Mice ; Animals ; Tandem Mass Spectrometry ; Alpha-Amanitin ; Chromatography, Liquid ; Metabolomics ; Chromatography, High Pressure Liquid/methods*

OBJECTIVE: To explore the genetic basis for two patients from a family with BCL11A-related intellectual disability (BCL11A-ID). METHODS: Clinical data of the proband and her family members was analyzed. Chromosomal karyotyping analysis, trio-whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were carried out. For the suspected genetic variants, Sanger sequencing was used to verify, and pathogenicity assessment was conducted. RESULTS: The proband and her mother both had intellectual and language impairment, and their fetal hemoglobin (HbF) was significantly elevated. A heterozygous c.1327_c.1328delTC (p.Ser443Hisfs*128) variant was found in exon 4 of the BCL11A gene by WES, which has resulted in truncated expression of the encoded protein, and Sanger sequencing has verified that the variant was inherited from the mother. The variant was not found in related databases. The variant was predicted as pathogenic according to the guidelines from the American College of Medical Genetics and Genomics (ACMG) (PVS1+PM2+PP1). No karyotypic abnormality was found in the proband, her parents and brother, and no pathogenic CNVs was found in the proband and her parents. CONCLUSION The c.1327_c.1328delTC (p.Ser443Hisfs*128) variant may underlay the BCL11A-ID in the proband and her mother. This de novo variant has expanded the mutational spectrum of the BCL11A gene.
Humans ; Male ; Female ; Intellectual Disability/genetics* ; DNA Copy Number Variations ; Pedigree ; Mutation ; Transcription Factors/genetics* ; Mothers ; Repressor Proteins/genetics*

Objective:To investigate the detecting method and clinical characteristics of anti-nodal/paranodal antibodies in chronic inflammatory demyelinating polyradiculopathy.Methods:Serum samples were collected from 212 patients with chronic inflammatory demyelinating polyradiculopathy who were admitted to Huashan Hospital of Fudan University or from other clinical centers from January 2018 to July 2021. Autoantibodies (anti-NF155, anti-NF186, anti-CNTN1) and IgG subtypes were detected with cell-based assay. According to the test results, patients were divided into anti-NF155 positive group, anti-NF186 positive group and anti-CNTN1 positive group, clinical characteristics of patients in each group, including limb weakness, superficial sensation and proprioception, tremor, cerebrospinal fluid protein level, brachial plexus magnetic resonance (MRI) were retrospectively analyzed and compared.Results:A total of 23 patients (10.8%,23/212) were positive for anti-NF155 antibody, 12 (5.7%,12/212) for anti-NF186 antibody, and 4 (1.9%,4/212) for anti-CNTN1 antibody. IgG 4 was the predominant subtype in anti-NF155 and anti-CNTN1 groups. In the anti-NF186 group, all cases were IgG positive and antibody subtypes could be detected in 4 cases (4/12). In anti-NF155 group, 23 patients (100%,23/23) had limb weakness and deep sensory disturbance, 19 patients (82.6%,19/23) had superficial sensory disturbance, 22 patients (95.7%,22/23) were symmetrically involved, 18 patients (78.3%,18/23) showed tremor, 19 patients (19/19) showed abnormal in brachial plexus MRI. In anti-NF186 group, 12 patients had limb weakness (12/12), 9 patients (9/12) and 6 patients (6/12) had superficial sensory disturbance and deep sensory disturbance respectively, 8 patients (8/12) were asymmetrically involved, and only 1 patient (1/12) showed tremor, 1 (1/7) showed abnormal brachial plexus MRI. In anti-CNTN1 group, 4 cases showed symmetrical limb weakness and sensory disturbance, 3 patients had tremor, and four patients showed brachial plexus MRI abnormality. There were statistically significant differences in onset age, proprioception, tremor and MRI abnormalities of brachial plexus among the 3 groups ( P<0.01). Conclusions:The clinical characteristics of CIDP patients with anti-NF155, anti-NF186 and anti-CNTN1 antibodies are different. Screening anti-nodal/paranodal antibodies is of great significance for accurate diagnosis and treatment of patients with peripheral neuropathy.

OBJECTIVE: To investigate the expression level and prognostic value of miR-21, miR-18a, miR-146a, and Let-7b derived from serum exosomes in patients with multiple myeloma (MM). METHODS: Serum exosomes were extracted from 57 MM patients and 20 healthy persons using ExoQuick exosome precipitation solution kit, and the relative expression level of miR-21, miR-18a, miR-146a, and Let-7b derived from serum exosomes was measured by RT-qPCR. Correlations of the expression levels of all miRNAs mentioned above with routine laboratory parameters were analyzed by Spearman correlation analysis. The relationship between the expression level of miR-21, miR-18a, miR-146a, and Let-7b derived from serum exosomes and overall survival of patients with MM was analyzed using the Kaplan-Meier survival curve. RESULTS: The expression levels of miR-21, miR-18a, and Let-7b derived from serum exosomes in patients with MM were significantly lower than those in the normal control group (P<0.001), while the expression level of miR-146a between the two groups was not significantly different (P>0.05). The expression level of miR-21 was strongly negatively correlated with serum β₂-microglobulin concentration (r=-0.830), and weakly negatively correlated with serum creatinine, corrected serum calcium, and cystatin C (r=-0.488, -0.282, -0.627). The expression levels of Let-7b and miR-18a were also weakly negatively correlated with the corrected serum calcium, β₂-microglobulin, and cystatin C concentration (r=-0.305, -0.362, -0.461; -0.317, -0.542, -0.434). However, there was no significant correlation between the expression level of miR-146a and routine laboratory parameters in MM patients. The overall survival rate of MM patients with low expression level of miR-21, miR-18a, and Let-7b significantly decreased compared with high expression level group (P<0.05), however, the expression level of miR-146a was not related to the overall survival rate. CONCLUSION Aberrant low expression levels of miR-21, miR-18a, and Let-7b derived from serum exosomes exist in patients with MM, which are associated with a worse overall survival rate.
Calcium/metabolism* ; Creatinine/metabolism* ; Cystatin C/metabolism* ; Exosomes/metabolism* ; Humans ; MicroRNAs/metabolism* ; Multiple Myeloma/metabolism*

Localized peripheral neuropathy amyloidosis is a rare disease that mainly occurred in elder people who present with focal neurological symptoms. AL is the main type of amyloid protein. Biopsy is the golden standard for diagnosis. Mass spectrometry and immunohistochemical analysis help to confirm the type of amyloid protein. This paper retrospectively analyzes the clinical and imaging data, auxiliary examinations, histological, and immunohistochemical markers. The patient, a 34-year-old woman, presented with a right neck mass and weakness of the right arm. Brachial plexus magnetic resonance imaging (MRI) showed a tumor-like lesion in the nerve root at C5 and C6 and in upper trunk. Electrophysiological studies revealed damage in the upper trunk of the brachial plexus. Positive staining with Congo red was found in brachial plexus biopsy. Mass spectrometry showed that the type of amyloid protein was AHL(G-λ). The patient underwent nerve graft for treatment. Meanwhile, literature review revealed that the average onset age of localized spinal nerve amyloidosis was 62.4 years old.The radial nerve was the most susceptible, followed by the lumbosacral plexus. Fifty percent of the type of amyloid protein is AL.Until now, no consolidated treatment is available. Here, we summarize the clinical characteristics of localized peripheral neuropathy amyloidosis in order to raise the awareness of the disease.

TANK-binding kinase 1 (TBK1), a core kinase of antiviral pathways, activates the production of interferons (IFNs). It has been reported that deacetylation activates TBK1; however, the precise mechanism still remains to be uncovered. We show here that during the early stage of viral infection, the acetylation of TBK1 was increased, and the acetylation of TBK1 at Lys241 enhanced the recruitment of IRF3 to TBK1. HDAC3 directly deacetylated TBK1 at Lys241 and Lys692, which resulted in the activation of TBK1. Deacetylation at Lys241 and Lys692 was critical for the kinase activity and dimerization of TBK1 respectively. Using knockout cell lines and transgenic mice, we confirmed that a HDAC3 null mutant exhibited enhanced susceptibility to viral challenge via impaired production of type I IFNs. Furthermore, activated TBK1 phosphorylated HDAC3, which promoted the deacetylation activity of HDAC3 and formed a feedback loop. In this study, we illustrated the roles the acetylated and deacetylated forms of TBK1 play in antiviral innate responses and clarified the post-translational modulations involved in the interaction between TBK1 and HDAC3.

Objective: To evaluate the associations of sarcopenia, handgrip strength and calf circumference with cognitive impairment among Chinese older adults. Methods: Totally 2,525 older adults were recruited from the Healthy Aging and Biomarkers Cohort Study. Cognitive impairment was assessed by the Chinese Mini-Mental State Examination. Handgrip strength was calculated from the means of the right and left hand values. Calf circumference was measured at the site of maximum circumference of the non-dominant leg. The formula developed by Ishii was used to define sarcopenia. Multiple logistic regression was performed to evaluate the associations of sarcopenia, handgrip strength, and calf circumference with cognitive impairment. Results: The prevalence of cognitive impairment was 34.36%. The adjusted odds ratio ( Conclusion Sarcopenia, identified by low handgrip strength and low calf circumference, was positively associated with cognitive impairment.
Aged ; Aged, 80 and over ; China/epidemiology* ; Cognitive Dysfunction/etiology* ; Female ; Hand Strength ; Humans ; Leg/anatomy & histology* ; Logistic Models ; Male ; Sarcopenia/pathology*

【Objective】 To study the mechanisms and therapeutic effects of human olfactory mucosa-derived mesenchymal stem cells（OMSC）on experimental autoimmune encephalomyelitis（EAE）in mice.【Methods】Under local anesthesia by using nasal endoscopy，olfactory epithelia of healthy donors were obtained，digested and cultured up to the 5th passage. OMSC were identified，differentiated and stained. EAE models were induced in C57 female mice by myelin oligodendrocyte glycoprotein（MOG35- 55）and pertussis toxin（PT）. Neurological function was documented daily. On day 16 after immunization（peak of incidence），the mice were divided randomly into two groups and treated with OMSC and PBS via tail vein injection respectively. On day 24 after immunization ，blood was collected from angular vein and levels of IL-10，IL-17，IFN-γ and IL-6 were determined by cytometric beads array（CBA）. The size of the spinal cord lesion in mice was observed and measured by using HE and LFB staining. Peripheral blood lymphocytes（PBL）of healthy donors were obtained and then co-cultured with OMSC. The proportions of CD4+ T cells secreting IFN- γ（Th1 cells）in lymphocyte group and co-culture group were compared after 2 days of cultivation. Adding IDO or COX pathway inhibitor to co- culture group and cultivating for 2 days，we observed and compared the proportions of Th1 cells in lymphocyte group，co-culture group and inhibitor treatment group respectively.【Results】OMSC exhibited certain mesenchymal stem cell-like characteristics with respect to expression of stem cell surface markers and multilineage differentiation potentials. After induced by MOG35- 55 and PT，EAE models showed different levels of neurological damage. Compared with those in PBS treatment group，in OMSC treatment group，the severity of neural dysfunction in mice was significantly reduced（P =0.002），the level of IFN-γ in serum was lower（P = 0.032），but no significant differences in the levels of IL-10，IL-17 and IL-6 were found between two groups. HE and LFB staining revealed that the inflammatory infiltration and demyelinating areas in OMSC treatment group were less than those in PBS treatment group. The proportion of Th1 cells was lower in co-culture group than that in lymphocyte group（P = 0.001），higher in IDO inhibitor group than that in co-culture group（P = 0.01），but no significant difference was found between IDO inhibitor group and lymphocyte group or between COX inhibitor group and co-culture group.【Conclusions】OMSC may regulate the proportion of Th1 lymphocytes through IDO pathway so as to inhibit the demyelinating injuries of EAE in mice. This study provides a new idea for the clinical treatment of multiple sclerosis.

OBJECTIVE: To analyze the characteristics of gene mutation in adult ALL and its clinical significance. METHODS: Clinical data of 134 primary adult ALL patients and DNA sequencing results of 16 kinds of gene mutation were collected. The characteristic of gene mutation and clinical significances were statistically analyzed. RESULTS: In 31 cases of 134 ALL cases (23.13%) the gene mutations were detected as follows: 19 cases of 114 B-ALL cases (16.67%), 11 cases of 19 T-ALL cases (57.89%) and 1 case of T/B-ALL. The incidence of T-ALL gene mutation was significantly higher than that of B-ALL (χ CONCLUSION There may be multiple gene mutations in adult ALL patients. IL7R and NOTCH1 are the most common gene mutations and NOTCH1 mutation may indicate poor prognosis. Detection of gene mutations is helpful to understand the pathogenesis of ALL and evaluate the prognosis of adult ALL patients.
Adult ; Humans ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Receptor, Notch1/genetics* ; Sequence Analysis, DNA

OBJECTIVE: In Singapore, the use of traditional Chinese medicine (TCM) alongside Western medicine (WM) is common. There are risks of adverse herb-drug interactions when taken concurrently. Current literature suggests that TCM use is not regularly reported to WM doctors in Singapore, but the underlying reasons are not understood. METHODS: A cross-sectional study was conducted across Singapore by administering questionnaires to TCM-using patients and WM-practising general practitioners (GPs). The questionnaire examined the following themes: (1) demographics and TCM use pattern; (2) respondents' (patients and GPs) knowledge and beliefs about TCM and the factors influencing the discussion of TCM during the WM consultation; and (3) respondents' qualitative suggestions to increase disclosure rate. RESULTS: A total of 484 patients and 334 GPs were surveyed. Factors associated with patients' initiation of TCM discussion include length of consultation (odds ratio [OR]: 2.1; P < 0.001), comfort level in discussing TCM (OR: 1.6; P < 0.001) and belief in importance of discussion (OR: 1.4; P = 0.017). Doctor's initiation of discussion (74%) was the top patient-ranked factor influencing their discussion of TCM. For doctors, knowledge of TCM indications (OR: 2.2; P < 0.001), belief in importance of discussion (OR: 2.1; P < 0.001) and comfort level in discussing TCM (OR: 1.9; P = 0.001) were associated with their initiation of TCM use discussion. Possible WM-TCM interactions (58%) was the top doctor-ranked factor influencing their discussion of TCM. CONCLUSION The discussion of TCM in a WM setting is multifactorial. Interventions include doctors' active screening for TCM use in patients and equipping doctors with TCM knowledge. Improving communication between patients and doctors is key to avoiding harmful herb-drug interactions.