A comparative study of hypothalamic involvement in patients with myelin oligodendrocyte glycoprotein antibody-associated disease, neuromyelitis optica spectrum disorder, and multiple sclerosis.

BACKGROUND AND PURPOSE: We aimed to characterize hypothalamic involvement in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and compare it with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). METHODS: A retrospective study was performed to identify hypothalamic lesions in patients diagnosed with MOGAD, NMOSD, or MS from January 2013 to May 2020. The demographic, clinical, and radiological features were recorded. Hypothalamic dysfunction and prognosis were assessed through physical examination, biochemical testing, sleep monitoring, and magnetic resonance imaging. RESULTS: Hypothalamic lesions were observed in seven of 96 patients (7.3%) with MOGAD, 34 of 536 (6.3%) with NMOSD, and 16 of 356 (4.5%) with MS (p = 0.407). The time from disease onset to development of hypothalamic lesions was shortest in MOGAD (12 months). The frequency of bilateral hypothalamic lesions was the lowest in MOGAD (p = 0.008). The rate of hypothalamic dysfunction in MOGAD was 28.6%, which was lower than that in NMOSD (70.6%) but greater than that in MS patients (18.8%; p = 0.095 and p = 0.349, respectively). Hypothalamic dysfunction in MOGAD manifests as hypothalamic-pituitary-adrenal axis dysfunction and hypersomnia. The proportion of complete regression of hypothalamic lesions in MOGAD (100%) was much greater than that in NMOSD (41.7%) and MS patients (18.2%; p = 0.007 and p = 0.001, respectively). An improvement in hypothalamic dysfunction was observed in all MOGAD patients after immunotherapy. CONCLUSIONS: MOGAD patients have a relatively high incidence of asymptomatic hypothalamic lesions. The overall prognosis of patients with hypothalamic involvement is good in MOGAD, as the lesions completely resolve, and dysfunction improves after immunotherapy.

Pregnancy outcomes in women with severe acute respiratory syndrome coronavirus 2 reinfections compared to those with a single infection: a retrospective cohort study.

BACKGROUND: To assess pregnancy outcomes in women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection. METHODS: This was a retrospective cohort study that included pregnant women who contracted coronavirus disease 2019 (COVID-19) once or twice during pregnancy and who gave birth between 1 October 2022 and 15 August 2023 in Shanghai First Maternity and Infant Hospital (Shanghai, China). We collected their clinical data and compared the frequency of adverse pregnancy outcomes between the reinfection group and the primary infection group, such as preterm birth, fetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), common pregnancy-related conditions, birth weight, and neonatal unit admission. RESULTS: We observed a 7.7% reinfection rate among the 1,405 women who contracted COVID-19 during pregnancy. There were no significant differences in the frequency of preterm birth, FGR, HDP, other common pregnancy-related conditions, birth weight, or rate of neonatal unit admission between the reinfection and single infection groups. All our participants were unvaccinated, and all had mild symptoms. CONCLUSION: Our study showed no significant association between SARS-CoV-2 reinfection and adverse pregnancy outcomes.

Taxonomy and anticancer potential of Streptomyces niphimycinicus sp. nov. against nasopharyngeal carcinoma cells.

Streptomyces species are ubiquitous, Gram-positive, spore-forming bacteria with the ability to produce various clinically relevant compounds. The strain 4503 T was isolated from mangrove sediments, showing morphological and chemical properties which were consistent with those of members of the genus Streptomyces. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate was primarily identified as members of the genus Streptomyces, sharing more than 99% sequence identity to Streptomyces yatensis DSM 41771 T, S. antimycoticus NBRC 12839 T, and S. melanosporofaciens NBRC 13061 T. Average nucleotide identities (ANI) and digital DNA-DNA hybridization (dDDH) values between strain 4503 T and its close relatives were all below 95-96% and 75% of the novel species threshold, respectively. Results from phylogenetic, genomic, phenotypic, and chemotaxonomic characteristics analyses confirmed that the isolate represented a novel species of the genus Streptomyces, for which the name Streptomyces niphimycinicus sp. nov. 4503 T (= MCCC 1K04557T = JCM 34996 T) is proposed. The bioassay-guided fractionation of the extract of strain 4503 T resulted in the isolation of a known compound niphimycin C, which showed cytotoxic activity against nasopharyngeal carcinoma (NPC) cell lines TW03 and 5-8F with half maximal inhibitory concentration (IC50) values of 12.24 µg/mL and 9.44 µg/mL, respectively. Further experiments revealed that niphimycin C not only exhibited the capacity of anti-proliferation, anti-metastasis, induction of cell cycle arrest, and apoptosis, but was also able to increase the reactive oxygen species (ROS) production and regulate several signaling pathways in NPC cells. KEY POINTS: • Strain 4503 T was classified as a novel species of Streptomyces. • Niphimycin C correlates with the cytotoxic effect of strain 4503 T against NPC cells. • Niphimycin C induces apoptosis, autophagic flux disruption and cell cycle arrest.

Novosphingobium beihaiensis sp. nov., a novel pesticide-tolerant bacterium isolated from mangrove sediments.

A novel Novosphingobium species, designated strain B2638T, was isolated from mangrove sediments which was collected from Beibu Gulf, Beihai, P. R. China. The isolate could grow in the presence of chlorpyrifos. Phylogenetic analysis based on 16S rRNA gene sequence revealed that the isolate belonged to the genus Novosphingobium, showing 99.9% sequence similarity with N. decloroationis 502str22T and less than 98% similarity with other type strain of species of this genus. Molecular typing by BOX-PCR divided strain B2638T and N. declorationis 502str22T into two clusters and indicated that they were not identical. Genomic comparison referenced by values of the DNA-DNA hybridization (dDDH) and the average nucleotide identity (ANI) between strain B2638T and its close phylogenetic neighbors were 20.0-29.5% and 75.3-85.3%, respectively, that were lower than proposed thresholds for bacterial species delineation. The major fatty acids (> 10%) were identified as C18:1 ω7c, C17:1 iso ω9c and C16:0. The main polar lipids contained diphosphatidylglycerol, phosphatidylethanolamine, sphingoglycolipid, phosphatidyl glycerol, unidentified lipid and unidentified aminolipid. Results from phenotypic, chemotaxonomic and genotypic analyses proposed that strain B2638T (= MCCC 1K07406T = KCTC 72968 T) is represented a novel species in the genus Novosphingobium, for which the names Novosphingobium beihaiensis sp. nov. is proposed.

Alterations in maternal plasma exosomal miRNAs revealed selective material exchange between maternal circulation and placenta.

AIM: Exosomes have emerged as important regulators in the communication between maternal peripheral blood and placenta. We aimed to compare maternal plasma exosomal miRNAs profile between healthy pregnant and nonpregnant women, screen for differential expressed miRNAs and their potential regulatory role during pregnancy. METHODS: We isolated exosomes from plasma of mid-trimester, last trimester, and nonpregnant women (n = 6 each group), analyzed the miRNA profile using next-generation sequencing. RESULTS: Several miRNA clusters were expressed in plasma exosomes, such as C19MC, C14MC, and let-7 family, miRNAs in each cluster may have synergistic effect during pregnancy. We assumed maternal circulating exosomal miRNA could be transported into placenta or selectively uptook by placenta, which was consistent with the fact that many pregnancy-associated or placenta highly expressed miRNAs reduced in exosomes during pregnancy. Some exosomal miRNAs were mainly secreted by the placenta, which could act as markers that reflect changes in the function and microenvironment of the placenta. CONCLUSIONS: Exosomal miRNAs are associated with placenta development and have potential as molecular markers.

Hypersensitivity may be involved in severe COVID-19.

BACKGROUND: Deaths attributed to Coronavirus Disease 2019 (COVID-19) are mainly due to severe hypoxemic respiratory failure. Although the inflammatory storm has been considered the main pathogenesis of severe COVID-19, hypersensitivity may be another important mechanism involved in severe cases, which have a perfect response to corticosteroids (CS). METHOD: We detected the serum level of anti-SARS-CoV-2-spike S1 protein-specific IgE (SP-IgE) and anti-SARS-CoV-2 nucleocapsid protein-specific IgE (NP-IgE) in COVID-19. Correlation of levels of specific IgE and clinical severity were analysed. Pulmonary function test and bronchial provocation test were conducted in early convalescence of COVID-19. We also obtained histological samples via endoscopy to detect the evidence of mast cell activation. RESULT: The levels of serum SP-IgE and NP-IgE were significantly higher in severe cases, and were correlated with the total lung severity scores (TLSS) and the PaO2 /FiO2 ratio. Nucleocapsid protein could be detected in both airway and intestinal tissues, which was stained positive together with activated mast cells, binded with IgE. Airway hyperresponsiveness (AHR) exists in the early convalescence of COVID-19. After the application of CS in severe COVID-19, SP-IgE and NP-IgE decreased, but maintained at a high level. CONCLUSION: Hypersensitivity may be involved in severe COVID-19.

The imaging quantification of multiple organs by dynamic 18F-FDG PET/CT in discharged COVID-19 patients: A prospective pilot study.

Purpose: To early identify abnormal lesions by applying the 18F-FDG PET dynamic modeling approach for discharged patients recovering from COVID-19. Methods: Seven discharged COVID-19 patients (COVID-19 group), twelve healthy volunteers (control group 1), and eight cancer patients with normal pulmonary function (control group 2) were prospectively enrolled. Control group 1 completed static 18F-FDG PET/CT only; COVID-19 group and control group 2 completed 60-min dynamic 18F-FDG PET/CT. Among COVID-19 group and control group 2, the uptake of FDG on the last frame (at 55-60 min) of dynamic scans was used for static analysis. Prior to performing scans, COVID-19 patients provided negative real-time Reverse Transcription-Polymerase Chain Reaction (rRT-PCR) of SARS-CoV-2, normal lung functions test, and normal laboratory test. Organ-to-liver standard uptake ratio (OLR, i.e. SUVmax evaluated organ/ SUVmax liver) from conventional static data and Patlak analysis based on the dynamic modeling to calculate the 18F-FDG net uptake rate constant (Ki) were performed. Results: Compared to the control groups, COVID-19 patients at two to three months after discharge still maintained significantly higher Ki values in multiple organs (including lung, bone marrow, lymph nodes, myocardium and liver), although results for regular OLR measurements were normal for all discharged COVID-19 patients. Taking the image of lung as an example, the differences of SUVmax images between COVID-19 group and control group were hard to distinguish. In contrast, a high 18F-FDG signal of the lung among the COVID-19 group was observed for Ki images. Conclusion: The Ki from 18F-FDG PET/CT dynamic imaging quantification might contribute to identifying residual lesions for COVID-19 survivors. Trial registration: The trial is registered with ClinicalTrials.gov, number NCT04519255 (IRB-approved number, K52-1).

Clinical Course and Factors Associated with Viral RNA Shedding and Radiologic Resolution in Patients with COVID-19: a Retrospective Study.

BACKGROUND: The outbreak of SARS-CoV-2 lead to a worldwide pandemic which poses substantial challenges to public health. METHODS: We enrolled 102 consecutive recovered patients with laboratory-confirmed SARS-CoV-2 infection. Epidemiological and demographic characteristics, temporal dynamic profiles of laboratory tests and findings on chest CT radiography, and clinical outcomes were collected and analyzed. RESULTS: Independent risk factors for prolonged fever, viral RNA shedding or radiologic recovery included age of more than 44 years, female gender, having symptoms of cough and fever, a delay from the symptom onset to hospitalization of more than 3 days, a lower CD4 count of less than 500/µL on admission, and severe or critical illness in hospitalization. The estimated median time from symptom onset was 6.4 (5.5 - 7.4) days to peak viral load, 9.1 (7.9 - 10.4) days to afebrile, 8 (6.7 - 9.4) days to worst radiologic finding, 12.7 (11.2 - 14.3) days to viral RNA negativity, and 26.7 (23.8 - 29.9) days to radiologic resolution. This study included the entire cross-section of patients seen in our clinical practice and reflected the real-world situation. CONCLUSIONS: These findings provide the rationale for strategies of active symptom monitoring, timing of quarantine and antiviral interventions, and duration of radiologic follow-up in patients with COVID-19.

Household Transmission of SARS-CoV-2, Zhuhai, China, 2020.

BACKGROUND: To illustrate the extent of transmission, identify affecting risk factors and estimate epidemiological modeling parameters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in household setting. METHODS: We enrolled 35 confirmed index cases and their 148 household contacts, January 2020-February 2020, in Zhuhai, China. All participants were interviewed and asked to complete questionnaires. Household contacts were then prospectively followed active symptom monitoring through the 21-day period and nasopharyngeal and/or oropharyngeal swabs were collected at 3-7 days intervals. Epidemiological, demographic, and clinical data (when available) were collected. RESULTS: Assuming that all these secondary cases were infected by their index cases, the second infection rate in household context is 32.4% (95% confidence interval [CI]: 22.4%-44.4%), with 10.4% of secondary cases being asymptomatic. Multivariate analysis showed that household contacts with underlying medical conditions, a history of direct exposure to Wuhan and its surrounding areas, and shared vehicle with an index patient were associated with higher susceptibility. Household members without protective measures after illness onset of the index patient seem to increase the risk for SARS-CoV-2 infection. The median incubation period and serial interval within household were estimated to be 4.3 days (95% CI: 3.4-5.3 days) and 5.1 days (95% CI: 4.3-6.2 days), respectively. CONCLUSION: Early isolation of patients with coronavirus disease 2019 and prioritizing rapid contact investigation, followed by active symptom monitoring and periodic laboratory evaluation, should be initiated immediately after confirming patients to address the underlying determinants driving the continuing pandemic.

Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase.

OBJECTIVE: This study investigated the influence of Coronavirus Disease 2019 (COVID-19) on lung function in early convalescence phase. METHODS: A retrospective study of COVID-19 patients at the Fifth Affiliated Hospital of Sun Yat-sen University were conducted, with serial assessments including lung volumes (TLC), spirometry (FVC, FEV1), lung diffusing capacity for carbon monoxide (DLCO),respiratory muscle strength, 6-min walking distance (6MWD) and high resolution CT being collected at 30 days after discharged. RESULTS: Fifty-seven patients completed the serial assessments. There were 40 non-severe cases and 17 severe cases. Thirty-one patients (54.3%) had abnormal CT findings. Abnormalities were detected in the pulmonary function tests in 43 (75.4%) of the patients. Six (10.5%), 5(8.7%), 25(43.8%) 7(12.3%), and 30 (52.6%) patients had FVC, FEV1, FEV1/FVC ratio, TLC, and DLCO values less than 80% of predicted values, respectively. 28 (49.1%) and 13 (22.8%) patients had PImax and PEmax values less than 80% of the corresponding predicted values. Compared with non-severe cases, severe patients showed higher incidence of DLCO impairment (75.6%vs42.5%, p = 0.019), higher lung total severity score (TSS) and R20, and significantly lower percentage of predicted TLC and 6MWD. No significant correlation between TSS and pulmonary function parameters was found during follow-up visit. CONCLUSION: Impaired diffusing-capacity, lower respiratory muscle strength, and lung imaging abnormalities were detected in more than half of the COVID-19 patients in early convalescence phase. Compared with non-severe cases, severe patients had a higher incidence of DLCO impairment and encountered more TLC decrease and 6MWD decline.

Bacillus cereus spores and toxins - The potential role of biofilms.

Bacillus cereus is a well-known foodborne pathogen capable of causing two types of gastrointestinal diseases, diarrhoea and emesis. It is of particular concern for the food industry causing food safety issues, due to the formation of spores, biofilms and diarrhoea and/or emetic toxins. This review reveals the possible link between two food safety issues - toxins and spores - and the role of biofilms. The review highlights genetic determinants that are involved in sporulation, toxin production and biofilm formation based on current research, and evidence showing the possible correlation of spore, toxin and biofilm formation of B. cereus. This is the first review highlighting the potential relationship between toxin production and biofilm formation in B. cereus.

Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson's disease.

BACKGROUND: Multiple risk factors contribute to the progression of Parkinson's disease, including oxidative stress and neuroinflammation. Epidemiological studies have revealed a link between higher urate level and a lower risk of developing PD. However, the mechanistic basis for this association remains unclear. Urate protects dopaminergic neurons from cell death induced by oxidative stress. Here, we investigated a novel role of urate in microglia activation in a lipopolysaccharide (LPS)-induced PD model. METHODS: We utilized Griess, ELISA, real-time PCR, Western blot, immunohistochemistry, and immunofluorescence to detect the neuroinflammation. For Griess, ELISA, Western blot, and immunofluorescence assay, cells were seeded in 6-well plates pre-coated with poly-L-lysine (PLL) and incubated for 24 h with the indicated drugs. For real-time PCR assay, cells were seeded in 6-well plates pre-coated with PLL and incubated for 6 h with the indicated drugs. For animal experiments, rats were injected with urate or its vehicle twice daily for five consecutive days before and after stereotaxic surgery. Rats were killed and brain tissues were harvested after 4 weeks of LPS injection. RESULTS: In cultured BV2 cells and rat primary microglia, urate suppressed proinflammatory cytokine production and inducible cyclooxygenase 2 and nitric oxide synthase expression to protect dopaminergic neurons from the toxic effects of activated microglia. The neuroprotective effects of urate may also be associated with the stimulation of anti-inflammatory factors interleukin 10 and transforming growth factor ß1. Intracellular urate level was increased in a dose-dependent manner upon co-treatment with urate and LPS as compared with LPS alone, an effect that was abrogated by pretreatment with probenecid (PBN), an inhibitor of both glucose transporter 9 and urate transporter 1 (URAT1). PBN also abolished the anti-inflammatory effect of urate. Consistent with these in vitro observations, the number of tyrosine hydroxylase-positive neurons was decreased and the loss of motor coordination was reversed by urate administration in an LPS-induced rat model of PD. Additionally, increased plasma urate level abolished the reduction of URAT1 expression, the increase in the expression of interleukin-1ß, and the number of ionized calcium-binding adaptor molecule 1-positive microglia along with changes in their morphology. CONCLUSIONS: Urate protects neurons against cytotoxicity induced by microglia activation via modulating urate transporter-mediated intracellular urate level.

Triptolide up-regulates metabotropic glutamate receptor 5 to inhibit microglia activation in the lipopolysaccharide-induced model of Parkinson's disease.

Metabotropic glutamate receptor (mGlu)5 regulates microglia activation, which contributes to inflammation. However, the role of mGlu5 in neuroinflammation associated with Parkinson's disease (PD) remains unclear. Triptolide (T10) exerts potent immunosuppressive and anti-inflammatory effects and protects neurons by inhibiting microglia activation. In this study, we investigated the role of mGlu5 in the anti-inflammatory effect of T10 in a lipopolysaccharide (LPS)-induced PD model. In cultured BV2 cells and primary microglia, blocking mGlu5 activity or knocking down its expression abolished T10-inhibited release of proinflammatory cytokines induced by LPS. Moreover, T10 up-regulated mGlu5 expression decreased by LPS through enhancing mRNA expression and protein stability. T10 also reversed the reduction in mGlu5 membrane localization and modulated receptor-mediated mitogen-activated protein kinase activity induced by LPS. Pharmacological inhibition of signaling molecules increased nitric oxide level and inducible nitric oxide synthase (iNOS), tumor necrosis factor-α, and interleukin (IL)-1ß and -6 transcript levels that were downregulated by treatment with T10. Consistent with these in vitro findings, blocking mGlu5 attenuated the anti-inflammatory effects of T10 in an LPS-induced PD model and blocked the decreases in the number and morphology of ionized calcium binding adaptor molecule 1-positive microglia and LPS-induced iNOS protein expression caused by T10 treatment. Besides, mGlu5 mediated the effect of T10 on microglia-induced astrocyte activation in vitro and in vivo. The findings provide evidence for a novel mechanism by which mGlu5 regulates T10-inhibited microglia activation via modulating protein expression of the receptor and its intracellular signaling. The study might contribute to the biological effects of Chinese herbs as an approach for protecting against neurotoxicity in PD.

Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site.

OBJECTIVES: The testes are a potential viral sanctuary site for HIV-1 infection. Our study aims to provide insight into the expression and localization of key drug transporters and metabolic enzymes relevant to ART in this tissue compartment. METHODS: We characterized gene and protein expression of 12 representative drug transporters and two metabolic enzymes in testicular tissue samples obtained from uninfected (n = 8) and virally suppressed HIV-1-infected subjects on ART (n = 5) and quantified antiretroviral drug concentrations in plasma and testicular tissues using LC/MS/MS from HIV-1-infected subjects. RESULTS: Our data demonstrate that key ABC drug transporters (permeability glycoprotein, multidrug-resistance protein 1, 2 and 4, and breast cancer resistance protein), solute carrier transporters (organic anion transporting polypeptides 1B1 and 2B1, organic anion transporter 1, concentrative nucleoside transporter 1, equilibrative nucleoside transporter 2) and cytochrome P450 metabolic enzymes (CYP3A4 and CYP2D6) previously shown to interact with many commonly used antiretroviral drugs are expressed at the mRNA and protein level in the testes of both subject groups and localize primarily at the blood-testis barrier, with no significant differences between the two groups. Furthermore, we observed that PIs known to be substrates for ATP-binding cassette membrane transporters, displayed variable testicular tissue penetration, with darunavir concentrations falling below therapeutic values. In contrast, the NRTIs emtricitabine, lamivudine and tenofovir displayed favourable tissue penetration, reaching concentrations comparable to plasma levels. We also demonstrated that nuclear receptors, peroxisome proliferator-activated receptors α and γ exhibited higher gene expression in the testicular tissue compared with pregnane X receptor and constitutive androstane receptor, suggesting a potential regulatory pathway governing drug transporter and metabolic enzyme expression in this tissue compartment. CONCLUSIONS: Our data suggest the testes are a complex pharmacological compartment that can restrict the distribution of certain antiretroviral drugs and potentially contribute to HIV-1 persistence.

Causal relationship between rheumatoid arthritis and bronchiectasis: a bidirectional mendelian randomization study.

BACKGROUND: Epidemiological observational studies have elucidated a correlation between rheumatoid arthritis (RA) and bronchiectasis. However, the causal nature of this association remains ambiguous. To clarify this potential causal linkage, we conducted a two-sample Mendelian randomization (MR) analysis to explore the bidirectional causality between RA and bronchiectasis. METHODS: Summary statistics for RA and bronchiectasis were obtained from the IEU OpenGWAS database We employed various methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode, to explore potential causal links between RA and bronchiectasis. Additionally, a series of sensitivity studies, such as Cochran's Q test, MR Egger intercept test, and leave-one-out analysis, were conducted to assess the MR analysis's accuracy further. RESULTS: In the forward MR analysis, the primary analysis indicated that a genetic predisposition to RA correlated with an increased risk of bronchiectasis in European populations (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20-1.37, p = 1.18E-13). Comparable results were noted in the East Asian subjects (IVW OR: 1.55, 95% CI: 1.30-1.34, p = 8.33E-07). The OR estimates from the other four methods were consistent with those obtained from the IVW method. Sensitivity analysis detected no evidence of horizontal pleiotropy or heterogeneity. Conversely, in the reverse MR analysis, we found no evidence to support a genetic causality between bronchiectasis and RA in either European or East Asian populations. CONCLUSION: This study indicates that genetic predisposition to RA correlates with a heightened risk of bronchiectasis in both European and East Asian populations. These results imply that routine screening for bronchiectasis in RA patients could be beneficial, and effective management of RA may contribute to a reduced risk of bronchiectasis. Future research should aim to clarify the underlying mechanisms linking these two conditions.

Clinical and imaging features of patients with late-onset myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: There is an age-dependent change in the clinical phenotype of Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the clinical features of late-onset MOGAD have not been well described. METHODS: Clinical data of 110 MOGAD patients, including 21 late-onset patients with onset age greater than or equal to 50 years old were retrospectively analyzed. RESULTS: Compared to pediatric- and younger adult-onset ones, late-onset MOGAD patients experienced milder disease onset (p < 0.001), more monophasic course (p < 0.001), fewer relapses (p = 0.007), less cerebrospinal fluid leukocytosis (p = 0.021), less longitudinally extensive transverse myelitis (onset p = 0.026, whole course p = 0.028), fewer lesions in basal ganglia (whole course p = 0.012), thalamus (whole course p = 0.040) and cerebellum (whole course p = 0.028). However, they had more cerebral symptoms (p = 0.021 onset and whole course), more lesions in white matter (onset p = 0.005, whole course p < 0.001) and periventricular area (onset p = 0.026), along with longer and delayed therapeutic intervention (p < 0.001). The main differences in clinical characteristics between late-onset patients with and without these brain involvements might be comorbidities. CONCLUSIONS: Late-onset MOGAD are more likely to experience delayed diagnosis. Brain involvement may be modulated by comorbidities of the elderly, which alter the clinical manifestations of late-onset MOGAD.

Downregulation of NEBL promotes migration and invasion of clear cell renal cell carcinoma by inducing epithelial-mesenchymal transition.

As a member of the nebulin protein family and a structural protein of cytoskeleton, NEBL plays an important role in cardiac diseases. Recently, literature have reported the involvement of NEBL in the occurrence and development of various cancers except clear cell renal cell carcinoma (ccRCC). In this study, we found that mRNA and protein of NEBL are downregulated remarkably in ccRCC tissues based on both the TCGA database and clinical samples we collected. The areas under curve values of NEBL analyzed based on the TCGA database, qRT-PCR and IHC results were 0.9376, 0.9733 and 0.9807, respectively. The lower mRNA level of NEBL was associated with worse outcomes in ccRCC patients. When overexpressing NEBL in ccRCC cell lines, the proliferation, migration and invasion of ccRCC cells were suppressed significantly, suggesting a tumor suppressor role of NEBL. In addition, we identified that NEBL is closely related to epithelial-mesenchymal transition (EMT), thereby reducing the motility of ccRCC cells. Furthermore, the lower expression of NEBL was correlated with ccRCC patients with distant organ metastasis. In summary, we firstly described the aberrant expression of NEBL and revealed its tumor suppressor role in ccRCC. Our data support that NEBL could serve as a valuable diagnostic and prognostic biomarker in ccRCC, as well as a promising therapeutic target.

Teriflunomide Promotes Blood-Brain Barrier Integrity by Upregulating Claudin-1 via the Wnt/ß-catenin Signaling Pathway in Multiple Sclerosis.

The blood-brain barrier (BBB) and tight junction (TJ) proteins maintain the homeostasis of the central nervous system (CNS). The dysfunction of BBB allows peripheral T cells infiltration into CNS and contributes to the pathophysiology of multiple sclerosis (MS). Teriflunomide is an approved drug for the treatment of MS by suppressing lymphocytes proliferation. However, whether teriflunomide has a protective effect on BBB in MS is not understood. We found that teriflunomide restored the injured BBB in the EAE model. Furthermore, teriflunomide treatment over 6 months improved BBB permeability and reduced peripheral leakage of CNS proteins in MS patients. Teriflunomide increased human brain microvascular endothelial cell (HBMEC) viability and promoted BBB integrity in an in vitro cell model. The TJ protein claudin-1 was upregulated by teriflunomide and responsible for the protective effect on BBB. Furthermore, RNA sequencing revealed that the Wnt signaling pathway was affected by teriflunomide. The activation of Wnt signaling pathway increased claudin-1 expression and reduced BBB damage in cell model and EAE rats. Our study demonstrated that teriflunomide upregulated the expression of the tight junction protein claudin-1 in endothelial cells and promoted the integrity of BBB through Wnt signaling pathway.

Safety and efficacy of inactivated COVID-19 vaccines in women vaccinated during the first trimester of pregnancy.

OBJECTIVES: This study aimed to investigate the safety of the inactivated COVID-19 vaccines in early pregnant women in view of their adverse-effect profile and associated maternal-fetal complications, as well as to evaluate their immunogenicity. METHODS: In this prospective observational cohort study, 232 women in their first trimester or those in the periconception period who inadvertently received two doses of inactivated COVID-19 vaccine between January 21, 2021, and January 14, 2022 were analyzed. Meanwhile, 735 unvaccinated early pregnancy women were also included in the study at a case-to-control ratio of 1:3. RESULTS: The vaccination group did not have an increased miscarriage rate compared with that of the control group (P = 0.918). Furthermore, the birth defect rates in the vaccine group and control group were 0.83% and 1.0%, respectively. Vaccination did not increase the risk of small for gestational age, gestational diabetes mellitus, preterm, or hypertensive disorders of pregnancy (P >0.01). Within 12 weeks after the second dose, the inactivated vaccine effectively produced neutralizing antibody (NAb) against SARS-CoV-2. The NAb levels in the paired umbilical cord serum and maternal serum samples during delivery were negative in both groups. The T-cell subset remained within the normal range in both groups. CONCLUSION: Therefore, our study proves that inactivated COVID-19 vaccines are safe for mothers and fetuses and also effective in producing NAb against SARS-CoV-2.