Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease.

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 µM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.

Cognitive behavioural therapy to improve social skills in children and adolescents with autism spectrum disorder: A meta-analysis of randomised controlled trials.

BACKGROUND: Cognitive behavioural therapy (CBT) is effective in treating various neurological and psychiatric diseases. It improves anxiety symptoms in children with autism spectrum disorder, gaining considerable empirical support. However, social skills results are mixed, leading to debate over its effectiveness, highlighting the need for further development. While the Social Responsiveness Scale (SRS) is a secondary indicator to measure anxiety symptoms, it primarily evaluates social skills, which are essential for rehabilitating children with autism. Therefore, evaluating social disorder improvement in children with autism is imperative. Social impairment is a core autism symptom. Therefore, we conducted a systematic review of randomised controlled trials assessing the effects of CBT on social skills in this population. METHODS: We reviewed articles published in several databases through October 2022 and relevant reference lists. We used the standardised mean difference (SMD) as the main effect size indicator and focused on SRS metrics from baseline to endpoint. We analysed subgroups, heterogeneity, bias risk, and publication bias. RESULTS: Our meta-analysis included 214 children from seven randomised controlled trials with nine datasets. Forest plot analysis shows CBT improved social skills in children with autism compared to controls. Subgroup analysis revealed parents' and teachers' SRS scores for children, SRS scores of CBT versus waitlist controls, and those of CBT versus non-waiting-list controls. LIMITATIONS: Most randomised controlled CBT trials for children with autism have explored anxiety symptom improvement. Further, social skill assessment was a secondary outcome or not assessed. Thus, social skills data are insufficient. CONCLUSIONS: CBT is effective in improving social impairment in children with autism. REGISTRATION: This meta-analysis was registered with the International Prospective Register of Systematic Reviews (CRD42022363423).

Systematic bibliometric and visualized analysis of research hotspots and trends in artificial intelligence in autism spectrum disorder.

Background: Artificial intelligence (AI) has been the subject of studies in autism spectrum disorder (ASD) and may affect its identification, diagnosis, intervention, and other medical practices in the future. Although previous studies have used bibliometric techniques to analyze and investigate AI, there has been little research on the adoption of AI in ASD. This study aimed to explore the broad applications and research frontiers of AI used in ASD. Methods: Citation data were retrieved from the Web of Science Core Collection (WoSCC) database to assess the extent to which AI is used in ASD. CiteSpace.5.8. R3 and VOSviewer, two online tools for literature metrology analysis, were used to analyze the data. Results: A total of 776 publications from 291 countries and regions were analyzed; of these, 256 publications were from the United States and 173 publications were from China, and England had the largest centrality of 0.33; Stanford University had the highest H-index of 17; and the largest cluster label of co-cited references was machine learning. In addition, keywords with a high number of occurrences in this field were autism spectrum disorder (295), children (255), classification (156) and diagnosis (77). The burst keywords from 2021 to 2023 were infants and feature selection, and from 2022 to 2023, the burst keyword was corpus callosum. Conclusion: This research provides a systematic analysis of the literature concerning AI used in ASD, presenting an overall demonstration in this field. In this area, the United States and China have the largest number of publications, England has the greatest influence, and Stanford University is the most influential. In addition, the research on AI used in ASD mostly focuses on classification and diagnosis, and "infants, feature selection, and corpus callosum are at the forefront, providing directions for future research. However, the use of AI technologies to identify ASD will require further research.

Why do children with autism spectrum disorder have abnormal visual perception?

Autism spectrum disorder (ASD) is associated with severe impairment in social functioning. Visual information processing provides nonverbal cues that support social interactions. ASD children exhibit abnormalities in visual orientation, continuous visual exploration, and visual-spatial perception, causing social dysfunction, and mechanisms underlying these abnormalities remain unclear. Transmission of visual information depends on the retina-lateral geniculate nucleus-visual cortex pathway. In ASD, developmental abnormalities occur in rapid expansion of the visual cortex surface area with constant thickness during early life, causing abnormal transmission of the peak of the visual evoked potential (P100). We hypothesized that abnormal visual perception in ASD are related to the abnormal visual information transmission and abnormal development of visual cortex in early life, what's more, explored the mechanisms of abnormal visual symptoms to provide suggestions for future research.

Exploring the mechanism of Chaihujia Longgu Muli decoction in the treatment of epilepsy in rats based on the RhoA/ROCK signaling pathway.

BACKGROUND: The Chinese herbal formula Chaihujia Longgu Muli Decoction (CD) has a good antiepileptic effect, but its mechanisms remain unclear. Therefore, in this study we explored the molecular mechanisms of CD against epilepsy. METHODS: Twelve-day-old SD rats were randomly divided into a normal group, model group, valproic acid group, and CD high, medium, and low groups. Except for the normal group, the other groups were given an intraperitoneal injection of pentylenetetrazol (PTZ) to establish epilepsy models, and the Racine score was applied for model judgment. After 14 consecutive days of dosing, the Morris water maze test was performed. Then, hippocampal Nissl staining and immunofluorescence staining were performed, and synaptic ultrastructure was observed by transmission electron microscopy (TEM). RhoA/ROCK signaling pathway proteins were detected. RESULTS: In PTZ model rats, the passing times were reduced, and the escape latency was prolonged in the Morris water maze test. Nissl staining showed that some hippocampal neurons swelled and ruptured, Nissl bodies in the cytoplasm were significantly reduced, and neurons were lost. Immunofluorescence detection revealed that the expression of PSD95 and SYP was significantly reduced. Electron microscopy results revealed that the number of synapses in hippocampal neurons was significantly reduced and the postsynaptic membrane length was significantly reduced. Western blot analysis showed that the RhoA/ROCK signaling pathway was activated, while SYP, SPD95, and PTEN expression was significantly decreased. After treatment with CD, neurobehavioral abnormalities and neuronal damage caused by epileptic seizures were improved. CONCLUSION: CD exerted an antiepileptic effect by inhibiting the activation of the RhoA/ROCK signaling pathway.

Children autism spectrum disorder and gut microbiota: A bibliometric and visual analysis from 2000 to 2023.

Autism spectrum disorder (ASD) has evolved from a narrow and rare childhood-onset disorder to a widely publicized and researched lifelong disease recognized as common and significantly heterogeneous. Researchers have suggested that gastrointestinal symptoms in ASD may be a manifestation of an underlying inflammatory process. However, there is a lack of bibliometric analysis of ASD and gut microbiota in children. Accordingly, this study conducts a bibliometric analysis of ASD and gut microbiota in children from 2000 to 2023, explores the current status and cutting-edge trends in the field of ASD and gut microbiota in children, and identifies new directions for future research. The literature on ASD and gut microbiota in children was screened using the Web of Science Core Collection from 2000 to 2023. Annual publications, countries, institutions, authors, journals, keywords, and references were visualized and analyzed using CiteSpace 5.8. R3 and VOSviewer1.6.18. This study included 1071 publications. Since the beginning of 2011, the overall number of articles shows an upward trend. The most productive country and institution are the United States and the University of California system, respectively. The most frequently cited author is Kang Dae-Wook, with 790 citations, who has contributed significantly to this field. Timothy Dinan is the most prolific author, with 34 articles. The journal with the most published articles on this topic is Nutrients, whereas PLOS One is the most cited journal. The most used keyword is "gut microbiota," and the reference for the highest outbreak intensity is Hsiao. The research hotspots and trends predicted in this study provide a reference for further in-depth research in this field.

Identifying patients with EVEN-plus syndrome using exome sequencing and clinical feature analysis: A case report.

BACKGROUND: The EVEN-plus syndrome (epiphyseal-vertebral-ear-nose dysplasia plus associated findings) is an extremely rare autosomal recessive inherited disease characterised by specific facial features and skeletal dysplasia. It has a prenatal onset due to defects in the HSPA9 gene. The syndrome has not been reported previously in China. METHODS: This study reported the characteristics, examination results, diagnosis and treatment of a female case aged 3 years and 3 months. RESULTS: The patient had global developmental delay and specific facial features, including a prominent forehead, a bilateral auricle deformity, a collapsed nose, a high palatine arch, a short neck and other appearance abnormalities. Her hip joint magnetic resonance imaging (MRI) results showed bilateral femoral head epiphyseal dysplasia with a fork-shaped malformation at the distal end, and her brain MRI showed white matter myelin dysplasia. HSPA9 compound heterozygous variants c.882_c.883delAG and c.613A>G were identified by exome sequencing. CONCLUSIONS: This finding expands the spectra of EVEN-plus syndrome phenotype and pathogenic variants and suggests that c.882_c.883delAG may have a higher distribution frequency in East Asian populations.

Cucumber-Derived Nanovesicles Containing Cucurbitacin B for Non-Small Cell Lung Cancer Therapy.

Purpose: In recent years, a variety of nanoparticles with excellent anticancer and delivery properties have emerged for cancer therapy. However, potential toxicity, high production cost and complex preparation procedures have been obstacles to their use in biomedicine. Here, we obtained cucumber-derived nanovesicles (CDNVs) at high yield and low cost by simple juicing and ultracentrifugation. The anticancer effects of CDNVs were evaluated in vitro and in vivo. Methods: Transmission electron microscope, nanoparticle tracking analysis and laser particle size analysis were used to characterize the morphology, diameter and zeta potential of CDNVs, respectively. The anticancer effects of CDNVs in vitro were evaluated by MTT and apoptosis assays. The mechanism was further explored by measuring the protein levels of signal transducer and activator of transcription 3 pathway, reactive oxygen species, cell cycle distribution and caspase activity. In-vivo anticancer efficacy was evaluated by measuring tumor volume and weight of mice in three different treatment groups (CDNVs, cucurbitacin B and PBS). Results: CDNVs inhibited proliferation of human non-small cell lung cancer cells by suppressing signal transducer and activator of transcription 3 activation, generating reactive oxygen species, promoting cell cycle arrest, and activating the caspase pathway. These CDNVs exhibited strong anticancer effects both in vitro and in vivo, and reduced the rate of tumor growth without obvious toxicity to mouse visceral organs. Compared with an equivalent dose of cucurbitacin B, CDNVs exerted stronger anticancer effects in vitro and in vivo. Conclusion: These results demonstrate that CDNVs suppress tumor growth. This study addresses the development of cancer therapeutic drugs using plant-derived nanovesicles that are cost-efficient, simple to produce in high yields, and provide an alternative approach to drug isolation that may help advance sustainability of medicinal plants.

Psychotherapy Combined with Western Medicine in the Treatment of Children with Tic Disorder: Systematic Review and Meta-Analysis.

Objective: To evaluate the efficacy of psychotherapy in children with tic disorder and to provide basis for the application of psychotherapy in the treatment of children with tic disorder. Methods: A detailed search was conducted based on PubMed, Cochrane library database, CNKI, Wanfang Data, and VIP database to determine the randomized controlled trial (RCT) of psychotherapy combined with drugs and oral drugs in the treatment of tic disorder. The search time was from the establishment of the database to August 20, 2021. All kinds of extracted data are meta analyzed, and the statistical software used is Review Manager 5.3 software. Results: According to the inclusion and exclusion criteria, 14 clinical trials were finally included, including 513 TD children, including 267 in the psychological intervention group and 246 in the control group. All trials were conducted in China and published from 2013 to 2021. In terms of clinical efficacy, compared with the control group, the psychotherapy combined with drugs group had more advantages in improving the effective rate (RR = 3.25, 95% CI: 2.17~4.85, Z = 5.74, P < 0.00001) and improving the clinical symptoms of children with TD (WM = -5.36, 95% CI: -6.41 ~ -4.30, Z = 9.97, P < 0.00000 1). Conclusion: Psychotherapy as an adjuvant therapy for clinical treatment of TD can improve the clinical efficacy, but due to the low methodological quality of the existing trials, the research may have potential bias. In the future, large sample, multicenter, and double-blind randomized controlled trials need to be carried out to provide further support.

[Effect of baicalin on growth state of attention deficit hyperactivity disorder animal model and its regulation on Ca MKâ ¡ and ERK1/2].

The aim of this study was to observe the effect of baicalin on the growth state of attention deficit hyperactivity disorder animal model and its regulation on Ca MKⅡand ERK1/2.In the present study,a total of 40 SHR rats were randomly divided into model group,methylphenidate hydrochloride group,and low,medium,and high dose baicalin groups,with 8 rats in each group.Eight WKYrats were selected as a normal control group.The methylphenidate hydrochloride group(0.07 g·L~(-1))and the low(3.33 g·L~(-1)),medium(6.67 g·L~(-1)),and high dose(10 g·L~(-1))baicalin groups received corresponding drugs by gavage administration according to the body weight(0.015 m L·g~(-1)),while the normal group and the model group received the same volume of normal saline by gavage.Thegavage administration lasted for 4 weeks,twice a day.The body weight of the rats and the amount of remaining feed were weighed daily,and the growth state of the rats was statistically evaluated weekly.Percoll density gradient centrifugation was used to prepare brain synaptosomes and an electron microscope was used to observe their structures.The Ca MKⅡand ERK1/2 protein and mRNA expression levels were detected with Western blot and Real-time PCR methods,respectively.RESULTS: showed that baicalin did not affect the normal eating and weight gain of rats,and the weight gain of rats was even more significant than that in the normal group(P<0.05).In the study of its effects on Ca MKⅡand ERK1/2 protein expression in rat synaptosomes,the expression of both proteins in each drug-administered group was higher than that in the model group(P<0.05);besides,the expression levels of Ca MKⅡand ERK1/2 protein were significantly increased in both baicalin high dose group and the methylphenidate hydrochloride group(P<0.05).The relative expression of Ca MKⅡand ERK1/2 mRNA in synaptosome was detected by PCR.The results showed that medium and high doses of baicalin and methylphenidate hydrochloride significantly increased the relative expression of Ca MKⅡand ERK1/2 mRNA in synaptosomes of SHR rats(P<0.05).In conclusion,baicalin does not affect the normal growth and development of SHR rats,so it is safe for administration.Both baicalin and methylphenidate hydrochloride could up-regulate the relative expression of Ca MKⅡand ERK1/2 in mRNA and protein,and the pharmacodynamic stability of baicalin is in a dose-dependent manner to certain extent.

Baicalin regulates the dopamine system to control the core symptoms of ADHD.

We aimed to test the therapeutic effects of baicalin on attention deficit hyperactivity disorder (ADHD) in an animal model and to explain the potential mechanism. We investigated the therapeutic effects and mechanisms of baicalin in a spontaneously hypertensive rat (SHR) model of ADHD depending on the dopamine (DA) deficit theory. In this study, fifty SHRs were randomly divided into five groups: methylphenidate (MPH), baicalin (50 mg/kg, 100 mg/kg, or 150 mg/kg), and saline-treated. Ten Wistar Kyoto (WKY) rats were used as controls. All rats were orally administered the treatment for four weeks. Motor activity, spatial learning and memory ability were assessed with the open-field and Morris water-maze tests. The mRNA and protein levels of tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), synaptosomal-associated protein of molecular mass 25kD (SNAP25) and synataxin 1a in synaptosomes were detected with real-time polymerase chain reaction (PCR) and Western blot. In addition, DA levels were measured in the prefrontal cortex and striatum. The results indicated that both MPH and baicalin at doses of 150 mg/kg and 100 mg/kg significantly decreased the hyperactivity and improved the spatial learning memory deficit in the SHRs and increased the synaptosomal mRNA and protein levels of TH, SNAP25, VMAT2 and synataxin 1a compared with saline treatment. MPH significantly increased DA levels in both the prefrontal cortex (PFC) and striatum, while baicalin significantly increased DA levels only in the striatum. The results of the present study showed that baicalin treatment was effective for controlling the core symptoms of ADHD. Baicalin increased DA levels only in the striatum, which suggested that baicalin may target the striatum. The increased DA levels may partially be attributed to the increased mRNA and protein expression of TH, SNAP25, VMAT2, and syntaxin 1a. Therefore, these results suggested that the pharmacological effects of baicalin were associated with the synthesis, vesicular localization, and release of DA and might be effective in treating ADHD. However, further studies are required to better understand the molecular mechanisms underlying these findings.

The Study of Effect for General Movements Assessment in the Diagnosis of Neurological Development Disorders: A Meta-Analysis.

OBJECTIVE: To discuss the value of general movements assessment in predicting the neurological disorders. METHODS: Using PubMed as the search engine, we searched to identify relevant studies in English and Chinese language published up to November 2014 and 19 studies were selected. Standard methods in meta-analyses were used to provide diagnostic accuracy by Meta-DiSc 1.4. RESULTS: For non-cerebral palsy (non-CP) as outcome for writhing period, the results suggested a good sensitivity and a specificity of 0.74, the Q-value was 0.80. The area under the curve (AUC) was 0.87. For non-CP as outcome for fidgety period, the results suggested both high level for sensitivity and specificity. And the Q-value was 0.914, the AUC was 0.9664. For CP as outcome for writhing and fidgety periods, good sensitivity and specificity were found in the analysis, and the Q-value was 0.9034 while the AUC was 0.9592. CONCLUSION: General movements assessment is a good predictor for diagnosing neurological disorders.

[Analysis of Applying Chinese Medical Clinical Pathway for Treating Attention-deficit Hyperactivity Disorder].

OBJECTIVE: To evaluate the application effect of Chinese medical clinical pathway for treating attention-deficit hyperactivity disorder (ADHD), and to provide evidence for further improving clinical pathways. METHODS: Totally 270 ADHD children patients were recruited and treated at pediatrics clinics of 9 cooperative hospitals from December 2011 to December 2012. The treatment course for all was 3 months. Scores of attention deficit and hyperactivity rating scale, scores of behavior, Conners index of hyperactivity (CIH), and Chinese medical syndrome scores were compared between before and after treatment. The efficacy difference in various sexes, ages, and disease courses were evaluated by judging standards for Chinese medical syndrome and ADHD. RESULTS: Fifteen children patients who entered clinical pathway dropped out, and the rest 255 completed this trial. Compared with before treatment, total scores of attention deficit and hyperactivity rating scale, scores of attention deficit and hyperactivity rating scale, CIH, and Chinese medical syndrome scores obviously decreased (all P < 0.01). The total effective rate in disease efficacy was 87.8% (224/255 cases), and the total effective rate in Chinese medical syndrome curative effect was 87.5% (223/255 cases). The clinical curative effect was not influenced by age, gender, or course of disease when statistically analyzed from judging standards for Chinese medical syndrome or for disease efficacy. CONCLUSION: Intervention by Chinese medical clinical pathway could improve ADHD patients' symptoms, and its efficacy was not influenced by sex, age, or course of disease.

Health care-associated respiratory infection surveillance among Chinese children with cerebral palsy.

BACKGROUND: To explore the characteristics and distribution of hospital length of stay (LOS) and direct hospitalization costs of children with cerebral palsy (CP) affected by health care-associated infection (HAI). METHODS: A prospective observational study was performed from March 2010 to February 2012 on HAI cases among hospitalized children with CP. Demographic, clinical, and HAI data were recorded. Mann-Whitney test, chi-square test, and multiple linear regressions were used for data analysis. RESULTS: Of 528 patients with CP, 151 (28.6%) suffered HAI in the form of respiratory tract infection. Male to female ratio was 2.87. About 50 patients had recurrent HAI. Upper respiratory infection and pneumonia were common infections. HAI occurring more than once contributed mainly to total LOS, and the length of HAI was >10 days in >50% of patients. Frequency of HAI was an independent predictor of LOS, and frequency of HAI and LOS were independent predictors of hospitalization costs. CONCLUSION: Health care-associated respiratory infection significantly impacted LOS and total cost of children with CP admitted for rehabilitation. These data should assist in establishing preventive and control measures for HAI to help improve the quality of rehabilitation and survival in the long run.

Methylenetetrahydrofolate reductase gene polymorphisms and cerebral palsy in Chinese infants.

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been suggested as being associated with cerebral palsy (CP) but the evidence is uncertain. The purpose of this study was to investigate whether MTHFR gene polymorphisms contribute to the development of CP in Chinese infants. For this study, 169 health controls and 159 infants with CP including 43 cases also suffering from mental retardation (MR) were recruited. Genomic DNA was prepared from venous blood and all five single nucleotide polymorphisms in MTHFR (rs4846049, rs1476413, rs1801131, rs1801133 and rs9651118) were genotyped using TaqMan technology. There were no significant differences in allele or genotype frequencies between the CP patients and controls at any of the five genetic polymorphisms. Subgroup analysis found statistically significant difference in allele and genotype frequencies between cases with both CP and MR (CP + MR) compared with both CP-only cases and controls at rs4846049, rs1476413 and rs1801131. The frequencies of the T alleles of rs4846049, rs1476413 and the G allele of rs1801131 were greater in the CP + MR patients than in the CP-only patients and controls. This study provides the first evidence pointing to a MTHFR gene polymorphism as a potential risk factor for CP combined with MR.

[Clinical observation on plum-blossom needle on Governor Vessel and point Jiaji (EX-B 2) for treatment of cerebral palsy of involuntary movement].

OBJECTIVE: To probe into an effective therapy for treatment of cerebral palsy of involuntary movement. METHODS: Sixty cases were randomly divided into two groups, the control group was treated with routine rehabilitation method (Bobath + Tuina + scalp acupuncture), while the observation group was treated with plum-blossom needle on Governor Vessel and point Jiaji (EX-B 2) on the basis of routine rehabilitation method. After 3 months of treatment, therapeutic effect, total percentage of Gross Motor Function Measurement (GMFM), incurvation reflex and muscular tension fluctuation were compared. RESULTS: The obvious effective rate of 53.3% (16/30) in the observation group was superior to that of 20.0% (6/30) in the control group (P < 0.05); the total percentage of GMFM increased, incurvation reflex disappeared, muscular tension fluctuation relieved in both groups after treatment (P < 0.05, P < 0.01), but the indices above all improved more significantly in the observation group than those in the control group (P < 0.05, P < 0.01). CONCLUSION: Plum-blossom needle on Governor Vessel and point Jiaji (EX-B 2) on the basis of routine rehabilitation method for treatment of cerebral palsy of involuntary movement can enhance the gross motor function, make the incurvation reflex disappear effectively, relieve the muscular tension fluctuation.