Bumetanide has been reported to alter synaptic excitation-inhibition (E-I) balance by potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score ≥ 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.

Objective: As two common neurodevelopmental disorders, autistic spectrum disorder and attention deficit hyperactivity disorder frequently occur together. Until now, only a few studies have investigated the co-occurrence of attention deficit hyperactivity disorder and autistic spectrum disorder, this is due to restrictions associated with previous Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Most previous research has focused on the developmental trajectories for autistic spectrum disorder and attention deficit hyperactivity disorder separately, while the neural mechanisms underpinning the co-occurrence of autistic spectrum disorder and attention deficit hyperactivity disorder remain largely unknown. Methods:We studied 162 autistic spectrum disorder individuals (including 79 co-attention deficit hyperactivity disorder and 83 non-attention deficit hyperactivity disorder patients) and 177 typical developing individuals using resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange II, an aggregated magnetic resonance imaging dataset from 19 centers. Independent component analysis was used to extract sub-networks from the classic resting-state networks. Functional connectivity values within (intra-iFC) and between (inter-iFC) these networks were then determined. Subsequently, we compared the ASD_coADHD group with the ASD_nonADHD group in relation to the abnormal intra-iFC and inter-iFC of autistic spectrum disorder group relative to the typical developing group. Results:The ASD_coADHD group showed more severe social impairment and decreased intra-iFC in the bilateral posterior cingulate cortex of the default mode network (independent component 17) and increased inter-iFC between the default mode network (independent component 8) and the somatomotor networks (independent component 2) compared to the ASD_nonADHD group. In addition, the strength of the intra-iFC in the default mode network was associated with the severity of autistic traits across the entire autistic spectrum disorder group and particularly the ASD_coADHD group. Conclusion:Our results showed that dysfunction of the default mode network is a central feature in the co-occurrence of autistic spectrum disorder and attention deficit hyperactivity disorder, including connectivity within the default mode network as well as between the default mode network and the somatomotor networks, thus supporting the existence of a clinically combined phenotype (autistic spectrum disorder + attention deficit hyperactivity disorder).

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With the drug therapy for the core symptoms of autism spectrum disorder (ASD) currently limited, here we reported a randomised, double-blind, placebo-controlled trial to investigate the efficacy, safety, and potential neural mechanism of bumetanide in children with ASD aged 3 to 6 years old. In this trial, 120 children with ASD were 1:1 randomly assigned to receive 0.5 mg bumetanide or placebo orally twice daily for 3 months. The primary outcome was the score reduction of Childhood Autism Rating Scale (CARS) and the secondary outcomes were the score of Clinical Global Impressions (CGI) Improvement scale (CGI-I) at 3 months and the change from baseline to 3-month in Autism Diagnostic Observation Schedule (ADOS). Magnetic resonance spectroscopy (MRS) was used to measure γ-aminobutyric acid (GABA) and glutamate neurotransmitter concentrations in the insular cortex (IC) before and after the treatment. As compared with the placebo, bumetanide treatment was significantly better in reducing severity. No patient withdrew from the trial due to adverse events. The superiority of bumetanide to placebo in reducing insular GABA, measured using MRS, was demonstrated. The clinical improvement was associated with the decrease in insular GABA in the bumetanide group. In children with predominantly moderate and severe ASD, the treatment of bumetanide at a dose of 0.5 mg twice daily attenuated the core symptoms, as compared with placebo, with few adverse events. The neuroimaging data demonstrated that bumetanide decreased GABA levels in insular cortex, which was associated with symptom reduction.

Chromosome microarray analysis (CMA) is a cost-effective molecular cytogenetic technique that has been used as a first-line diagnostic test in neurodevelopmental disorders in the USA since 2011. The impact of CMA results on clinical practice in China is not yet well studied, so we aimed to better evaluate this phenomenon. We analyzed the CMA results from 434 patients in our clinic, and characterized their molecular diagnoses, clinical features, and follow-up clinical actions based on these results. The overall diagnostic yield for our patients was 13.6% (59 out of 434). This gave a detection rate of 14.7% for developmental delay/intellectual disability (DD/ID, 38/259) and 12% for autism spectrum disorders (ASDs, 21/175). Thirty-three recurrent (n ≥ 2) variants were found, distributed at six chromosomal loci involving known chromosome syndromes (such as DiGeorge, Williams Beuren, and Angelman/Prader-Willi syndromes). The spectrum of positive copy number variants in our study was comparable to that reported in Caucasian populations, but with specific characteristics. Parental origin tests indicated an effect involving a significant maternal transmission bias to sons. The majority of patients with positive results (94.9%) had benefits, allowing earlier diagnosis (36/59), prioritized full clinical management (28/59), medication changes (7/59), a changed prognosis (30/59), and prenatal genetic counseling (15/59). Our results provide information on de novo mutations in Chinese children with DD/ID and/or ASDs. Our data showed that microarray testing provides immediate clinical utility for patients. It is expected that the personalized medical care of children with developmental disabilities will lead to improved outcomes in long-term developmental potential. We advocate using the diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility.

Hematopoietic stem cells (HSCs) aging is associated with hematopoietic dysfunction and diseases. Our previous study showed that lead exposure induced a functional decline in HSCs. Allicin, a chemical extracted from the garlic (Allium sativum L.), has been reported to have antioxidative and anti-inflammatory effects. However, the biological activities of allicin on lead-induced toxicity, especially in the hematopoietic system, remain unclear. Here, we found that lead exposure elicited aging phenotypes in HSCs, including perturbed cell quiescence, disabled self-renewal function and colony-forming ability, and myeloid-biased differentiation, all of which contributed to significant hematopoietic disorders in mice. Intragastric administration of allicin substantially ameliorated lead-induced HSCs aging phenotypes in vivo. Lead exposure induced a peroxide condition in HSCs leading to DNA damage, which reduced expression of the glycolytic enzyme pyruvate kinase M2 isoform (PKM2), a phenotype which was significantly ameliorated by allicin treatment. These findings suggested that allicin alleviated lead-induced HSCs aging by up-regulating PKM2 expression; thus, it could be a natural herb for preventing lead toxicity.

Glioblastoma is one of the most aggressive primary brain tumors with few treatment strategies. β-Elemene is a sesquiterpene known to have broad spectrum antitumor activity against various cancers. However, the signaling pathways involved in β-elemene induced apoptosis of glioblastoma cells remains poorly understood. In this study, we reported that β-elemene exhibited antiproliferative activity on U87 and SHG-44 cells, and induced cell death through induction of apoptosis. Incubation of these cells with β-elemene led to the activation of caspase-3 and generation of reactive oxygen species (ROS). Western blot assay showed that β-elemene suppressed phosphorylation of STAT3, and subsequently down-regulated the activation of p-JAK2 and p-Src. Moreover, pre-incubation of cells with ROS inhibitor N-acetyl-L-cysteine (NAC) significantly reversed β-elemene-mediated apoptosis effect and down-regulation of JAK2/Src-STAT3 signaling pathway. Overall, our findings implied that generation of ROS and suppression of STAT3 signaling pathway is critical for the apoptotic activity of β-elemene in glioblastoma cells.

ObjectivesThe aim of this study was to assess comorbidity patterns and functional impairment in children with and without attention deficit hyperactivity disorder (ADHD).DesignHospital-based retrospective cross-sectional study; data collection occurred between 2016 and 2019.Settings and patientsA total of 8256 children and adolescents, 6–17 years of age, with suspected ADHD agreed to participate in this hospital-based cross-sectional study over a 4-year period in China. Comorbidities and social functions were assessed according to the scales Vanderbilt ADHD Diagnostic Parent Rating Scale and Weiss Functional Impairment Rating Scale-Parent Form, which were completed by the parents of the study participants.ResultsOf the 8256 children, 5640 were diagnosed with ADHD. Other 2616 children who did not meet the ADHD diagnostic criteria were classified as the N-ADHD group . The proportion of comorbidities (47.4%) and functional impairments (84.5%) in the ADHD group were higher than the N-ADHD group (p≤0.001). The functional impairment scores in all of the six domains, including family, academic, life skills, self-concept, social activities and risky activities, were significantly higher in the ADHD group than the N-ADHD group (p≤0.001). The functional impairment in ADHD group with comorbidities was more severe than those without comorbidities (p≤0.001). Comorbidities and core symptoms both can affect the functions of children with ADHD. Logistics regression analysis indicated that in all of the six functional domains, the effect of comorbidities on functional impairment exceeded the effects of ADHD core symptoms.ConclusionsComorbidities had the greatest influence on different areas of adaptive functioning in children with ADHD. Clinical management of children suspected to have ADHD should address multiple comorbidities and functional impairments assessment, as well as core symptom analysis.