Galectin from Trichinella spiralis alleviates DSS-induced colitis in mice by regulating the intestinal microbiota.

According to numerous reports, Trichinella spiralis (T. spiralis) and its antigens can reduce intestinal inflammation by modulating regulatory immunological responses in the host to maintain immune homeostasis. Galectin has been identified as a protein that is produced by T. spiralis, and its characterization revealed this protein has possible immune regulatory activity. However, whether recombinant T. spiralis galectin (rTs-gal) can cure dextran sulfate sodium (DSS)-induced colitis remains unknown. Here, the ability of rTs-gal to ameliorate experimental colitis in mice with inflammatory bowel disease (IBD) as well as the potential underlying mechanism were investigated. The disease activity index (DAI), colon shortening, inflammatory cell infiltration, and histological damage were used as indicators to monitor clinical symptoms of colitis. The results revealed that the administration of rTs-gal ameliorated these symptoms. According to Western blotting and ELISA results, rTs-gal may suppress the excessive inflammatory response-mediated induction of TLR4, MyD88, and NF-κB expression in the colon. Mice with colitis exhibit disruptions in the gut flora, including an increase in gram-negative bacteria, which in turn can result in increased lipopolysaccharide (LPS) production. However, injection of rTs-gal may inhibit changes in the gut microbiota, for example, by reducing the prevalence of Helicobacter and Bacteroides, which produce LPS. The findings of the present study revealed that rTs-gal may inhibit signalling pathways that involve enteric bacteria-derived LPS, TLR4, and NF-κB in mice with DSS-induced colitis and attenuate DSS-induced colitis in animals by modulating the gut microbiota. These findings shed additional light on the immunological processes underlying the beneficial effects of helminth-derived proteins in medicine.

Enhanced exclusive enteral nutrition delivery during the first 7 days is associated with decreased 28-day mortality in critically ill patients with normal lactate level: a post hoc analysis of a multicenter randomized trial.

BACKGROUND AND AIMS: Exclusive enteral nutrition (EN) is often observed during the first week of ICU admission because of the extra costs and safety considerations for early parenteral nutrition. This study aimed to assess the association between nutrition intake and 28-day mortality in critically ill patients receiving exclusive EN. METHODS: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion. RESULTS: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L. CONCLUSIONS: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L. TRIAL REGISTRATION: ISRCTN12233792, registered on November 24, 2017.

Bacterial cellulose production by a strain of Komagataeibacter rhaeticus isolated from residual loquat.

In this study, loquat extract was selected as a promising substrate for bacterial cellulose (BC) production. A new BC-producing bacterial strain was isolated from residual loquat and identified as Komagataeibacter rhaeticus. BC production with different carbon sources and with loquat extract was investigated. Among all tested carbon sources, glucose was demonstrated to be the best substrate for BC production by K. rhaeticus, with up to 7.89 g/L dry BC obtained under the optimal initial pH (5.5) and temperature (28 °C) with 10 days of fermentation. The total sugar and individual sugars were investigated in different loquat extracts, in which fructose, glucose, and sucrose were the three main sugars. When loquat extract was prepared with a solid‒liquid (S-L) ratio of 2:1, the concentrations of glucose, fructose, and sucrose were 7.91 g/L, 9.31 g/L, and 2.84 g/L, respectively. The BC production obtained from loquat extract was higher than that of other carbon sources except glucose, and 6.69 g/L dry BC was obtained from loquat extract with an S-L ratio of 2:1. After BC production, all sugars substantially decreased, with the utilization of glucose, fructose, and sucrose reaching 93.9%, 87.9%, and 100%, respectively. These results suggested that the different sugars in loquat extract were all carbon sources participating in BC production by K. rhaeticus. Structural and physicochemical properties were investigated by SEM, TGA, XRD, and FT-IR spectroscopy. The results showed that the structural, chemical group, and water holding capacity of BC obtained from loquat extract were similar to those of BC obtained from glucose, but the crystallinity and thermal stability of BC were higher than those of BC from mannose and lactose but lower than those of BC from glucose and fructose. KEY POINTS: • A new BC-producing strain was isolated and identified as Komagataeibacter rhaeticus. • Loquat extract is an alternative substrate for BC production. • The BC obtained from loquat extract owns advanced physicochemical properties.

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BACKGROUND: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. METHODS: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. RESULTS: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups. CONCLUSIONS: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. TRIAL REGISTRATION: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Blueberry-derived exosomes-like nanoparticles ameliorate nonalcoholic fatty liver disease by attenuating mitochondrial oxidative stress.

Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress play a pivotal role in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). In this study, we found that blueberry-derived exosomes-like nanoparticles (BELNs) could ameliorate oxidative stress in rotenone-induced HepG2 cells and high-fat diet (HFD)-fed C57BL/6 mice. Preincubation with BELNs decreased the level of reactive oxygen species (ROS), increased the mitochondrial membrane potential, and prevented cell apoptosis by inducing the expression of Bcl-2 and heme oxygenase-1 (HO-1) and decreasing the content of Bax in rotenone-treated HepG2 cells. We also found that preincubation with BELNs accelerated the translocation of Nrf2, an important transcription factor of antioxidative proteins, from the cytoplasm to the nucleus in rotenone-treated HepG2 cells. Moreover, administration of BELNs improved insulin resistance, ameliorated the dysfunction of hepatocytes, and regulated the expression of detoxifying/antioxidant genes by affecting the distribution of Nrf2 in the cytoplasm and nucleus of hepatocytes of HFD-fed mice. Furthermore, BELNs supplementation prevented the formation of vacuoles and attenuated the accumulation of lipid droplets by inhibiting the expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1), the two key transcription factors for de novo lipogenesis in the liver of HFD-fed mice. These findings suggested that BELNs can be used for the treatment of NAFLD because of their antioxidative activity.

Imipenem cilastatin sodium-associated thrombocytopenia in an older patient: A case report and literature review.

Imipenem cilastatin sodium, as a member of a new generation of ß-lactam antibiotics, has a broad spectrum of antibacterial activity and a very wide range of application. Thrombocytopenia has been reported as a rare adverse event in several studies of patients treated with imipenem cilastatin sodium. In this study, we present a case of thrombocytopenia associated with imipenem cilastatin sodium in an older patient. The 78-year-old male patient with pulmonary infection was initiated on anti-infection therapy with imipenem cilastatin sodium. On the 9th day after imipenem cilastatin sodium administration, the patient experienced a sudden and dramatic decrease in platelet count. Similarly, on the 4th day after the re-administration of imipenem cilastatin sodium for anti-infection therapy, the patient's platelet count showed a remarkable downward trend again. A time correlation between the drug therapy and the occurrence of platelet reaction was found. The patient's platelet count gradually returned to the normal level on the 6th day after the first drug withdrawal and the 13th day after the second drug withdrawal, respectively. Considering the widespread use of imipenem cilastatin sodium, healthcare providers should improve the notification of thrombocytopenia associated with imipenem cilastatin sodium.

Altered neurovascular coupling in neuromyelitis optica.

Neurovascular coupling reflects the close relationship between neuronal activity and cerebral blood flow (CBF), providing a new mechanistic insight into health and disease. Neuromyelitis optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system and shows cognitive decline-related brain gray matter abnormalities besides the damage of optic nerve and spinal cord. We aimed to investigate neurovascular coupling alteration and its clinical significance in NMO by using regional homogeneity (ReHo) to measure neuronal activity and CBF to measure vascular response. ReHo was calculated from functional MRI and CBF was computed from arterial spin labeling (ASL) in 56 patients with NMO and 63 healthy controls. Global neurovascular coupling was assessed by across-voxel CBF-ReHo correlations and regional neurovascular coupling was evaluated by CBF/ReHo ratio. Correlations between CBF/ReHo ratio and clinical variables were explored in patients with NMO. Global CBF-ReHo coupling was decreased in patients with NMO relative to healthy controls (p = .009). Patients with NMO showed decreased CBF/ReHo ratio (10.9%-17.3% reduction) in the parietal and occipital regions and increased CBF/ReHo ratio (8.0%-13.3% increase) in the insular, sensorimotor, temporal and prefrontal regions. Some of these abnormalities cannot be identified by a single CBF or ReHo analysis. Both abnormally decreased and increased CBF/ReHo ratios were correlated with more severe clinical impairments and cognitive decline in patients with NMO. These findings suggested that patients with NMO show abnormal neurovascular coupling, which is associated with disease severity and cognitive impairments.

Enteral nutrition feeding in Chinese intensive care units: a cross-sectional study involving 116 hospitals.

BACKGROUND: There is a lack of large-scale epidemiological data on the clinical practice of enteral nutrition (EN) feeding in China. This study aimed to provide such data on Chinese hospitals and to investigate factors associated with EN delivery. METHODS: This cross-sectional study was launched in 118 intensive care units (ICUs) of 116 mainland hospitals and conducted on April 26, 2017. At 00:00 on April 26, all patients in these ICUs were included. Demographic and clinical variables of patients on April 25 were obtained. The dates of hospitalization, ICU admission and nutrition initiation were reviewed. The outcome status 28 days after the day of investigation was obtained. RESULTS: A total of 1953 patients were included for analysis, including 1483 survivors and 312 nonsurvivors. The median study day was day 7 (IQR 2-19 days) after ICU entry. The proportions of subjects starting EN within 24, 48 and 72 h after ICU entry was 24.8% (84/352), 32.7% (150/459) and 40.0% (200/541), respectively. The proportion of subjects receiving > 80% estimated energy target within 24, 48, 72 h and 7 days after ICU entry was 10.5% (37/352), 10.9% (50/459), 11.8% (64/541) and 17.8% (162/910), respectively. Using acute gastrointestinal injury (AGI) 1 as the reference in a Cox model, patients with AGI 2-3 were associated with reduced likelihood of EN initiation (HR 0.46, 95% CI 0.353-0.599; p < 0.001). AGI 4 was significantly associated with lower hazard of EN administration (HR 0.056; 95% CI 0.008-0.398; p = 0.004). In a linear regression model, greater Sequential Organ Failure Assessment scores (coefficient - 0.002, 95% CI - 0.008 to - 0.001; p = 0.024) and male gender (coefficient - 0.144, 95% CI - 0.203 to - 0.085; p < 0.001) were found to be associated with lower EN proportion. As compared with AGI 1, AGI 2-3 was associated with lower EN proportion (coefficient - 0.206, 95% CI - 0.273 to - 0.139; p < 0.001). CONCLUSIONS: The study showed that EN delivery was suboptimal in Chinese ICUs. More attention should be paid to EN use in the early days after ICU admission.

Impact of Ae-GRD on Ivermectin Resistance and Its Regulation by miR-71-5p in Aedes aegypti.

iGABAR, a member of the Cys-loop ligand-gated ion channel superfamily, is a significant target of the insecticide ivermectin (IVM). GRD is the potential subunit of the insect iGABAR. However, little information about GRD in Ae. aegypti has been reported. In this study, we involved cloning and characterizing the iGABAR subunit GRD of Ae. aegypti (Ae-GRD). Sequence analysis indicated that Ae-GRD, as part of the cysteine-loop ligand-gated ion channel family, is similar to other insect GRD. RNA interference (RNAi) was employed to explore IVM resistance in Ae. aegypti, resulting in a significant reduction in Ae-GRD expression (p < 0.05), and the mortality of Ae. aegypti adults with Ae-GRD knockdown was significantly decreased after exposure to ivermectin. Bioinformatics prediction identified miR-71-5p as a potential regulator of Ae-GRD. In vitro, dual-luciferase reporter assays confirmed that Ae-GRD expression was regulated by miR-71-5p. Microinjection of miR-71-5p mimics upregulated miR-71-5p expression and downregulated Ae-GRD gene expression, reducing mortality by 34.52% following IVM treatment. Conversely, microinjection of a miR-71-5p inhibitor decreased miR-71-5p expression but did not affect the susceptibility to IVM despite increased Ae-GRD expression (p < 0.05). In conclusion, Ae-GRD, as one of the iGABA receptor subunits, is a potential target of ivermectin. It may influence ivermectin resistance by modulating the GABA signaling pathway. The inhibition of Ae-GRD expression by miR-71-5p decreased ivermectin resistance and consequently lowered the mortality rate of Ae. aegypti mosquitoes. This finding provides empirical evidence of the relationship between Ae-GRD and its miRNA in modulating insecticide resistance, offering novel perspectives for mosquito control strategies.

Genes associated with grey matter volume reduction in multiple sclerosis.

There is extensive grey matter volume (GMV) reduction in multiple sclerosis (MS), which may account for cognitive impairment in this disabling disorder. Although genome-wide association studies (GWASs) have identified hundreds of genes associated with MS, we know little about which genes associated with GMV reduction and cognitive decline in MS. In the present study, we aimed to uncover genes associated with GMV reduction in MS by performing cross-sample (1473 brain tissue samples) partial least squares regression between gene expression from 6 postmortem brains and case-control GMV difference of MS from a meta-analysis of 1391 patients and 1189 controls (discovery phase) and from the intergroup comparison between 69 patients and 70 controls (replication phase). We identified 623 genes whose brain spatial expression profiles were significantly associated with GMV reduction in MS. These genes showed significant enrichment for MS-related genes identified by GWAS; were functionally associated with ion channel, synaptic transmission, axon and neuron projection; and showed more significant cell type-specific expression in neurons than other cell types. More importantly, the identified genes showed significant enrichment for those genes with downregulated rather than upregulated expression in MS. The spatial distribution patterns of the expression of the identified genes showed more significant correlations with brain activation patterns of memory and language tasks. These findings indicate that grey matter atrophy in MS may be resulted from the joint effects of multiple genes that are associated with this disorder, especially genes with downregulated expression in MS.

Functional analysis reveals ionotropic GABA receptor subunit RDL is a target site of ivermectin and fluralaner in the yellow fever mosquito, Aedes aegypti.

BACKGROUND: Ionotropic γ-aminobutyric acid (iGABA) receptors are involved in various physiological activities in insects, including sleep, olfactory memory, movement, and resistance to viruses. Ivermectin and fluralaner can disturb the insect nervous system by binding to iGABA receptors, and are therefore an effective means for controlling insect pests. However, the molecular mechanisms underlying the insecticidal effect of both the compounds on Aedes. aegypti remain unexplored. RESULTS: In this study, we investigated the spatiotemporal expression profile of Ae. aegypti RDL (Ae-RDL), a subunit of iGABA receptor. RDL dsRNA suppressed the expression of Ae-RDL mRNA in Ae. aegypti larvae and adult by 60% and 50.67%,  resepectly. However, the physiology of Ae. aegypti larvae was not significantly affected. The mortality of Ae. aegypti larvae and adult females subjected to Ae-RDL knockdown significantly decreased after exposure to ivermectin and fluralaner. Additionally, Ae-RDL was cloned into Xenopus laevis oocytes and characterized using the two-electrode voltage-clamp method. The inward current was induced by GABA binding to the functional Ae-RDL homomeric receptors at a median effective concentration (EC50 ) of 100.4 ± 59.95 µM (n > 3). The significant inhibitory effect of ivermectin and fluralaner on inward current indicated that both insecticides exerted a significant antagonistic effect on Ae-RDL. However, ivermectin also showed strong agonistic as well as weak activation effects on Ae-RDL. These contrasting effects of ivermectin on Ae-RDL depended on ivermectin concentration. CONCLUSION: Our study revealed that Ae-RDL subunit is a target of ivermectin and fluralaner, providing new insights into the insecticidal mechanism of both compounds in Ae. aegypti. © 2022 Society of Chemical Industry.

Deletion of the Serotonin Receptor 7 Gene Changed the Development and Behavior of the Mosquito, Aedes aegypti.

Serotonin (5-HT) plays a vital role in many physiological processes in insects, regulating physiological activities such as growth and movement through multiple 5-HT receptors (5-HTRs), which were potential targets for some new insecticides. However, the specific function of individual 5-HTRs in Ae. aegypti is still unclear. In this study, we investigated the function of the 5-HT7A receptor during Ae. aegypti development. 5-HTR7A transcripts were detected at all stages of development by real-time PCR. The results indicated that the gene expression was highest in the limbs (p < 0.01). We also generated 5-HTR7A mutant mosquitoes using CRISPR-mediated gene editing. The mutants had an abnormal phenotype at the larval stage, including an aberrant head-to-chest ratio and decreased motor activity. The mutant pupae developed abnormally, and most died (56.67%) (p < 0.0001). Using external stimuli to larvae and pupae with abnormal phenotypes, we found the mutant G1 and G2 generations responded to external stimuli in a longer time than the wild-type (WT) mosquitoes, and most of the mutants were 2 to 3 s slower than the WTs to respond to external stimuli (p < 0.01). Due to higher mortality, mutant larvae and pupae had fewer numbers than the WTs. The egg hatching rate of mutant G1 and G2 generations was lower than that of the WTs (p < 0.01). The expression level of 5-HTR7A in the mutants decreased by about 65% compared with the control group using real-time PCR (p < 0.05). In all, the 5-HT7A receptor plays an important role in the metamorphosis, development and motor function of Aedes aegypti.

Recurrent pulmonary cryptococcosis during chronic HBV infection: A case report.

RATIONALE: Pulmonary cryptococcosis is one of the important opportunistic infections and has a wide range of symptoms depending on the underlying conditions. Here, we reported a case living with chronic hepatitis B virus infection who had a recurrent pulmonary cryptococcosis. PATIENT CONCERNS: A 51-year-old male patient was admitted to our center because of cough, fatigue, and shortness of breath for 2 weeks. DIAGNOSIS: Pulmonary infection was suggested by chest computed tomography. Most lab examinations for infection were negative and only cryptococcal antigen testing was positive. Therefore, a clinical diagnosis of pulmonary cryptococcosis was made. INTERVENTIONS: Fluconazole (200 mg/day) and bicyclol (50 mg/day) was given orally. OUTCOMES: During the follow-up of 3 and 6 months, his conditions improved, and he recovered fully. Moreover, cryptococcal antigen level was 12.57 ng/mL. During the 2-year follow-up, no recurrence occurred. LESSONS: This case highlights the importance of the awareness of opportunistic infections during chronic hepatitis B virus infection, especially the potential of recurrence.

Functional characterization of two clip domain serine proteases in innate immune responses of Aedes aegypti.

BACKGROUND: Clip domain serine proteases (CLIPs), a very diverse group of proteolytic enzymes, play a crucial role in the innate immunity of insects. Innate immune responses are the first line of defense in mosquitoes against the invasion of pathogenic microorganisms. The Toll pathway, immunodeficiency (IMD) pathway and melanization are the main processes of innate immunity in Aedes aegypti. CLIPS are classified into five subfamilies-CLIPA, CLIPB, CLIPC, CLIPD, and CLIPE-based on their sequence specificity and phylogenetic relationships. We report the functional characterization of the genes that code for two CLIPs in Ae. aegypti (Ae): Ae-CLIPB15 and Ae-CLIPB22. METHODS: Clustal Omega was used for multiple amino acid sequence alignment of Ae-CLIPB15 and Ae-CLIPB22 with different CLIP genes from other insect species. The spatiotemporal expression profiles of Ae-CLIPB15 and Ae-CLIPB22 were examined. We determined whether Ae-CLIPB15 and Ae-CLIPB22 respond to microbial challenge and tissue injury. RNA interference (RNAi) was used to explore the function of Ae-CLIPB15 and Ae-CLIPB22 in the defense of Ae. aegypti against bacterial and fungal infections. The expression levels of nuclear factor kappa B (NF-κB) transcription factors REL1 and REL2 in the Toll pathway and IMD pathway after bacterial infection were investigated. Finally, the change in phenoloxidase (PO) activity in Ae-CLIPB15 and Ae-CLIPB22 knockdown adults was investigated. RESULTS: We performed spatiotemporal gene expression profiling of Ae-CLIPB15 and Ae-CLIPB22 genes in Ae. aegypti using quantitative real-time polymerase chain reaction. These genes were expressed in different stages and tissues. The messenger RNA (mRNA) levels for both genes were also up-regulated by Gram-negative bacteria Escherichia coli, Gram-positive bacteria Staphylococcus aureus and fungal Beauveria bassiana infections, as well as in the tissue injury experiments. RNAi-mediated knockdown of Ae-CLIPB15 led to a significant decrease of PO activity in the hemolymph of Ae. aegypti, while other RNAi experiments revealed that both Ae-CLIPB15 and Ae-CLIPB22 were involved in immune defense against bacterial and fungal infections. The mRNA expression of NF-κB transcription factors REL1 and REL2 in the Toll pathway and IMD pathway differed between Ae-CLIPB15 and Ae-CLIPB22 knockdown mosquitoes infected with bacteria and wild type mosquitoes infected with bacteria. CONCLUSIONS: Our findings suggest that Ae-CLIPB15 and Ae-CLIPB22 play a critical role in mosquito innate immunity, and that they are involved in immune responses to injury and infection. Their regulation of transcription factors and PO activity indicates that they also play a specific role in the regulation of innate immunity.

Primary ciliated muconodular papillary tumor: A rare pulmonary disease and literature review of 65 cases.

A ciliated muconodular papillary tumor (CMPT) or bronchiolar adenoma (BA) is a rather rare and unique type of lung tumor characterized by tripartite cellular components with a papillary-predominant structure including ciliated columnar cells, mucinous cells, and basal cells. Here, we present the case of a 64-year-old woman who was diagnosed with CMPT in our center. In addition to reporting the clinicopathological characteristics of this case, we also conducted whole exome sequencing (WES) to explore the underlying mechanism. According to current evidence, CMPTs tends to be benign or of low grade malignancy. However, this requires further validation.

Differentiate aquaporin-4 antibody negative neuromyelitis optica spectrum disorders from multiple sclerosis by multimodal advanced MRI techniques.

BACKGROUND: It is clinically essential to distinguish aquaporin-4 antibody (AQP4-Ab) negative neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) because of different therapeutic strategies. Since clinical and lesion features may not allow the distinction, we aimed to identify advanced imaging features that could improve the distinction between two disorders. METHODS: Multimodal imaging measures included fractional anisotropy, mean, axial, radial diffusivity (MD, AD, RD) and kurtosis (MK, AK, RK) from diffusion kurtosis imaging; functional connectivity strength (FCS) and density, regional homogeneity, amplitude of low frequency fluctuations from resting-state functional MRI; gray matter volume from structural MRI; and cerebral blood flow from arterial spin labeling imaging. Voxel-wise comparisons were performed to identify inter-group differences in imaging measures, and the performance of differentiating these two disorders was estimated by receiver operating characteristic curves. RESULTS: Compared to MS, patients with AQP4-Ab negative NMOSD showed decreased MD and AD but increased MK and AK in white matter regions; and reduced FCS in the occipital cortex (P < 0.05, FWE corrected). The joint-use of these five imaging measures distinguished the two disorders with an accuracy of 94% (P < 0.001, 95%CI = 0.84-0.98). Other imaging measures showed no significant differences between the two patient groups. CONCLUSIONS: The study showed less white matter damage and a more severe functional disconnection of the occipital cortex in patients with AQP4-Ab negative NMOSD compared to MS. The combined use of diffusion and functional connectivity could facilitate a better distinction between NMO and MS with seronegative AQP4-Ab in clinical management.

[Effects of Hippo signaling on anti-oxidative stress of mesenchymal stem cells in vitro].

OBJECTIVE: To explore the effects of Hippo signaling on anti-oxidative stress of mouse marrow mesenchymal stem cells (mMSCs) in vitro. METHODS: mMSCs derived from C57BL/6 mice were identified using fluorescence-activated cell sorting analysis and the capabilities of osteogenic, chondrogenic and adipogenic differentiation were evaluated. 2-deoxy-D-glucose (2-DG) or XMU-MP-1 was used to modulate Hippo signaling. Oxidative stress was induced by H2O2 treatment and the effect of oxidative stress induced by H2O2 on survival of mMSCs was evaluated using methyl thiazolyl tetrazolium (MTT) assay. The effect of oxidative stress induced by H2O2 on Hippo signaling and the effect of Hippo signaling on capability of anti-oxidative stress of mMSCs were analyzed through apoptosis-regulated proteins (Bcl-2 and Bax) using Western Blot. RESULTS: Hippo signaling was activated by 2-DG in a concentration-dependent manner and the effect was most prominent by 5 mmol/L of 2-DG [compared with the blank control group, large tumor suppressor 1 (LATS1) protein (grey value): 2.33±0.25 vs. 0.98±0.03, phosphorylated Yes-associated protein (p-YAP)/YAP protein ratio (grey value): 2.30±0.35 vs. 1.01±0.05, 14-3-3 protein (grey value): 2.19±0.40 vs. 0.99±0.04, all P < 0.05]; Hippo signaling was inhibited by 100 nmol/L of XMU-MP-1 [compared with the blank control group, LATS1 protein (grey value): 0.69±0.10 vs. 0.98±0.03, p-YAP/YAP protein ratio (grey value): 0.65±0.06 vs. 1.01±0.05, 14-3-3 protein (grey value): 0.75±0.11 vs. 0.99±0.04, all P < 0.05]. Death of mMSCs was induced by H2O2 in a concentration-dependent manner and the minimal effective concentration was 0.1 mmol/L [compared with the blank control group, survival rate of mMSCs: (81.25±11.85)% vs. (100.44±12.39)%, P < 0.05]. Inhibition of Hippo signaling was induced by H2O2 in a concentration-dependent manner and the minimal effective concentration was also 0.1 mmol/L [compared with the blank control group, LATS1 protein (grey value): 0.75±0.06 vs. 1.01±0.09, p-YAP/YAP protein ratio (grey value): 0.69±0.05 vs. 0.98±0.05, both P < 0.05], those effects might associate with reduction of Bcl-2/Bax ratio (grey value: 0.48±0.18 vs. 1.06±0.09, P < 0.05). Compared with the treatment of 0.1 mmol/L of H2O2, activation of Hippo signaling by 5 mmol/L of 2-DG [LATS1 protein (grey value): 0.95±0.05 vs. 0.64±0.06, p-YAP/YAP protein ratio (grey value): 0.87±0.03 vs. 0.45±0.16, both P < 0.05] improved survival of mMSCs [(92.80±9.43)% vs. (75.47±9.43)%, P < 0.05] through an increase of Bcl-2/Bax ratio (grey value: 1.14±0.16 vs. 0.77±0.12, P < 0.05); however, inhibition of Hippo signaling by 100 nmol/L of XMU-MP-1 [LATS1 protein (grey value): 0.39±0.03 vs. 0.64±0.06, p-YAP/YAP protein ratio (grey value): 0.28±0.04 vs. 0.45±0.16, both P < 0.05] decreased survival of mMSCs [(57.54±4.59)% vs. (75.47±9.43)%, P < 0.05] through an decrease of Bcl-2/Bax ratio (grey value: 0.63±0.20 vs. 0.77±0.12, P < 0.05). Compared with normal lung tissue, acute respiratory distress syndrome (ARDS) lung tissue markedly activate Hippo signaling in mMSCs [LATS1 protein (grey value): 1.71±0.08 vs. 1.00±0.10, p-YAP/YAP protein ratio (grey value): 2.46±0.39 vs. 1.01±0.04, 14-3-3 protein (grey value): 2.27±0.52 vs. 1.01±0.08, all P < 0.05]. CONCLUSIONS: Hippo signaling could affect survival and capability of anti-oxidative stress of mMSCs via modulation of Bcl-2/Bax ratio in vitro.

Cerebral Blood Flow Changes in Multiple Sclerosis and Neuromyelitis Optica and Their Correlations With Clinical Disability.

Distinguishing relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO) is clinically important because they differ in prognosis and treatment. This study aimed to identify perfusion abnormalities in RRMS and NMO and their correlations with gray matter volume (GMV) atrophy and clinical parameters. Structural and arterial spin labeling MRI scans were performed in 39 RRMS patients, 62 NMO patients, and 73 healthy controls. The gray matter cerebral blood flow (CBF) values were voxel-wisely compared among the three groups with and without GMV correction. The regional CBF changes were correlated with the Expanded Disability Status Scale scores in the corresponding patient groups. Although multiple brain regions showed CBF differences among the three groups without GMV correction, only three of these regions remained significant after GMV correction. Specifically, both the RRMS and NMO groups showed reduced CBF in the occipital cortex and increased CBF in the right putamen compared to the control group. The RRMS group had increased CBF only in the medial prefrontal cortex compared to the other two groups. The occipital CBF was negatively correlated with clinical disability in the NMO group; however, the CBF in the right putamen was positively correlated with clinical disability in both patient groups. These findings suggest that there are perfusion alterations independent of GMV atrophy in RRMS and NMO patients. The regional CBF in the occipital cortex and putamen could be used as imaging features to objectively assess clinical disability in these patients.