The activity of cholinergic neurons in the basal forebrain interferes with anesthesia-arousal process of propofol.

Previous research has demonstrated that basal forebrain (BF) regulates arousal during propofol anesthesia. However, as the BF comprises cholinergic neurons alongside two other types of neurons, the specific role of cholinergic neurons has not been definitively elucidated. In our study, calcium signal imaging was utilized to monitor the real-time activities of cholinergic neurons in the BF during propofol anesthesia. Additionally, we selectively stimulated these neurons to investigate EEG and behavioral responses during propofol anesthesia. Furthermore, we specifically lesioned cholinergic neurons in the BF to investigate the sensitivity to propofol and the induction time. The results revealed that propofol suppressed calcium signals of cholinergic neurons within the BF following intraperitoneal injection. Notably, upon recovery of the righting reflex, the calcium signals partially recovered. Spectral analysis of the EEG elucidated that optical stimulation of cholinergic neurons led to a decrease in δ power underlie propofol anesthesia. Conversely, depletion of cholinergic neurons in the BF enhanced sensitivity to propofol and shortened the induction time. These findings clarify the role of cholinergic neurons in the anesthesia-arousal process, as well as the depth and the sensitivity of propofol anesthesia.

Airways epithelial exposure to Streptococcus pneumoniae in the presence of the alarmin IL-33 induces a novel subset of pro-inflammatory ILC2s promoting a mixed inflammatory response.

BACKGROUND: We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored. METHODS: Airways inflammation was induced by repeated, intranasal exposure of Il-4-/-, Rag1-/- and Rag2-/-Il2rg-/- mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry. RESULTS: In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4-/- and Rag1-/- deficient mice but abolished in the Rag2-/-Il2rg-/- mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1+Ly6a+subset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses. CONCLUSION: Local accumulation of KLRG1+Ly6a+ ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.

Comparative Study on the Satisfaction of Healthcare Service Providers with the Synergistic Development of Rural Healthcare Systems in China: Medical Alliance Counties vs. Non-Medical Alliance Counties.

Introduction: This study aimed to explore whether the establishment of county medical alliances can improve satisfaction with the vertical integration of healthcare systems among rural medical and healthcare service provider managers and service providers. Our study also sought to provide recommendations for the sustainable development of vertical integration in healthcare systems. Methods: A semi-structured interview with 30 healthcare service providers was employed in this research, and Nvivo software was utilized to analyze factors that influence vertical integration. From April to July 2021, a multi-stage random sampling method was used to select participants. The sample included two leading hospitals in medical consortia, 15 member units (healthcare service providers and medical staff), two county-level hospitals, and 15 township health centers/community healthcare service centers from non-medical consortia. Questionnaire surveys were conducted with these groups. Factor analysis was used to calculate satisfaction scores for healthcare service providers with the cross-institutional synergistic development of healthcare systems in both medical and non-medical consortia (denoted as M(IQR)). Propensity score matching was employed to reduce confounding factors between groups. The Mann-Whitney U test was used to compare satisfaction differences between groups. Results: The overall satisfaction scores for lead-county hospital managers, member institution managers, medical staff at the lead-county hospital, and medical staff at member institutions were 4.80 (1.00), 4.17 (1.17), 4.00 (1.38), and 4.00 (1.12), respectively. Lead-county hospital managers' satisfaction with cross-institutional collaboration, development capacity enhancement, and structure and resource integration in the Medical Alliance group showed higher satisfaction than the Non-Medical Alliance. Similarly, lead-county hospital medical staff in the Medical Alliance group reported greater satisfaction with collaboration efforts, supportive environment, and development capacity enhancement. Notably, while the Medical Alliance group's satisfaction scores were higher, the differences between the two groups were not statistically significant for lead-county hospital managers and medical staff. The Medical Alliance group did show statistically significant differences in member institution managers' satisfaction with collaboration, development capacity enhancement, and structure and resource integration. Additionally, medical staff of member institutions in the Medical Alliance group reported statistically significant higher satisfaction with collaboration, supportive environment, development capacity enhancement, healthcare service integration, and human resource development. Conclusion: To facilitate the establishment of county medical alliances, managers of leading county-level hospitals should adopt a healthcare system integration strategy. This strategy involves evolution from being a member of a single institution to a coordinator of cross-institutional vertical integration of medical and healthcare services. Additionally, revamping remuneration and appraisal systems for members of county medical alliances is necessary. This will encourage cooperation among healthcare institutions within the three-tiered system and their medical staff, ultimately facilitating the provision of integrated services.

Decoding Cosmetic Complexities: A Comprehensive Guide to Matrix Composition and Pretreatment Technology.

Despite advancements in analytical technologies, the complex nature of cosmetic matrices, coupled with the presence of diverse and trace unauthorized additives, hinders the application of these technologies in cosmetics analysis. This not only impedes effective regulation of cosmetics but also leads to the continual infiltration of illegal products into the market, posing serious health risks to consumers. The establishment of cosmetic regulations is often based on extensive scientific experiments, resulting in a certain degree of latency. Therefore, timely advancement in laboratory research is crucial to ensure the timely update and adaptability of regulations. A comprehensive understanding of the composition of cosmetic matrices and their pretreatment technologies is vital for enhancing the efficiency and accuracy of cosmetic detection. Drawing upon the China National Medical Products Administration's 2021 Cosmetic Classification Rules and Classification Catalogue, we streamline the wide array of cosmetics into four principal categories based on the following compositions: emulsified, liquid, powdered, and wax-based cosmetics. In this review, the characteristics, compositional elements, and physicochemical properties inherent to each category, as well as an extensive overview of the evolution of pretreatment methods for different categories, will be explored. Our objective is to provide a clear and comprehensive guide, equipping researchers with profound insights into the core compositions and pretreatment methods of cosmetics, which will in turn advance cosmetic analysis and improve detection and regulatory approaches in the industry.

Staphylococcus aureus lysate induces an IgE response via memory B cells in nasal polyps.

BACKGROUND: Locally increased IgE levels plays a pathologic role in chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: This study aimed to investigate whether Staphylococcus aureus could induce aberrant IgE synthesis in CRSwNP and the potential mechanisms involved. METHODS: Total IgE, IL-4, IL-5, and IL-13 concentrations in the supernatants of the cultures stimulated with S aureus lysate were assessed by ELISA. S aureus-induced cellular responses were investigated by single-cell RNA sequencing. Flow cytometry and quantitative reverse transcription PCR were used to analyze B-cell subsets and stimulated cell ε-germline transcript expression, respectively. IgE-positive B-cell and germinal center localization were assessed by immunohistochemistry and immunofluorescence. RESULTS: S aureus lysate induced IgE production in the supernatants of nasal polyp (NP) tissues but not in those of healthy nasal mucosa. Moreover, IgE levels increased from days 2 to 4 after stimulation, paralleling the enhanced ε-germline transcript, IL-5, and IL-13 expression. Single-cell RNA sequencing revealed that there were increased IL-5 and IL-13 in group 2 innate lymphoid cells and identified a clonal overlap between unstimulated memory B cells and S aureus-stimulated plasma cells. The enriched IgE within NPs was mainly produced by IgE-negative memory B cells. Cellular evidence indicated that the IgE memory response to S aureus might also exist in the peripheral blood of CRSwNP patients. The S aureus-induced IgE memory response was associated with elevated IgE levels in NPs, asthma, and postoperative CRSwNP recurrence. CONCLUSIONS: S aureus induced an IgE response via IgE-negative memory B cells in CRSwNP patients, possibly contributing to CRSwNP development.

Improved classification and pathogenicity assessment by comprehensive functional studies in a large data set of KCNQ2 variants.

AIMS: The paucity of functional annotations on hundreds of KCNQ2 variants impedes the diagnosis and treatment of KCNQ2-related disorders. The aims of this work were to determine the functional properties of 331 clinical KCNQ2 variants, interpreted the pathogenicity of 331 variants using functional data，and explored the association between homomeric channel functions and phenotypes. MAIN METHODS: We collected 145 KCNQ2 variants from 232 epilepsy patients and 186 KCNQ2 missense variants from the ClinVar database. Whole-cell patch-clamp recording was used to classify the function of 331 variants. Subsequently, we proposed 24 criteria for the pathogenicity interpretation of KCNQ2 variants and used them to assess pathogenicity of 331 variants. Finally, we analyzed the clinical phenotypes of patients carrying these variants, and explored the correlations between functional mechanisms and phenotypes. KEY FINDINGS: In the homozygous state, 287 were classified as loss-of-function and 14 as gain-of-function. In the more clinically relative heterozygous state, 200 variants exhibited functional impairment, 121 of which showed dominant-negative effects on wild-type KCNQ2 subunits. After introducing functional data as strong-level evidence to interpret pathogenicity, over half of variants (169/331) were reclassified and 254 were classified as pathogenic/likely pathogenic. Moreover, dominant-negative effect and haploinsufficiency were identified as primary mechanisms in DEE/ID and SeLNE, respectively. The degree of impairment of channel function correlated with the phenotype severity. SIGNIFICANCE: Our study reveals the possible cause of KCNQ2-related disorders at the molecular level, provides compelling evidence for clinical classification of KCNQ2 variants, and expands the knowledge of correlations between functional mechanisms and phenotypes.

Telemedicine during the COVID-19 epidemic improves outcomes in children with tuberous sclerosis complex: A 1206 visits retrospective cohort study.

AIMS: To evaluate the benefits of telemedicine in children with tuberous sclerosis complex during the COVID-19 pandemic. METHODS: A retrospective cohort study was conducted, comparing telemedicine and in-person visits within the timeframe spanning from June 1, 2021, to June 1, 2022. Disparities in demographics, emergency visits, hospitalizations, adverse effects (AEs) associated with sirolimus, and the incidence of drug-refractory epilepsy (DRE) between telehealth and in-person care were assessed. Additionally, distinctions between audio and video telehealth, as well as varying frequencies of telehealth encounters, were investigated and reported as odds ratios (ORs). RESULTS: A total of 378 patients with 1206 visits were included, of which 137 were telemedicine patients and 241 were in-person patients. The median age was 5.0 years (IQR 2.8-10.0 years). There were 197 males (52.12%), 691 in-person visits (57.30%), and 515 telemedicine visits (42.70%). Children under 12 years old, those farther away from the center, mothers with more than 12 years of education, and children treated with sirolimus were more likely to visit via telemedicine. Telehealth was associated with significantly fewer emergency visits, hospitalizations, AEs of sirolimus, and DRE. With 10 or more visits, the incidence of emergency visits, hospitalization, and DRE was significantly reduced. CONCLUSION: Telemedicine visits are almost as close in number as in-person visits. Younger patients, patients in remote areas, and mothers with higher education levels are more willing to complete telemedicine visits. Telemedicine visits were associated with a significantly lower number of emergency visits, hospitalizations, and AEs of sirolimus. Patients with more than 10 visits per year seemed to have better clinical outcomes.

Cigarette smoke aggravates asthma via altering airways inflammation phenotypes and remodelling.

INTRODUCTION: Many asthmatic patients are exposed to cigarette smoke actively or passively, which contributes to asthma exacerbation and poor control. This study is to explore the effects of cigarette smoke on pathological changes in murine surrogate of asthma. METHODS: C57BL/6 mice were sensitised and challenged with ovalbumin (OVA) to establish a surrogate of asthma and then administered with cigarette smoke extract (CSE). Airways hyperresponsiveness (AHR) was measured using the Flexivent system. Histological staining (haematoxylin-eosin [HE], periodic acid Schiff [PAS], Congo red and Masson's trichrome) was employed to measure pathological changes in sections of lung tissue of experimental mice. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentrations of total and OVA-specific IgE, cytokines and chemokines (eotaxin-1, IL-13, IL-1ß, TNF-α, IL-17A, IL-33) in the lung tissue homogenates. Immunoreactivity for vWF and α-SMA in lung tissue sections was detected by immunohistochemistry. RESULTS: Exposure of the animals to CSE significantly reduced OVA-induced AHR, the number of eosinophils in bronchoalveolar lavage fluid (BALF) and eosinophils infiltrating into the lung tissue, as well as concentrations of some cytokines in lung homogenate. In contrast, it significantly enhanced the number of macrophages and M2 in BALF, as well as collagen deposition, smooth muscle thickness and alveolar destruction in lung tissue. CONCLUSION: CSE inhibits OVA-induced AHR, changes inflammation 'phenotypes', while accelerates some aspects of airways remodelling, which might contribute to worse symptoms and be refractory to anti-inflammation therapies for asthmatics.

Rebalancing liver-infiltrating CCR3+ and CD206+ monocytes improves diet-induced NAFLD.

Melatonin has been reported to improve nonalcoholic fatty liver disease (NAFLD), and exploring the underlying mechanisms will be beneficial for better treatment of NAFLD. Choline-deficient high-fat diet (CDHFD)- and methionine/choline-deficient diet (MCD)-fed mice with melatonin intervention exhibit significantly decreased liver steatosis, lobular inflammation, and focal liver necrosis. Single-cell RNA sequencing reveals that melatonin selectively inhibits pro-inflammatory CCR3+ monocyte-derived macrophages (MoMFs) and upregulates anti-inflammatory CD206+ MoMFs in NAFLD mice. Liver-infiltrating CCR3+CD14+ MoMFs are also significantly increased in patients with NAFLD. Mechanistically, melatonin receptor-independent BTG2-ATF4 signaling plays a role in the regulation of CCR3+ MoMF endoplasmic reticulum stress, survival, and inflammation. In contrast, melatonin upregulates CD206+ MoMF survival and polarization via MT1/2 receptors. Melatonin stimulation also regulates human CCR3+ MoMF and CD206+ MoMF survival and inflammation in vitro. Furthermore, CCR3 depletion antibody monotherapy inhibits liver inflammation and improves NAFLD in mice. Thus, therapies targeting CCR3+ MoMFs may have potential benefits in NAFLD treatment.

Metabolomics of cerebrospinal fluid reveals prognostic biomarkers in pediatric status epilepticus.

AIMS: Status epilepticus (SE) is the most common neurological emergency in pediatric patients. This study aimed to screen for prognostic biomarkers of SE in the cerebrospinal fluid (CSF) using metabolomics. METHODS: Ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) was conducted to identify prognostic biomarkers in CSF metabolomics by comparing the poor outcome group (N = 13) with the good outcome group (N = 15) of children with SE. Differentially expressed metabolites were identified using Mann-Whitney U test corrected by Benjamini-Hochberg and partial least squares discriminant analysis (PLS-DA). RESULTS: The PLS-DA model identified and validated significant metabolic differences between the poor and good outcome groups of children with SE (PLS-DA with R2 Y = 0.992 and Q2 = 0.798). A total of 49 prognosis-related metabolites were identified. Of these metabolites, 20 including glutamyl-glutamine, 3-iodothyronamine, and L-fucose had an area under the curve (AUC) ≥ 80% in prognostic prediction of SE. The logistic regression model combining glutamyl-glutamine and 3-iodothyronamine produced an AUC value of 0.976, with a sensitivity of 0.863 and specificity of 0.956. Pathway analysis revealed that dysregulation of the citrate cycle (TCA) and arginine biosynthesis may contribute to poor SE prognosis. CONCLUSIONS: This study highlighted the prognosis-related metabolomic disturbances in the CSF of children with SE and identified potential prognostic biomarkers. A prognostic prediction model combining glutamyl-glutamine and 3-iodothyronamine with high predictive value was established.

Cortical and subcortical morphological alteration in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder with serious seizures. We aim to explore the brain morphometry of patients with AS and figure out whether the seizure is associated with brain development. METHODS: Seventy-three patients and 26 healthy controls (HC) underwent high-resolution structural brain MRI. Group differences between the HC group and the AS group and also between AS patients with seizure (AS-Se) and age-matched AS patients with non-seizure (AS-NSe) were compared. The voxel-based and surface-based morphometry analyses were used in our study. Gray matter volume, cortical thickness (CTH), and local gyrification index (LGI) were assessed to analyze the cortical and subcortical structure alteration in the AS brain. RESULTS: Firstly, compared with the HC group, children with AS were found to have a significant decrease in gray matter volume in the subcortical nucleus, cortical, and cerebellum. However, the gray matter volume of AS patients in the inferior precuneus was significantly increased. Secondly, patients with AS had significantly increased LGI in the whole brain as compared with HC. Thirdly, the comparison of AS-Se and the AS-NSe groups revealed a significant decrease in caudate volume in the AS-Se group. Lastly, we further selected the caudate and the precuneus as ROIs for volumetric analysis, the AS group showed significantly increased LGI in the precuneus and reduced CTH in the right precuneus. Between the AS-Se and the AS-NSe groups, the AS-Se group exhibited significantly lower density in the caudate, while only the CTH in the left precuneus showed a significant difference. CONCLUSIONS: These results revealed cortical and subcortical morphological alterations in patients with AS, including globally the decreased brain volume in the subcortical nucleus, the increased gray matter volume of precuneus, and the whole-brain increase of LGI and reduction of CTH. The abnormal brain pattern was more serious in patients with seizures, suggesting that the occurrence of seizures may be related to abnormal brain changes.

Disrupted Topological Organization of White Matter Network in Angelman Syndrome.

BACKGROUND: Angelman syndrome (AS) is a genetic disorder that affects neurodevelopment. The investigation of changes in the brain white matter network, which would contribute to a better understanding of the pathogenesis of AS brain, was lacking. PURPOSE: To investigate both local and global alterations of white matter in patients with AS. STUDY TYPE: Prospective. SUBJECTS: A total of 29 AS patients (6.6 ± 1.4 years, 15 [52%] females) and 19 age-matched healthy controls (HC) (7.0 ± 1.5 years, 10 [53%] females). FIELD STRENGTH/SEQUENCE: A 3-T, three-dimensional (3D) T1-weighted imaging by using gradient-echo-based sequence, single shell diffusion tensor imaging by using spin-echo-based echo-planar imaging. ASSESSMENT: Network metrics including global efficiency (Eg ), local efficiency (Eloc ), small world coefficient (Swc), rich-club coefficient (Φ), and nodal degree (ND) were estimated from diffusion MR (dMR) data. Connections among highly connected (hub) regions and less connected (peripheral) regions were also assessed. Correlation between the topological parameters and age for each group was also calculated to assess the development of the brain. STATISTICAL TESTS: Linear regression model, permutation test. P values estimated from the regression model for each brain region were adjusted by false discovery rate (FDR) correction. RESULTS: AS patients showed significantly lower Eg and higher swc compared to HC. Φn significantly increased at higher k-levels in AS patients. In addition, the connections among hub regions and peripheral regions were significantly interrupted in AS patients. DATA CONCLUSION: The AS brain showed diminished connectivity, reflected by reduced network efficiency compared to HC. Compared to densely connected regions, less connected regions were more vulnerable in AS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Unrelated umbilical cord blood transplantation for children with hereditary leukodystrophy: A retrospective study.

Objective: To analyze the efficiency of unrelated umbilical cord blood transplantation (UCBT) in the treatment of hereditary leukodystrophy following busulfan- and cyclophosphamide-based myeloablative chemotherapy. Methods: A retrospective study was performed in patients with hereditary leukodystrophy who underwent UCBT after myeloablative chemotherapy between April 2015 and March 2020. Results: The study cohort included 12 pediatric patients (ten males), nine with cerebral adrenoleukodystrophy (ALD) and three with juvenile globoid cell leukodystrophy (GLD). All received HLA-matched or partially mismatched unrelated UCBT. There were no cases of graft rejection. Median neutrophil engraftment time was 20 days [12-33 days] and median platelet engraftment time was 29 days [14-65 days]. Median follow-up was 36 months [1-86 months], and the overall survival rate for patients with cerebral ALD and juvenile GLD after UCBT was 77.8% (7/9) and 100% (3/3), respectively. In patients with ALD, although lipid profiles (serum very-long-chain fatty acid) were improved post-UCBT, six patients demonstrated worse neurologic function score and performance status post-UCBT, and six patients had higher Loes scores at last follow-up compared with baseline. In patients with juvenile GLD, all patients showed stable neurologic function score and performance status despite the Loes score of one patient increased slightly after transplantation. Conclusion: In patients with cerebral ALD, patients with no or mild neurological symptoms can benefit from UCBT, while UCBT cannot reverse advanced disease. In patients with juvenile GLD, UCBT is safe and contributes to stabilize neurological function.

Synthesis and biological evaluation of novel N, N'-diarylurea derivatives as potent antibacterial agents against MRSA.

A series of new N, N'-diarylurea derivatives were designed and synthesized, some of which exhibited potent antibacterial activity against the drug-susceptible and drug-resistant Gram-positive strains. Especially, compounds 2c, 2g-2l showed broader antibacterial spectrum and more potent antibacterial activity (MIC = 0.30-2.72 µM) against MRSA and MRSE than the control levofloxacin (MIC = 0.69-22.14 µM). In addition, compounds 2c, 2g, 2h and 2l exhibited much better antibacterial activity (MIC = 1.29-2.86 µM) against VRE (E. faecium) than sorafenib (MIC = 275.37 µM), PK150 (MIC = 5.07-10.13 µM) and SC78 (MIC = 2.40-4.79 µM). More importantly, the low cytotoxicity of compounds on cell lines HeLa and HepG2 implied a relatively wide therapeutic window, which was of high importance for further study.

An Analysis of Phenotype and Genotype in a Large Cohort of Chinese Children with Angelman Syndrome.

Angelman syndrome (AS) is a neurodevelopmental genetic disorder, but there has been limited analysis of a large cohort of Chinese children with Angelman syndrome. This study aims to assess the phenotype and genotype of Chinese children with Angelman syndrome. We retrospectively analyzed data through a detailed online survey combined with an on-site study. Furthermore, phenotype analysis stratified by deletion and non-deletion groups was carried out. The responses of family members of 695 individuals with AS revealed that 577 patients (83.02%) had maternal deletions, 65 patients (9.35%) carried UBE3A mutations, 31 (4.46%) patients had UPD15pat (one patient with UPD15pat constituted by a mosaic), 10 patients (1.44%) had imprinting defects and 12 (1.58%) patients only showed abnormal methylation without further detection. We identified 50 different pathogenic variants in this cohort, although 18 of these variants were unreported. Recurrent variant c.2507_2510del (p.K836Rfs*4) was found in 7 patients. In the deletion group, patients were diagnosed at an earlier age, had a more severe clinical phenotype, a higher rate of epilepsy with more multiple seizure types, and more frequently combined medication. Strabismus and sleep disturbances were both common in deletion and non-deletion groups. The top three resources invested in caring for AS children are: daily involvement in patient care, rehabilitation cost, and anti-epileptic treatment. Our study showed the genetic composition of Chinese children with 83.02% of maternal deletions, and the mutation spectrum for UBE3A variants was expanded. Developmental outcomes are associated with genotype, and this was confirmed by deletion patients having a worse clinical phenotype and complex epilepsy.

Hyaline fibromatosis syndrome with a novel 4.41-kb deletion in ANTXR2 gene: A case report and literature review.

BACKGROUND: Hyaline fibromatosis syndrome is a rare autosomal recessive disorder with ANTXR2 mutations characterised by the accumulation of hyaline substances in tissues. We present a case with the severe form-infantile systemic hyalinosis (ISH)-with long survival and review the literature. METHODS AND RESULTS: Trio-exome sequencing revealed compound heterozygous mutations, including a novel 4.41 kb deletion on 4q21.21 and the previously reported c.1294C > T mutation, in the ANTXR2 gene. He was diagnosed with ISH and treated symptomatically. After follow-ups until 4 years of age, his recurrent respiratory infections and diarrhoea improved after one severe diarrhoea attack treated with intravenous gamma globulin. He is now awaiting surgical excision of gingival hypertrophy and joint contractures. CONCLUSION: The novel gross deletion in ANTXR2 enriches the genetic mutation spectrum of hyaline fibromatosis syndrome. The manifestation of decreased foetal movement, acute-infection attack or intravenous gamma globulin treatment may be associated with hyaline fibromatosis syndrome. A review of 116 reported cases reveals that missense mutations in the vWA domain are associated with joint symptoms, respiratory tract infection and diarrhoea, while frameshift mutations are associated with facial deformities and speech delays. We have enriched the current knowledge of the clinical manifestations and genetic mutation spectrum of HFS.

Epilepsy and Molecular Phenotype Affect the Neurodevelopment of Pediatric Angelman Syndrome Patients in China.

Objective: This study investigated the mental development of children with Angelman syndrome (AS) in China and evaluated the relationship between neurodevelopment and molecular subtype, age, epilepsy, and sex using the Chinese version of the Griffith Mental Development Scale (GMDS-C) to provide detailed baseline data regarding neurodevelopment with AS in China. Methods: Participants were recruited from the AS Natural History Study. The GMDS-C was used to evaluate all participants' mental age and developmental quotients. The general quotient (GQ) and quotients of five subscales (sports, personal-social, auditory language, eye-hand coordination, and comprehensive performance) were calculated. Results: A total of 119 children (average age: 42.12 months; range, 7.5-95.5 months) with a genetic diagnosis of AS were enrolled. The median GQ score of the GMDS was 29.6 points (95% confidence interval, 28.6-33.25). The children had relatively good locomotor and personal-social skills but poor language skills. Overall, 89% (106/119) had mental ages younger than 24 months for all five subscales. The non-deletion group (i.e., without deletion in chromosome 15q11-13) had higher GQs and locomotor, personal-social, and performance subscale quotients. The GQ was significantly different among the three age subgroups and significantly correlated with age. Compared with the non-epilepsy group, the epilepsy group had lower GQs and lower quotients for the locomotor, personal-social, speech, language, and eye-hand coordination subscales. Conclusion: Children with AS in China experience severe neurodevelopmental deterioration. In addition to age, molecular subtypes and the onset of seizures may also correlate with these patients' intellectual development. The GMDS-C is an accurate tool that can assess the clinical characteristics of AS. The data of this study can be used as baseline data for clinical trials performed to evaluate drug development or other AS treatment development.

The Critical and Diverse Roles of CD4-CD8- Double Negative T Cells in Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Hepatic inflammation is a hallmark of nonalcoholic fatty liver disease (NAFLD). Double negative T (DNT) cells are a unique subset of T lymphocytes that do not express CD4, CD8, or natural killer cell markers, and studies have suggested that DNT cells play critical and diverse roles in the immune system. However, the role of intrahepatic DNT cells in NAFLD is largely unknown. METHODS: The proportions and RNA transcription profiling of intrahepatic DNT cells were compared between C57BL/6 mice fed with control diet or methionine-choline-deficient diet for 5 weeks. The functions of DNT cells were tested in vitro and in vivo. RESULTS: The proportion of intrahepatic DNT cells was significantly increased in mice with diet-induced NAFLD. In NAFLD mice, the proportion of intrahepatic TCRγδ+ DNT cells was increased along with elevated interleukin (IL) 17A; in contrast, the percentage of TCRαß+ DNT cells was decreased, accompanied by reduced granzyme B (GZMB). TCRγδ+ DNT cell depletion resulted in lowered liver IL17A levels and significantly alleviated NAFLD. Adoptive transfer of intrahepatic TCRαß+ DNT cells from control mice increased intrahepatic CD4 and CD8 T cell apoptosis and inhibited NAFLD progression. Furthermore, we revealed that adrenic acid and arachidonic acid, harmful fatty acids that were enriched in the liver of the mice with NAFLD, could induce apoptosis of TCRαß+ DNT cells and inhibit their immunosuppressive function and nuclear factor kappa B (NF-κB) or AKT signaling pathway activity. However, arachidonic acid facilitated IL17A secretion by TCRγδ+ DNT cells, and the NF-κB signaling pathway was involved. Finally, we also confirmed the variation of intrahepatic TCRαß+ DNT cells and TCRγδ+ DNT cells in humans. CONCLUSIONS: During NAFLD progression, TCRγδ+ DNT cells enhance IL17A secretion and aggravate liver inflammation, whereas TCRαß+ DNT cells decrease GZMB production and lead to weakened immunoregulatory function. Shifting of balance from TCRγδ+ DNT cell response to one that favors TCRαß+ DNT regulation would be beneficial for the prevention and treatment of NAFLD.

D-Mannose Suppresses γδ T Cells and Alleviates Murine Psoriasis.

Psoriasis is a chronic skin disorder associated with multiple sequelae, such as psoriatic arthritis and cardiovascular diseases. Increasing evidence has shown that γδ T cells, as sources of IL-17A, play critical roles in psoriatic inflammations. However, there still lack effective ways to manipulate these pathogenic γδ T cells, which are less well studied than αß T cells. The present study aims to characterize the phenotype of γδ T cells and evaluate the impact of D-mannose (a C-2 epimer of glucose) on γδ T cell-mediated psoriasis. We found that skin-draining LN γδ T cells underwent robust proliferation and acquired an IL-17-producing phenotype during psoriasis. The transcriptomic profiles of these psoriatic γδ T cells had elevated glycolytic signatures. Importantly, D-mannose treatment suppressed the γδ T cell reaction and successfully alleviated the local and systematic inflammation induced by imiquimod. The decreased AKT/mTOR/HIF-1α signaling and glycolytic ability may contribute to the suppression of γδ T cells achieved by D-mannose. Our study increased understanding of γδ T cells in psoriasis and promoted D-mannose utilization as a potential clinical application for autoimmune diseases driven by γδ T cells.

Clinical characteristics, disease course, and outcomes of paediatric patients with myelin oligodendrocyte glycoprotein-Ab associated disease: A retrospective clinical study.

OBJECTIVE: To delineate the outcomes of paediatric patients with myelin oligodendrocyte glycoprotein antibody disease (MOGAD). METHODS: We retrospectively analyzed the clinical characteristics, treatment, and outcomes of 34 paediatric patients with MOGAD from July 2015 to January 2020. RESULTS: The median age at disease onset was 75.5 months (range: 19-170 months). The female-to-male ratio was 1:1.1. The median follow-up duration was 34.5 months (range: 14-63 months). Acute disseminated encephalomyelitis (ADEM) was the most common initial phenotype (52.9%), followed by optic neuritis (ON) (20.6%). Children with ADEM were younger than those with ON (P = 0.045). Twenty-eight (82.4%) and 18 (56.3%) children had abnormal brain and spinal magnetic resonance imaging, respectively, during the first acute attack. MOG-abs titers in children with ON were statistically higher than those in children with ADEM (P = 0.04). Thirty-two children accepted glucocorticoid treatment, while 33 (97%) children demonstrated clinical improvement within 1 week, 21 children (61.8%) achieved clinical recovery within 1 month. Eight children (23.5%) suffered a relapse, the median interval between the initial attack and recurrence was 13 (range: 3-36) months. We detected neurological sequelae in seven (20.6%) children, with visual dysfunction being the most common sequela (85.7%). CONCLUSION: ADEM was the most common phenotype in both monophasic and relapsed paediatric MOGAD, followed by ON. Majority of pediatric MOGAD patients were highly responsive to glucocorticoid. Despite a benign prognosis in most patients, some patients endure neurological sequelae, mainly visual impairment. Patients with initial visual impairment should be carefully evaluated and administered individualized immunotherapy.