluble sugars, starch, and NSC and yield and biomass (standardized major axis analyses slope b ≠ 1). Tree age significantly affected biomass and its allocation and NSC levels, especially the yield of Fengdan plants. The results of the investigation of the variations in the relationships between the yield and seasonal fluctuations of NSC and biomass indicate that roots is the key storage structure, whereas stems both serve as sink and/or source functions for the adult (7-9a) plants. NSC level, particularly the concentration of soluble sugars, in stems mainly influences Fengdan yield. These findings together provide new insights into the mechanisms underlying the yield formation of Fengdan and have implications for manipulating sink-source relationship to achieve high yield.

Trends in the availability of community-based psychological counselling services for oldest-old in China, 2005 to 2018.

BACKGROUND: Community-based psychological counselling services (CPCS) is crucial for the oldest-old who often faces challenges or are reluctant to seek care at the healthcare settings. This study aims to examine trends in availability of CPCS over time and rural-urban disparities in service availability among nationwide oldest-old in China. METHODS: Multiple cross-sectional data were derived from the 2005-2018 Chinese Longitudinal Health Longevity Survey. Service availability was reported by each oldest-old participant or their next-of-kins as having CPCS in one's neighborhood. We used Cochran-Armitage tests to estimate service availability trends and applied sample-weighted logistic regression models to examine its rural-urban disparities. RESULTS: Of 38,032 oldest-old, CPCS availability decreased from 6.7 % in 2005 to 4.8 % in 2008/2009, followed by continual increases to 13.6 % in 2017/2018. In 2017/2018, rural oldest-old's neighborhoods had no greater service availability. Oldest-old residing in the Central (6.7 %), Western (13.4 %) and Northeast China (8.1 %) were less likely to report having services locally than their Eastern counterparts (17.8 %). Oldest-old having any disability or living in the nursing homes reported having greater service availability than those without disability or living at home. LIMITATION: Service availability might have been disrupted during the COVID-19 pandemic. CONCLUSIONS: Despite the increasing service availability, as of 2017/2018, only 13.6 % oldest-old in China had reported CPCS availability. It raises concerns on the disproportionate access to and continuity of mental health care, especially for those living the Central, Western China and those living at home. Policy efforts are needed to incentivize service expansion and eliminate disparities in the service availability.

Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD. Highlights: Discovery of a plasma Parkinson's Disease biomarker candidate, pS65-Ubiquitin (pUb)Plasma pUb levels correlate with disease status and progression in PD patients.Identification of a potent, brain penetrant PINK1 activator, MTK458MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complexMTK458 drives clearance of α-synuclein pathology and normalizes pUb in in vivo Parkinson's models.

Rural-urban disparities in the unmet need for home visiting services among oldest-old in China: Changes over time and decomposition analysis.

PURPOSE: This study aims to assess trends in rural-urban disparities in the prevalence of unmet community-based home visiting services need and their contributing factors from 2005 to 2018 among oldest-old in China. METHODS: The Chinese Longitudinal Healthy Longevity Survey data of oldest-old collected with a targeted random-sampling approach from half of counties/cities from 23 provinces across China was used. Unmet need was measured as the differences between healthcare services expected and available. We used Cochran-Armitage tests to test linear trends in prevalence of unmet need. Average marginal differences were estimated to measure magnitude of rural-urban disparities in prevalence of unmet need. Changes in rural-urban disparities were decomposed using Blinder-Oaxaca Decomposition technique to logit models. All analysis was performed by Stata 15.0. RESULTS: From 2005-2018, decreased trends in prevalence of unmet need were observed (overall: 62.4% to 48.6%; rural: 65.9% to 47.3%; urban: 57.5% to 49.8%) (all ptrend < 0.001). In 2017/2018, urban oldest-old reported greater prevalence of unmet need (average marginal difference, 95% CI: 3.7% [0.4%-7.1%]); affluent oldest-old reported less unmet need than their peers. Oldest-old from Central and Western China reported greater prevalence of unmet need than their Eastern peers. Increases in income (percentages of explained change, overall: 21.3%; rural: 16.9%, urban: 36.9%) mainly contributed to decreased trends in prevalence of unmet need. CONCLUSIONS: Oldest-old with socioeconomic disadvantages or living in Central and Western China reported greater prevalence of unmet need. Policy efforts are warranted to ensure equitable access to home visiting services among those oldest-old.

Synthesis and Characterization of Benzoxazine Resin Based on Furfurylamine.

This paper presents an investigation of the modification of natural oxazines to traditional bisphenol A benzoxazines. Eugenol was reacted with furfurylamine to synthesize a new type of benzoxazine (eugenol-furfurylamine benzoxazine), with a yield of 77.65%; and another new type of benzoxazine (bisphenol A-furfurylamine benzoxazine) was generated from bisphenol A and furfurylamine, with the highest yield of 93.78%. In order to analyze and study the target molecules, IR (infrared radiation) spectroscopy, GPC (gel-permeation chromatograph), mass spectrometry, 1H-NMR (nuclear magnetic resonance), DSC (differential scanning calorimetry), and DMA (dynamic mechanical analysis) tests were conducted. Eugenol-furfurylamine benzoxazine and conventional bisphenol A-aniline benzoxazine (BZ) composite was also analyzed and cured at different mass ratios of 2:98, 5:95, 10:90, 20:80, and 40:60. When the content of eugenol furfurylamine in the blend reached 5%, the strength of the composite was greatly enhanced, while the strength decreased with the increase in eugenol furfurylamine oxazine content. Moreover, octamaleimide phenyl POSS (OMPS, polyhedral oligomeric silsesquioxane) and bisphenol A furamine benzoxazine were mixed at different molar ratios of 1:16, 1:8, 1:4, 1:2, and 1:1. The curing temperature sharply decreased with the increase in OMPS content. When the molar ratio reached 1:1, the curing temperature decreased from 248 to 175℃. A further advantage of using eugenol and furfurylamine is that they are renewable resources, which is important in terms of utilizing resources effectively and developing environmentally friendly products.

Efficacy and safety of antiseizure medication for Lennox-Gastaut syndrome: a systematic review and network meta-analysis.

AIM: To compare and rank the efficacy and safety of antiseizure medication (ASM) in patients with Lennox-Gastaut syndrome (LGS). METHOD: We included randomized controlled trials (RCTs) assessing the efficacy of ASM for LGS compared with placebo or with each other. The efficacy and safety were reported in terms of an at least 50% monthly seizure frequency reduction in drop seizures, dropout, and serious adverse events. Outcomes were ranked according to the surface under the cumulative ranking curve (SUCRA). RESULTS: A total of eight RCTs with 1171 patients were included, involving six ASMs: lamotrigine, rufinamide, cannabidiol, topiramate, clobazam, and felbamate. The calculated SUCRA showed that rufinamide, cannabidiol, and topiramate had the highest probability of achieving a response; however, no significant differences were found among these treatments. Cannabidiol, topiramate, and rufinamide were more likely to result in dropouts; moreover, a significantly greater percentage of patients receiving cannabidiol experienced premature discontinuation as compared to placebo, clobazam, and lamotrigine. INTERPRETATION: All ASMs showed a significantly higher response rate than placebo. SUCRA ranking demonstrated that rufinamide and cannabidiol are more efficacious than other treatments in reducing drop seizures. However, there was no significant difference between these treatments.

Comparative antiseizure medications of adjunctive treatment for children with drug-resistant focal-onset seizures: A systematic review and network meta-analysis.

Purpose: In this study, we intended to compare and rank the efficacy and acceptability of antiseizure medications (ASMs) for adjunctive treatment of children with drug-resistant focal-onset seizures. Method: We conducted a computerized search of PubMed, EMBASE, Cochrane Library, Web of Science, and Google Scholar to identify eligible randomized controlled trials (RCTs) published before 31 May 2022. We included studies evaluating the efficacy and tolerability of antiseizure medications for children with drug-resistant focal-onset seizures. The efficacy and safety were reported in terms of responder and dropout rate along with serious adverse events, the outcomes were ranked with the surface under the cumulative ranking curve (SUCRA). Results: A total of 14 studies (16 trials) with 2,464 patients were included, involving 10 active antiseizure medications. For the primary endpoint of at least 50% reduction in focal-onset seizures, the surface under the cumulative ranking curve ranking suggested that lamotrigine and levetiracetam were more effective as compared with other antiseizure medications; moreover, levetiracetam had the highest probability of rank first for achieving seizure freedom. Concerning tolerability, oxcarbazepine and eslicarbazepine acetate were associated with higher dropout rates relative to other antiseizure medications and placebo, and topiramate was associated with higher occurrence of side effects. No significant differences were found between active antiseizure medications concerning dropout for side effects. Conclusion: According to the surface under the cumulative ranking curve ranking, lamotrigine, levetiracetam, and oxcarbazepine were more efficacious than other active antiseizure medications in terms of responder rate. Concerning tolerability, oxcarbazepine was more likely to lead to dropout and topiramate was associated with higher occurrence of side effects.

Novel Polyaniline-Silver-Sulfur Nanotube Composite as Cathode Material for Lithium-Sulfur Battery.

The preparation and characterization of a polyaniline-silver-sulfur nanotube composite were reported in this paper. The polyaniline-silver nanotube composite was synthesized via an oxidation-reduction method in the sodium dodecyl sulfate (SDS) solution. After being vulcanized, the polyaniline-silver-sulfur (Poly (AN-Ag-S)) nanotube composite was prepared as active cathode material and assembled into lithium-sulfur (Li-S) batteries with electrolyte and negative electrode materials. When the feed ratio of raw materials (aniline and AgNO3) was 2:1, the initial specific capacity of poly (AN-Ag-S) composite cells reached 1114 mAh/g. The specific capacity was kept at 573 mAh/g, and the capacity retention rate stayed above 51% after 100 cycles. The introduction of Ag into the composite cathode material can effectively solve the poor conductivity of sulfur and improve the Li-S battery performance.

Lamellar Polypyrene Based on Attapulgite-Sulfur Composite for Lithium-Sulfur Battery.

We report on the preparation and characterization of a novel lamellar polypyrrole using an attapulgite-sulfur composite as a hard template. Pretreated attapulgite was utilized as the carrier of elemental sulfur and the attapulgite-sulfur-polypyrrole (AT @400 °C-S-PPy) composite with 50 wt.% sulfur was obtained. The structure and morphology of the composite were characterized with infrared spectroscopy (IR), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). An AT @400 °C-S-PPy composite was further utilized as the cathode material for lithium-sulfur batteries. The first discharge specific capacity of this kind of battery reached 1175 mAh/g at a 0.1 C current rate and remained at 518 mAh/g after 100 cycles with capacity retention close to 44%. In the rate test, compared with the polypyrrole-sulfur (PPy-S) cathode material, the AT @400 °C-S-PPy cathode material showed lower capacity at a high current density, but it showed higher capacity when the current came back to a low current density, which was attributed to the "recycling" of pores and channels of attapulgite. Therefore, the lamellar composite with special pore structure has great value in improving the performance of lithium-sulfur batteries.

Efficacy and safety of cenobamate in patients with uncontrolled focal seizures: A meta-analysis.

OBJECTIVE: To investigate the efficacy and safety of adjunctive cenobamate for treatment of uncontrolled focal seizures. METHODS: We performed a systematic search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE and Google Scholar to identify eligible studies. We included randomized placebo-controlled trials (RCTs) for uncontrolled focal seizures. We calculated the risk ratio (RR) of ≥50%, ≥75% and 100% reduction in seizure frequency from baseline, as well as dropout and serious adverse events related to treatment. Quality of included trials was assessed using the Cochrane Collaboration's tool. RESULTS: Two RCTs with a total of 658 patients were included. A significantly larger proportion of patients allocated to cenobamate achieved 50% seizure reduction (RR 2.06, 95% CI 1.70-2.51, p < 0.001) as compared to placebo, subgroup analysis demonstrated that the most effective dose was at 400 mg (RR 2.28, 95% CI 1.57-3.32, p < 0.001). Patients achieving seizure-freedom during the treatment period were 14.9% with cenobamate and 4.5% with placebo (RR 5.32, 95% CI 2.94-9.62, p < 0.001). Dropouts (RR 1.40, 95% CI 1.01-1.94, p = 0.05) and incidence of serious adverse events (RR 1.48, 95% CI 0.93-2.33, p = 0.1) were not significantly higher in patients receiving cenobamate. However, subgroup analyses based on doses suggested that patients exposed to 400 mg cenobamate were more likely to dropout than placebo (RR 2.09, 95% CI 1.17- 3.71, p = 0.012). CONCLUSION: Cenobamate demonstrated favourable efficacy for treatment of uncontrolled focal seizures and showed a dose-related fashion. Cenobamate could be well tolerated, the most common adverse events associated with cenobamate were dizziness, somnolence, fatigue, headache and nausea. Nevertheless, majority of them were mild to moderate in severity.

Systematic elucidation of the pharmacological mechanisms of Rhynchophylline for treating epilepsy via network pharmacology.

ABSTACT: BACKGROUND: Epilepsy, one of the most common neurological disorders, affects over 70 million people worldwide. Rhynchophylline displays a wide variety of pharmacologic actives. However, the pharmacologic effects of rhynchophylline and its mechanisms against epilepsy have not been systematically elucidated. METHODS: The oral bioavailability and druglikeness of rhynchophylline were evaluated using the Traditional Chinese Medicine Systems Pharmacology Database. Rhynchophylline target genes to treat epilepsy were identified using PharmMapper, SwissTargetPrediction and DrugBank databases integration. Protein-protein interaction analysis was carried out by utilizing the GeneMANIA database. WebGestalt was employed to perform Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The drug-disease-target-Gene Ontology-pathway network was constructed using Cytoscape. RESULTS: The oral bioavailability and druglikeness of rhynchophylline were calculated to be 41.82% and 0.57, respectively. A total of 20 rhynchophylline target genes related to epilepsy were chosen. Among the 20 genes and their interacting genes, 54.00% shared protein domains and 16.61% displayed co-expression characteristics. Gene ontology, Kyoto Encyclopedia of Genes and Genomes and network analyses illustrate that these targets were significantly enriched in regulation of sensory perception, morphine addiction, neuroactive ligand-receptor interaction and other pathways or biological processes. CONCLUSION: In short, rhynchophylline targets multiple genes or proteins, biological processes and pathways. It shapes a multiple-layer network that exerts systematic pharmacologic activities on epilepsy.

Efficacy and safety of fenfluramine in patients with Dravet syndrome: A meta-analysis.

BACKGROUND: Dravet syndrome (DS) is a severe, drug-resistant, developmental epileptic encephalopathy. Despite multiple anti-epileptic drug regimens, the syndrome remains poorly controlled and nearly half of patients still experience at least four tonic-clonic seizure per month. Recently, several clinical trials demonstrated that fenfluramine may provide a significant reduction in convulsive seizure frequency in the treatment of Dravet syndrome. METHODS: A computerized literature search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE, and Google Scholar was performed from inception until December 31, 2019. We included randomized placebo-controlled trials for the treatment of Dravet syndrome. We calculated the risk ratio (RR) of ≥50% and 100% reduction seizure frequency from baseline, along with the treatment-related withdrawals and serious adverse events, using the fixed-effect model. Quality assessment of included studies was performed with the Cochrane Collaboration's tool. KEY RESULTS: Two trials with a total of 206 patients were included. The pooled RR of 5.49 (95% CI 3.13-9.65) showed that a significantly greater proportion in the fenfluramine group achieved ≥50% reduction in monthly convulsive seizure frequency (MCSF). As for the complete seizure free rate, the pooled RR of 5.75 (95% CI 1.03-32.07) also demonstrated the favorable efficacy of fenfluramine, even though the difference was not statistically significant (p = 0.046). However, a significantly greater proportion of patients in the fenfluramine group experienced no more than one seizure during the treatment period (RR 13.82, 95% CI 2.68-71.27, p = 0.002). There were no significant differences in withdrawals and serious adverse events between the two treatment groups. No valvular heart disease or pulmonary arterial hypertension was observed in participants. The most common adverse events reported by included trials were diarrhea, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, decreased appetite, and weight loss. CONCLUSIONS: Fenfluramine is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency, and generally could be well tolerated.

Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia.

This study aimed to explore the underlying mechanism of relapsed acute lymphoblastic leukemia (ALL).Datasets of GSE28460 and GSE18497 were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between diagnostic and relapsed ALL samples were identified using Limma package in R, and a Venn diagram was drawn. Next, functional enrichment analyses of co-regulated DEGs were performed. Based on the String database, protein-protein interaction network and module analyses were also conducted. Moreover, transcription factors and miRNAs targeting co-regulated DEGs were predicted using the WebGestalt online tool.A total of 71 co-regulated DEGs were identified, including 56 co-upregulated genes and 15 co-downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in the cell cycle, and DNA replication, and repair related pathways. POLD1, MCM2, and PLK4 were hub proteins in both protein-protein interaction network and module, and might be potential targets of E2F. Additionally, POLD1 and MCM2 were found to be regulated by miR-520H via E2F1.High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL, and could serve as potential therapeutic targets for the treatment of relapsed ALL.

Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector.

Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-ß (Aß) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aß production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.

A meta-analysis of randomized controlled trials on levetiracetam in the treatment of pediatric patients with epilepsy.

OBJECTIVE: To evaluate clinical efficacy, safety, and tolerability of levetiracetam as mono- or adjunctive therapy in the treatment of children and adolescents with epilepsy. MATERIALS AND METHODS: We performed a meta-analysis of randomized controlled trials published from January 2007 to December 2016 in the databases Web of Science, Medline, Embase, Cochrane Library, and PubMed, Bing, Baidu, Google Scholar, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Data. All of the studies eligible were compared for the efficacy, safety, and tolerability of levetiracetam with other antiepileptic drugs (AEDs) in epilepsy. RESULTS: Thirteen randomized controlled trials on a total of 1,013 patients met the inclusion criteria in present study. Compared with other AEDs (oxcarbazepine, valproate, sulthiame, carbamazepine, and placebo), we found that levetiracetam had a comparable seizure-free rate (RR 1.16, 95% CI 1.03-1.31; P=0.30). Regarding seizure-frequency reduction ≥50% from baseline, levetiracetam also seemed equivalent to other AEDs (RR 1.08, 95% CI 1.01-1.16; P=0.35). In spite of patients treated with levetiracetam having a lower incidence of side effects compared with patients treated with other AEDs (RR 0.90, 95% CI 0.77-1.06), the difference between them was minute and not statistically significant (P=0.22). CONCLUSION: Based on this meta-analysis, it seemed that levetiracetam had comparable effects concerning efficacy, tolerability, and adverse events. Nevertheless, 13 studies were insufficient to draw a conclusion that levetiracetam is effective as mono- and adjunctive therapy for all types of epilepsy syndromes and seizures. Larger-sample and more well-designed trials are needed to justify the widespread use of levetiracetam in the treatment of children and adolescents.

Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis.

BACKGROUND: The aim of this meta-analysis was to investigate the prenatal, perinatal, and postnatal risk factors for children autism. METHODS: PubMed, Embase, Web of Science were used to search for studies that examined the prenatal, perinatal, and postnatal risk factors for children autism. A fixed-effects model or random-effects model was used to pool the overall effect estimates. RESULTS: Data from 37,634 autistic children and 12,081,416 nonautistic children enrolled in 17 studies were collated. During the prenatal period, the factors associated with autism risk were maternal and paternal age≥35 years, mother's and father's race: White and Asian, gestational hypertension, gestational diabetes, maternal and paternal education college graduate+, threatened abortion, and antepartum hemorrhage. During perinatal period, the factors associated with autism risk were caesarian delivery, gestational age≤36 weeks, parity≥4, spontaneous labor, induced labor, no labor, breech presentation, preeclampsia, and fetal distress. During the postnatal period, the factors associated with autism risk were low birth weight, postpartum hemorrhage, male gender, and brain anomaly. Parity≥4 and female were associated with a decreased risk of autism. In addition, exposure to cigarette smoking, urinary infection, mother's and father's race: Black and Hispanic, mother's country of birth outside Europe and North America, umbilical cord around neck, premature membrane rupture, 5-minutes Apgar score<7, and respiratory infection were not associated with increased risk of autism. CONCLUSION: The present meta-analysis confirmed the relation between some prenatal, perinatal, and postnatal factors with autism. All these factors were examined individually, thus it was still unclear that whether these factors are causal or play a secondary role in the development of autism. Further studies are needed to verify our findings, and investigate the effects of multiple factors on autism, rather than the single factor.