Clinical characteristics and long-term outcome of CASPR2 antibody-associated autoimmune encephalitis in children.

BACKGROUND: Contactin-associated protein-2(CASPR2) antibody-associated autoimmune encephalitis(AE) is rare in children. This study aimed to report the clinical characteristics and long-term outcome of CASPR2 autoimmunity in children to expand the disease spectrum. METHODS: Children who were hospitalized in our hospital with clinically suspected AE from May 2015 to April 2022 and underwent neuronal surface antibodies detections were retrospectively analyzed. Clinical data of patients with CASPR2 autoimmunity were collected. RESULTS: Patients who were positive for NMDAR-IgG, CASPR2-IgG, LGI1-IgG and IgLON5-IgG occupied 95.2%(119/125),3.2%(4/125),0.8%(1/125) and 0.8%(1/125), respectively.The median onset age of the 4 patients with CASPR2-IgG was 5.6 years. The most common symptoms were psychiatric symptoms/abnormal behavior(3/4) and sleep dysfunction(3/4). One patient developed a phenotype of Rasmussen encephalitis(RE). Tumor was absent in our patients. Two patients showed abnormal findings on initial brain magnetic resonance imaging(MRI) scans. All the patients showed favorable response to immunotherapy except the patient with RE experienced recurrent symptoms who finally achieved remission after surgery. All the patients had a favorable long-term outcome at the last follow-up(33-58months). CONCLUSIONS: CASPR2 autoimmunity may be the second most common anti-neuronal surface antibodies associated neurological disease in children. Psychiatric symptoms/abnormal behavior and sleep disorder were common in children with CASPR2-associated AE. Tumor was rare in those patients. Most pediatric patients had a favorable long-term outcome.

One-Pot Etching Pyrolysis to Defect-Rich Carbon Nanosheets to Construct Multiheteroatom-Coordinated Iron Sites for Efficient Oxygen Reduction.

Constructing multiheteroatom coordination structure in carbonaceous substrates demonstrates an effective method to accelerate the oxygen reduction reaction (ORR) of supported single-atom catalyst. Herein, the novel etching route assisted by potassium thiocyanate (KCNS) is developed to convert metal-organic framework to 2D defect-rich porous N,S-co-doped carbon nanosheets for anchoring atomically dispersed iron sites as the high-performance ORR catalysts (Fe-SACs). The well-designed KCNS-assisted etching route can generate spatial confinement template to direct the carbon nanosheet formation, etching condition to form defect-rich structure, and additional sulfur atoms to coordinate iron species. Spectral and microscopy analysis reveals that the iron element in Fe-SACs is highly isolated on carbon nanosheet and anchored by nitrogen and sulfur atoms in unsymmetrical Fe-S1N3 structure. The optimized Fe-SACs with large specific surface area could show remarkable alkaline ORR performances with a high half-wave potential of 0.920 V versus RHE and excellent durability. The rechargeable zinc-air battery assembled with Fe-SACs air electrodes delivers a large power density of 350 mW cm-2 and a stable voltage platform during charge and discharge over more than 1300 h. This work proposes a novel strategy for the preparation of single-atom catalysts with multiheteroatom coordination structure and highly exposed active sites for efficient ORR.

Pediatric Ocular Myasthenia Gravis: Single-Center Experience.

BACKGROUND: Currently, there is no universally accepted standard treatment for ocular myasthenia gravis (OMG) in children. We aimed to investigate the possible proper regimens and timing of treatment for pediatric OMG cases based on the clinical manifestations: OMG with ptosis only and OMG with other features. METHODS: One hundred and forty two OMG cases attended at the Department of Pediatrics, Xiangya Hospital, Central South University, from 2010 to 2019 were included, and information from medical records was reviewed and recorded. Comparisons of clinical characteristics between patients with OMG with ptosis only and patients with OMG with other features as well as between patients treated with glucocorticoid (GC) within or after six months from disease onset were performed. RESULTS: OMG with other features constituted about 54.9% of the cases, and 66.2% of the patients achieved optimal outcome. Patients with OMG with ptosis only responded to pyridostigmine alone more than patients with OMG with other features who required several therapies (P < 0.001). Patients with OMG with ptosis only had a larger proportion of optimal outcome than the patients with OMG with other features (P = 0.002), and the difference remained significant even when the individual outcome groups were compared (P < 0.001). Patients who received GC within six months had a greater proportion of optimal outcome than those who received it after six months (P < 0.001). CONCLUSIONS: Although OMG with other features is a more common subtype of OMG, it is also more severe than OMG with ptosis only. An earlier addition of GC leads to optimal outcome.

Application of Machine-learning based on Radiomics Features in Differential Diagnosis of Superficial Lymphadenopathy.

OBJECTIVE: The accurate diagnosis of superficial lymphadenopathy is challenging. We aim to explore a non-invasive and accurate machine-learning method for distinguishing benign lymph nodes, lymphoma, and metastatic lymph nodes. METHODS: The clinical data and ultrasound images of 160 patients with superficial lymphadenopathy (58 benign lymph nodes, 62 lymphoma, 40 metastatic lymph nodes) admitted to our hospital from January 2020 to November 2022 were retrospectively studied. Patients were randomly divided into a training set and test set according to the ratio of 6:4. Firstly, the radiomics features of each lymph node were extracted, and then a series of statistical methods were used to avoid over-fitting. Then, the gradient boosting machine(GBM) was used to build the model. The area under receiver(AUC) operating characteristic curve, precision, recall rate and F1 value were calculated to evaluate the effectiveness of the model. RESULTS: Ten robust features were selected to build the model. The AUC values of benign lymph nodes, lymphoma and metastatic lymph nodes in the training set were 1.00, 0.98 and 0.99, and the AUC values of the test set were 0.96, 0.84 and 0.90, respectively. CONCLUSION: It was a reliable and non-invasive method for the differential diagnosis of lymphadenopathy based on the model constructed by machine learning.

Clinical and radiological features, treatment responses and prognosis in pediatric patients with co-existing anti-N-methyl-D-aspartate receptor and myelin oligodendrocyte glycoprotein antibody-associated encephalitis: A single center study.

OBJECTIVES: To characterize the clinical and radiological features, treatment responses and outcomes of children with co-existing anti-N-methyl-D-aspartate receptor(NMDAR) and myelin oligodendrocyte glycoprotein(MOG) antibody-associated encephalitis. METHODS: Clinical manifestations, imaging features, effectiveness of treatment and outcomes of patients who were cerebral spinal fluid(CSF)-positive for NMDAR-antibody(NMDAR-ab) and seropositive for MOG-antibody(MOG-ab) were analyzed. RESULTS: Twelve patients including 8 females and 4 males were enrolled. The median onset age was 9 years, ranging from 2.2 to 12.8 years. Behavioral changes and/or psychiatric symptoms (n = 8/12), seizures (n = 8/12), encephalopathy (n = 7/12) were 3 of the most common symptoms. Brain magnetic resonance imaging(MRI) of all the patients showed T2/fluid attenuation inversion recovery(FLAIR) abnormal signal in the cerebral white matter at least once in the courses of disease, 2 of whom developed new brain lesions which were asymptomatic. All of the patients had supratentorial lesions. Spinal cord MRI was performed in 7 patients. Only 1 patient showed related abnormalities with increased T2 signal in the spinal cord C1-5. Nine patients underwent optic nerve MRI; 5 patients demonstrated abnormal results, among whom 4 exhibited T2 abnormal signal (2 were symptom-free) and 1 showed a little effusion in bilateral optic nerve sheats. Intravenous immunoglobulin (IVIG) and intravenous methylprednisolone (IVMP) were the most common used therapies in those patients. Nine patients were treated with second-line therapy to prevent relapses. For total 29 clinical attacks, the median modified Rankin Scale (mRS) before treatment and after therapy of acute stage was 1 and 0, respectively. Seven of 12 patients(58.3 %) experienced clinical relapses. In terms of outcome, all of the patients' mRS of last follow-up (≥6 months) was ≤2. CONCLUSIONS: Behavioral changes and/or psychiatric symptoms, seizures and encephalopathy were common in children with co-existing anti-NMDAR and MOG antibody-associated encephalitis. A minority of subjects may develop asymptomatic lesions on brain and optic nerve MRI. The relapse rate of this disease is relatively high. The majority of patients responded well to the immunotherapies and had a good outcome(mRS of last follow-up≤2).

Interferon-gamma treatment of human umbilical cord mesenchymal stem cells can significantly reduce damage associated with diabetic peripheral neuropathy in mice.

BACKGROUND: Diabetic peripheral neuropathy causes significant pain to patients. Umbilical cord mesenchymal stem cells have been shown to be useful in the treatment of diabetes and its complications. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cells treated with interferon-gamma can ameliorate nerve injury associated with diabetes better than human umbilical cord mesenchymal stem cells without interferon-gamma treatment. METHODS: Human umbilical cord mesenchymal stem cells were assessed for adipogenic differentiation, osteogenic differentiation, and proliferation ability. Vonfry and a hot disc pain tester were used to evaluate tactile sensation and thermal pain sensation in mice. Hematoxylin-eosin and TUNEL staining were performed to visualize sciatic nerve fiber lesions and Schwann cell apoptosis in diabetic mice. Western blotting was used to detect expression of the apoptosis-related proteins Bax, B-cell lymphoma-2, and caspase-3 in mouse sciatic nerve fibers and Schwann cells. Real-Time Quantitative PCR was used to detect mRNA levels of the C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10 in mouse sciatic nerve fibers and Schwann cells. Enzyme-linked immunosorbent assay was used to detect levels of the inflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α in serum and Schwann cells. RESULTS: The adipogenic differentiation capacity, osteogenic differentiation capacity, and proliferation ability of human umbilical cord mesenchymal stem cells were enhanced after interferon-gamma treatment. Real-Time Quantitative PCR revealed that interferon-gamma promoted expression of the adipogenic markers, PPAR-γ and CEBP-α, as well as of the osteogenic markers secreted phosphoprotein 1, bone gamma-carboxyglutamate protein, collagen type I alpha1 chain, and Runt-related transcription factor 2. The results of hematoxylin-eosin and TUNEL staining showed that pathological nerve fiber damage and Schwann cell apoptosis were reduced after the injection of interferon-gamma-treated human umbilical cord mesenchymal stem cells. Expression of the apoptosis-related proteins, caspase-3 and Bax, was significantly reduced, while expression of the anti-apoptotic protein B-cell lymphoma-2 was significantly increased. mRNA levels of the cell chemokines, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10, were significantly reduced, and levels of the inflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α, were decreased. Tactile and thermal pain sensations were improved in diabetic mice. CONCLUSION: Interferon-gamma treatment of umbilical cord mesenchymal stem cells enhanced osteogenic differentiation, adipogenic differentiation, and proliferative potential. It can enhance the ability of human umbilical cord mesenchymal stem cells to alleviate damage to diabetic nerve fibers and Schwann cells, in addition to improving the neurological function of diabetic mice.

Macromolecular NO-Donor Micelles for Targeted and Augmented Chemotherapy against Prostate Cancer.

Mitoxantrone (MTO) is clinically utilized for treating hormone-refractory prostate cancer (PCa), however, the therapeutic outcome is far from optimal due to the lack of proper drug carrier as well as the inherent MTO detoxification mechanisms of DNA lesion repair and anti-oxidation. Herein, a bombesin-installed nanoplatform combining the chemotherapeutic MTO and the chemotherapeutic sensitizer of nitric oxide (NO) is developed based on MTO-loaded macromolecular NO-donor-containing polymeric micelles (BN-NMMTO ) for targeted NO-sensitized chemotherapy against PCa. BN-NMMTO actively target and accumulates in PCa sites and are internalized into the tumor cells. The macromolecular NO-donor of BN-NMMTO undergoes a reductive reaction to unleash NO upon intracellular glutathione (GSH), accompanying by micelle swelling and MTO release. The targeted intracellular MTO release induces DNA lesion and reactive oxygen species (ROS) generation in tumor cells without damage to the normal cells, and MTO's cytotoxicity is further augmented by NO release via the inhibition of both DNA repair and anti-oxidation pathways as compared with traditional MTO therapies.

Black Phosphorus-Synergic Nitric Oxide Nanogasholder Spatiotemporally Regulates Tumor Microenvironments for Self-Amplifying Immunotherapy.

The lack of tumor immunogenicity coupled with the presence of tumor immunosuppression severely hinders antitumor immunity, especially in the treatment of "immune cold" tumors. Here, we have developed a drug-free and NIR-enabled nitric oxide (NO)-releasing nanogasholder (NOPS@BP) composed of an outer cloak of nitrate-containing polymeric NO donor and an inner core of black phosphorus (BP) as the energy converter to spatiotemporally regulate NO-mediated tumor microenvironment remodeling and achieve multimodal therapy. Following NIR-irradiation, BP-induced photothermia and its intrinsic reducing property accelerate NO release from the outer cloak, by which the instantaneous NO burst concomitant with mild photothermia, on the one hand, induces immunogenic cell death (ICD), thereby provoking antitumor responses such as the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs); on the other hand, it reverses tumor immunosuppression via Treg inhibition, M2 macrophage restraint, and PD-L1 downregulation, further strengthening antitumor immunity. Therefore, this drug-free NOPS@BP by means of multimodal therapy (NO gas therapy, immune therapy, photothermal therapy) realizes extremely significant curative effects against primary and distant tumors and even metastasis in B16F10 tumor models, providing a new modality to conquer immune cold tumors by NO-potentiated ICD and immunosuppression reversal.

NEXMIF mutations in intellectual disability and epilepsy: A report of 2 cases and literature review. / NEXMIFåŸºå› çªå˜å¯¼è‡´æ™ºåŠ›éšœç¢åˆå¹¶ç™«ç—«2ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

More than 100 genes located on the X chromosome have been found to be associated with X-linked intellectual disability (XLID) to date, and NEXMIF is a pathogenic gene for XLID. In addition to intellectual disability, patients with NEXMIF gene mutation can also have other neurological symptoms, such as epilepsy, abnormal behavior, and hypotonia, as well as abnormalities of other systems. Two children with intellectual disability and epilepsy caused by NEXMIF gene mutation were treated in the Department of Pediatrics, Xiangya Hospital, Central South University from March 8, 2017 to June 20, 2020. Patient 1, a 7 years and 8 months old girl, visited our department because of the delayed psychomotor development. Physical examination revealed strabismus (right eye), hyperactivity, and loss of concentration. Intelligence test showed a developmental quotient of 43.6. Electroencephalogram showed abnormal discharge, and cranial imaging appeared normal. Whole exome sequencing revealed a de novo heterozygous mutation, c.2189delC (p.S730Lfs*17) in the NEXMIF gene (NM_001008537). During the follow-up period, the patient developed epileptic seizures, mainly manifested as generalized and absent seizures. She took the medicine of levetiracetam and lamotrigine, and the seizures were under control. Patient 2, a 6-months old boy, visited our department due to developmental regression and seizures. He showed poor reactions to light and sound, and was not able to raise head without aid. Hypotonia was also noticed. The electroencephalogram showed intermittent hyperarrhythmia, and spasms were monitored. He was given topiramate and adrenocorticotrophic hormone (ACTH). Whole exome sequencing detected a de novo c.592C>T (Q198X) mutation in NEXMIF gene. During the follow-up period, the seizures were reduced with vigabatrin. He had no obvious progress in the psychomotor development, and presented strabismus. There were 91 cases reported abroad, 1 case reported in China, and 2 patients were included in this study. A total of 85 variants in NEXMIF gene were found, involving 83 variants reported in PubMed and HGMD, and the 2 new variants presented in our patients. The patients with variants in NEXMIF gene all had mild to severe intellectual disability. Behavioral abnormalities, epilepsy, hypotonia, and other neurological symptoms are frequently presented. The phenotype of male partially overlaps with that of female. Male patients often have more severe intellectual disability, impaired language, and autistic features, while female patients often have refractory epilepsy. Most of the variants reported so far were loss-of-function resulted in the reduced protein expression of NEXMIF. The degree of NEXMIF loss appears to correlate with the severity of the phenotype.

A Risk Prediction Model for Prolonged Length of Stay in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Retrospective Study of 225 Patients in a Single Center in Kunming, China.

BACKGROUND We aimed to develop an effective prediction model of prolonged length of stay (LOS) in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). MATERIAL AND METHODS We systematically enrolled 225 patients admitted for AECOPD to our hospital and divided them into a normal LOS group (≤7 days) and prolonged LOS group (>7 days). To analyze differences in laboratory data at different times, 3 logistic regression models were established. To develop the prediction model, all variables with statistical significance were included in the model. The area under the curve (AUC) was used to evaluate discrimination, and the Hosmer-Lemeshow test was used to assess the calibration of the model. RESULTS Factors found to be independently associated with the increased risk of prolonged LOS included the use of corticosteroids during hospitalization, elevated HCO3⁻, decreased pH, and reductions in platelets (PLTs) and procalcitonin (PCT) between the fourth and first day of hospitalization. The risk prediction model including these factors had an AUC of 0.795, suggesting the good discrimination of our model. The Hosmer-Lemeshow test also showed good calibration of the model, which confirmed its good predictive performance. CONCLUSIONS A clinical prediction model was developed with good predictive performance, which could help clinicians identify patients with a higher risk of prolonged LOS, help shorten hospital stay, reduce the disease burden of patients, and improve the outcomes of AECOPD.

Black phosphorus assisted polyionic micelles with efficient PTX loading for remotely controlled release and synergistic treatment of drug-resistant tumors.

Nanomedicines have been widely used in the effective delivery of chemotherapeutic drugs due to their advantages such as increasing the half-life of drugs, selectively targeting tumor tissues, and thus reducing systemic toxicity. However, the low drug entrapment rate and the difficulty of real-controlled release at tumor sites hinder their further clinical translations. Here we have developed biodegradable polyionic micelles (PD-M) to facilitate black phosphorus (BP) encapsulation (PD-M@BP) for improved drug loading. With the introduction of BP, PTX-loaded PD-M@BP (PD-M@BP/PTX) with sizes of 124-162 nm exhibited superior encapsulation efficiency over 94% and excellent colloidal stability. Meanwhile, PD-M well protected BP from fast degradation to show the good photothermal performance under near-infrared (NIR) irradiation, thus achieving the remotely controlled fast PTX release due to micelle core melting and dissociation, accompanied by the synergistic photothermal tumor therapy. The in vivo results demonstrated that the PD-M@BP/PTX nanosystem not only realized significant inhibition of multi-drug resistant (MDR) cervical tumors (HeLa/PTXR tumor) by remote NIR-regulation, but also reduced the potential damage of chemotherapeutic drugs to the whole body, rendering these hybrid nanosystems as great tools to treat MDR tumors synergistically.

A dynamic nomogram for predicting the risk of asthma: Development and validation in a database study.

BACKGROUND: Asthma remains a serious health problem with increasing prevalence and incidence. This study was to develop and validate a dynamic nomogram for predicting asthma risk. METHODS: Totally 597 subjects whose age ≥18 years old with asthma, an accurate age at first cigarette, and clear smoking status were selected from the National Health and Nutrition Examination Survey (NHANES) database (2013-2018). The dataset was randomly split into the training set and the testing set at a ratio of 4:6. Simple and multiple logistic regressions were used for identifying independent predictors. Then the nomogram was developed and internally validated using data from the testing set. The receiver operator characteristic (ROC) curve was used for assessing the performance of the nomogram. RESULTS: According to the simple and multiple logistic regressions, smoking ≥40 years, female gender, the age for the first smoking, having close relative with asthma were independently associated with the risk of an asthma attack. The nomogram was thereby developed with the link of https://yanglifen.shinyapps.io/Dynamic_Nomogram_for_Asthma/. The ROC analyses showed an AUC of 0.726 (0.724-0.728) with a sensitivity of 0.887 (0.847-0.928) in the training set, and an AUC of 0.702 (0.700-0.703) with a sensitivity of 0.860 (0.804-0.916) in the testing set, fitting well in calibration curves. Decision curve analysis further confirmed the clinical usefulness of the nomogram. CONCLUSION: Our dynamic nomogram could help clinicians to assess the individual probability of asthma attack, which was helpful for improving the treatment and prognosis of asthma.

LINC00202 attenuates the progression of gastric cancer via suppressing expression level of KLF2.

PURPOSE: We aimed to investigate the function of LINC00202 in influencing the malignant progression of gastric cancer (GC). METHODS: The relative level of LINC00202 in GC and adjacent normal tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The difference in LINC00202 level among GC patients with different TNM stages was compared. Subsequently, regulatory effects of LINC00202 on proliferative capacity of AGS and SGC-7901 cells were evaluated. Subcellular distribution of LINC00202 was analyzed. The interaction and correlation between LINC00202 and Krüppel-like factor 2 (KLF2) were analyzed by RNA immunoprecipitation (RIP), Chromatin immunoprecipitation (ChIP) and linear regression test. Finally, the involvement of KLF2 in LINC00202-mediated proliferative ability of GC cells was clarified. LINC00202 was upregulated in GC tissues compared with that in adjacent normal ones. Its level remained higher in GC patients with stage III-IV than those with stage I-II. Silencing LINC00202 markedly attenuated the proliferation of GC cells. RESULTS: LINC00202 was mainly enriched in nucleus. KLF2 level was negatively correlated to and interacted with LINC00202. Transfection of LINC00202 decreased the recruitment ability of EZH2 on KLF2. Importantly, KLF2 partially reversed the regulatory effect of LINC00202 on the proliferative ability of GC cells. CONCLUSIONS: LINC00202 enhances the proliferative ability of GC cells via negatively regulating KLF2, thus aggravating the progression of GC.

Metabolic modulation of redox state confounds fish survival against Vibrio alginolyticus infection.

Vibrio alginolyticus threatens both humans and marine animals, but hosts respond to V. alginolyticus infection is not fully understood. Here, functional metabolomics was adopted to investigate the metabolic differences between the dying and surviving zebrafish upon V. alginolyticus infection. Tryptophan was identified as the most crucial metabolite, whose abundance was decreased in the dying group but increased in the survival group as compared to control group without infection. Concurrently, the dying zebrafish displayed excessive immune response and produced higher level of reactive oxygen species (ROS). Interestingly, exogenous tryptophan reverted dying rate through metabolome re-programming, thereby enhancing the survival from V. alginolyticus infection. It is preceded by the following mechanism: tryptophan fluxed into the glycolysis and tricarboxylic acid cycle (TCA cycle), promoted adenosine triphosphate (ATP) production and further increased the generation of NADPH. Meanwhile, tryptophan decreased NADPH oxidation. These together ameliorate ROS, key molecules in excessive immune response. This is further supported by the event that the inhibition of pyruvate metabolism and TCA cycle by inhibitors decreased D. reiro survival. Thus, our data indicate that tryptophan is a key metabolite for the host to fight against V. alginolyticus infection, representing an alternative strategy to treat bacterial infection in an antibiotic-independent way.

Thymic stromal lymphopoietin induced early stage of epithelial-mesenchymal transition in human bronchial epithelial cells through upregulation of transforming growth factor beta 1.

Purpose: Epithelial-mesenchymal transition (EMT) involved in asthmatic airway remodeling. Thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine, was a key component in airway immunological response in asthma. But the role of TSLP in the EMT process was unknown. We aimed to access whether TSLP could induce EMT in airway epithelia and its potential mechanism. Materials and Methods: Human bronchial epithelial (HBE) cells were incubated with TSLP or transforming growth factor beta 1 (TGF-ß1) or both. SB431542 was used to block TGF-ß1 signal while TSLP siRNA was used to performed TSLP knockdown. Changes in E-cadherin, vimentin, collagen I and fibronectin level were measured by real-time PCR, western blot and immunofluorescence staining. Expressions of TGF-ß after TSLP administration were measured by real-time PCR, western blot and ELISA. Results: TSLP induced changes of EMT relevant markers alone and promoted TGF-ß1-induced EMT in HBEs. Intracellular and extracellular expression of TGF-ß1 were upregulated by TSLP. SB431542 blocked changes of EMT relevant markers induced by TSLP. Knockdown of TSLP not only reduced TSLP and TGF-ß1 expression but also inhibited changes of EMT relevant markers induced by TGF-ß1 in HBEs. Conclusions: TSLP could induce early stage of EMT in airway epithelial cells through upregulation of TGF-ß1. This effect may act as a targeting point for suppression of asthma.

Modulation of B cell activation threshold mediated by BCR/CD40 costimulation by targeting Cbl-b for ubiquitination.

It has been shown that CD40 is required for optimal B cell activation. Casitas-B-lineage lymphoma-b (Cbl-b), a RING finger E3 ubiquitin ligase, inhibits B cell activation. In this report, we demonstrate that CD40 stimulation markedly enhances IgM-induced B cell proliferation in wild-type (WT) mice, whereas this cell proliferation was reduced in CD40-deficient (Cd40 -/-) mice. Interestingly, CD40 ligation strongly augments IgM-induced Cbl-b ubiquitination and degradation in primary mouse B cells, which closely correlates with their proliferation capacity. Cbl-b deficiency uncouples BCR-induced B cell proliferation from CD40 costimulation. Our results indicate that Cbl-b negatively regulates costimulation of BCR and CD40, possibly by setting the threshold for B cell activation via controlling Cbl-b expression.

A Case With 4 de Novo Copy Number Variations With Clinical Features That Overlap 1q43q44 Microdeletion and 3q29 Microduplication Syndromes.

1q43q44 microdeletion syndrome is characterized by intellectual disability/global developmental delay, epilepsy, dysmorphic facies, stereotypic movement, language delay, recurrent infections, dental anomalies, and hand and foot anomalies. Microcephaly and corpus callosum dysplasia are present in some cases depending on gene content. 3q29 microduplication syndrome is characterized by intellectual disability, language delay, microcephaly, and dental anomalies. We report the first case with 4 de novo copy number variations with clinical features which overlap 1q43q44 microdeletion and 3q29 microduplication syndromes. Our case presented with global developmental delay, epilepsy, recurrent infections, stereotypic movements, speech delay, microcephaly, facial dysmorphism, bilateral clinodactyly, and small puffy feet with metatarsus varus; however, she had no corpus callosum dysplasia. Our case highlights the role of multiple copy number variations in the occurrence of a certain phenotype. Moreover, it supports the theory that the loss of HNRNPU gene function cannot explain the occurrence of microcephaly and abnormalities of the corpus callosum in 1q43q44 microdeletion syndrome.

Aberrant epithelial remodeling with impairment of cilia architecture in non-cystic fibrosis bronchiectasis.

BACKGROUND: Aberrant epithelial remodeling and/or abnormalities in mucociliary apparatus in airway epithelium contribute to infection and inflammation. It is uncertain if these changes occur in both large and small airways in non-cystic fibrosis bronchiectasis (non-CF bronchiectasis). In this study, we aim to investigate the histopathology and inflammatory profile in the epithelium of bronchi and bronchioles in bronchiectasis. METHODS: Excised lung tissue sections from 52 patients with non-CF bronchiectasis were stained with specific cellular markers and analyzed by immunohistochemistry and immunofluorescence to assess the epithelial structures, including ciliated cells and goblet cells morphology. Inflammatory cell counts and ciliary proteins expression levels of centrosomal protein 110 (CP110) and dynein heavy chain 5, axonemal (DNAH5) were assessed. RESULTS: Epithelial hyperplasia is found in both bronchi and bronchioles in all specimens, including hyperplasia and/or hypertrophy of goblet cells. The median cilia length is longer in hyperplastic epithelium [bronchi: 8.16 (7.03-9.14) µm, P<0.0001; bronchioles: 7.46 (6.41-8.48) µm, P<0.0001] as compared to non-hyperplastic epithelium (bronchi: 5.60 µm; bronchioles: 4.89 µm). Hyperplastic epithelium is associated with overexpression of CP110 and decreased intensity of DNAH5 expression in both bronchial and bronchiolar epithelium. Though infiltration of neutrophils is predominant (63.0% in bronchi and 76.7% in bronchioles), eosinophilic infiltration is also present in the mucosa of bronchi (30.8%) and bronchioles (54.8%). CONCLUSIONS: Aberrant epithelial remodeling with impaired mucociliary architecture is present in both large and small airways in patients with refractory non-CF bronchiectasis. Future studies should evaluate the interplay between these individual components in driving chronic inflammation and lung damage in patients.

ECMO as an effective rescue therapeutic for fulminant myocarditis complicated with refractory cardiac arrest.

Fulminant myocarditis (FM) is a life-threatening disease in children. With a rapid, progressive course of deterioration, it causes refractory cardiorespiratory failure even with optimal clinical intervention. We present the case of a 9-year-old girl with FM complicated by cardiogenic shock, malignant arrhythmia, and refractory cardiac arrest. She received effective cardiopulmonary resuscitation, therapeutic hypothermia, and other supportive treatments. However, the patient rapidly worsened into pulseless ventricular tachycardia and refractory cardiac arrest. Therefore, we performed extracorporeal membrane oxygenation (ECMO) to establish spontaneous circulation after the failure of standard resuscitation measures. The girl recovered with intact cardiac and neurocognitive functions after continued ECMO treatment for 221 hours. Therefore, ECMO is an effective rescue therapeutics for FM, especially when complicated with refractory cardiac arrest.

Neonatal Cutaneous Invasive Aspergillosis Accompanied by Hemophagocytic Lymphohistocytosis.

We describe a 6-week-old female infant with cutaneous invasive aspergillosis accompanied with hemophagocytic lymphohistocytosis. Aspergillus flavus was isolated from biopsies of necrotic skin lesions on the forehead and scalp; morphologic identification was confirmed by molecular analysis. In vitro antifungal susceptibility testing showed that amphotericin B and triazoles had potent activity. The patient responded well to treatment with intravenous amphotericin B combined with oral posaconazole and local wound care. The hemophagocytic lymphohistocytosis abated after treatment of cutaneous aspergillosis. Both cutaneous invasive aspergillosis and hemophagocytic lymphohistocytosis are severe disorders with high morbidity and mortality requiring prompt diagnosis and treatment.