Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.

CONTEXT.­: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.­: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.­: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.­: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.­: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

Empagliflozin Induces Vascular Relaxation in Rat Coronary Artery Due to Activation of BK Channels.

Purpose: The aim of this study was to investigate the effects and mechanisms of SGLT2 inhibitor empagliflozin on diabetic coronary function. Methods: A rat diabetic model was established by injection of streptozotocin. Rats in the treated group were administered empagliflozin by gavage and rat coronary vascular tensions were measured after eight weeks. Large conductance calcium activated K+ channel currents were recorded using a patch clamp technique, while human coronary artery smooth muscle cells were used to explore the underlying mechanisms. Results: After incubation with empagliflozin (10, 30, 100, 300, 1000 µmol/L), the Δ relaxation % of rat coronary arteries were 2.459 ± 1.304, 3.251 ± 1.119, 6.946 ± 3.407, 28.36 ± 11.47, 86.90 ± 3.868, respectively. Without and with empagliflozin in the bath solution, BK channel opening probabilities at a membrane potential of +60 mV were 0.0458 ± 0.0517 and 0.3413 ± 0.2047, respectively (p < 0.05, n = 4 cells). After incubation with iberiotoxin, the Δ tensions of rat coronary arteries in the control (Ctrl), untreated (DM), low empagliflozin (10 mg/kg/d)-treated (DM+L-EMPA) and high empagliflozin (30mg/kg/d)-treated (DM+H-EMPA) group were 103.20 ± 5.85, 40.37 ± 22.12, 99.47 ± 28.51, 78.06 ± 40.98, respectively (p < 0.01 vs Ctrl, n = 3-7; p < 0.001 vs DM+L-EMPA, n = 5-7). Empagliflozin restored high glucose-induced downregulation of Sirt1, Nrf2, and BK-ß1, while the effect of empagliflozin disappeared in the presence of EX-527, a Sirt1 selective inhibitor. Conclusion: Empagliflozin has a vasodilation effect on the coronary arteries in a concentration-dependent manner and can activate BK channels via the Sirt1-Nrf2 mechanism.

Correlation between telomere shortening in maternal peripheral blood and fetal aneuploidy.

BACKGROUND: This study aimed to assess whether maternal telomere length is a more accurate predictor of trisomy 21 than maternal age while also exploring the factors influencing maternal and fetal telomere length. METHODS: Forty mothers with fetuses carrying extra maternal copies of chromosome 21 were defined as trisomy 21 cases, and 18 mothers with normal karyotype fetuses were defined as controls. Telomere lengths of maternal blood lymphocytes and amniotic fluid cells were determined using real-time polymerase chain reaction. Fetal and maternal telomere lengths were compared between the two groups. Moreover, we analyzed the factors influencing maternal and fetal telomere length in the trisomy 21 pedigree. A logistic regression model was used to analyze the correlation between maternal telomere length and trisomy 21 risk. In addition, receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using maternal telomere length as an indicator of trisomy 21 risk. RESULTS: The study revealed that both maternal and fetal telomere lengths were significantly shorter in trisomy 21 cases than in the controls. In the trisomy 21 group, the maternal age, occupation, and nationality showed no significant correlation with their telomere length; fetal telomere length exhibited a positive correlation with maternal telomere length. Furthermore, maternal telomere length shortening is associated with trisomy 21 (OR = 0.311; 95% CI, 0.109-0.885, P < 0.05). The results of ROC curve analysis indicated that a combined assessment of maternal age and maternal telomere length predicted fetal chromosome trisomy more effectively than a single assessment (area under the curve 0.808, 95% CI, 0.674-0.941, P < 0.001). CONCLUSION: Maternal age combined with maternal telomere length proved to be a superior predictor of trisomy risk. Additionally, maternal telomere length was found to influence fetal telomere length.

Glucose fluctuations aggravated the late sodium current induced ventricular arrhythmias via the activation of ROS/CaMKII pathway.

BACKGROUND: Recent evidence revealed that glucose fluctuation might be more likely to cause arrhythmia than persistent hyperglycemia, whereas its mechanisms were elusive. We aimed to investigate the effect of glucose fluctuation on the occurrence of ventricular arrhythmia and its mechanism. METHODS: Streptozotocin (STZ) induced diabetic rats were randomized to five groups: the controlled blood glucose (C-STZ) group, uncontrolled blood glucose (U-STZ) group, fluctuated blood glucose (GF-STZ) group, and GF-STZ rats with 100 mg/kg Tempol (GF-STZ + Tempol) group or with 5 mg/kg KN93 (GF-STZ + KN93) group. Six weeks later, the susceptibility of ventricular arrhythmias and the electrophysiological dysfunctions of ventricular myocytes were evaluated using electrocardiogram and patch-clamp technique, respectively. The levels of reactive oxygen species (ROS) and oxidized CaMKII (ox-CaMKII) were determined by fluorescence assay and Western blot, respectively. Neonatal rat cardiomyocytes and H9C2 cells in vitro were used to explore the underlying mechanisms. RESULTS: The induction rate of ventricular arrhythmias was 10%, 55%, and 90% in C-STZ group, U-STZ group, and GF-STZ group, respectively (P < 0.05). The electrophysiological dysfunctions of ventricular myocytes, including action potential duration at repolarization of 90% (APD90), APD90 short-term variability (APD90-STV), late sodium current (INa-L), early after depolarization (EAD) and delayed after depolarizations (DAD), as well as the levels of ROS and ox-CaMKII, were significantly increased in GF-STZ group. In vivo and ex vivo, inhibition of ROS or ox-CaMKII reversed these effects. Inhibition of INa-L also significantly alleviated the electrophysiological dysfunctions. In vitro, inhibition of ROS increase could significantly decrease the ox-CaMKII activation induced by glucose fluctuations. CONCLUSIONS: Glucose fluctuations aggravated the INa-L induced ventricular arrhythmias though the activation of ROS/CaMKII pathway.

Glucose fluctuations aggravate myocardial fibrosis via activating the CaMKII/Stat3 signaling in type 2 diabtetes.

BACKGROUND: Glucose fluctuations (GF) are a risk factor for cardiovascular complications associated with type 2 diabetes. However, there is a lack of adequate research on the effect of GF on myocardial fibrosis and the underlying mechanisms in type 2 diabetes. This study aimed to investigate the impact of glucose fluctuations on myocardial fibrosis and explore the potential mechanisms in type 2 diabetes. METHODS: Sprague Dawley (SD) rats were randomly divided into three groups: the control (Con) group, the type 2 diabetic (DM) group and the glucose fluctuations (GF) group. The type 2 diabetic rat model was established using a high-fat diet combined with low-dose streptozotocin injection and the GF model was induced by using staggered glucose and insulin injections daily. After eight weeks, echocardiography was used to assess the cardiac function of the three groups. Hematoxylin-eosin and Masson staining were utilized to evaluate the degree of pathological damage and fibrosis. Meanwhile, a neonatal rat cardiac fibroblast model with GF was established. Western and immunofluorescence were used to find the specific mechanism of myocardial fibrosis caused by GF. RESULTS: Compared with rats in the Con and the DM group, cardiac function in the GF group showed significant impairments. Additionally, the results showed that GF aggravated myocardial fibrosis in vitro and in vivo. Moreover, Ca2+/calmodulin­dependent protein kinase II (CaMKII) was activated by phosphorylation, prompting an increase in phosphorylation of signal transducer and activator of transcription 3 (Stat3) and induced nuclear translocation. Pretreatment with KN-93 (a CaMKII inhibitor) blocked GF-induced Stat3 activation and significantly suppressed myocardial fibrosis. CONCLUSIONS: Glucose fluctuations exacerbate myocardial fibrosis by triggering the CaMKII/Stat3 pathway in type 2 diabetes.

Radiofrequency ablation of premature ventricular contractions guided by robotic magnetic navigation combined with pattern matching filter.

BACKGROUND: This study's intent is to evaluate the usefulness of pattern matching filter (PMF) function combined with robotic magnetic navigation (RMN) in guiding the ablation of premature ventricular contractions (PVCs). HYPOTHESIS: Assume that PMF can improve the outcomes of PVCs ablation using RMN. METHODS: A retrospective analysis was completed consisting of 118 consecutive patients with PVCs who underwent radiofrequency ablation guided by RMN. According to the application of PMF, patients were divided into two groups: 20 patients underwent ablation without PMF (group A), and another 98 patients received ablation incorporating PMF (group B). RESULTS: Compared with group A, the procedure time (135.0 ± 28.3 min vs. 106.3 ± 37.9 min, p = 0.02) in group B was significantly decreased, while the X-ray exposure time (6.0 ± 2.6 min vs. 6.5 ± 3.6 min, p = 0.705) and dose (3.2 ± 2.4 gycm2 vs. 3.9 ± 2.7 gycm2 ，p = 0.208) had no significant difference. Group B had a more than twofold number of points acquired (66.9 ± 23.0 vs. 143.9 ± 68.3, p < 0.001) and required a shorter radiofrequency ablation time (13.2 ± 3.5 min vs. 8.1 ± 2.9 min, p < 0.001). There were no serious complications in either group. The acute success rate was similar [90.0% (18/20) vs. 87.8% (86/98), p = 1.000] in two groups, and the success rate was also similar in the long-term follow-up [83.3% (15/18) vs. 87.2% (75/86), p = 0.776]. CONCLUSIONS: The ablation of PVCs guided by RMN is safe and effective. Combined with the functional capability of PMF, both procedure time and radiofrequency ablation time were significantly decreased.

Significance of serum Th1/Th2 cytokine levels in underlying disease classification of childhood HLH.

OBJECT: Goal of this research was to investigate values of serum cytokines in childhood HLH with different triggers, with the expectation to find secretion spectrum of 5 main types of underlying diseases. METHOD: 118 newly diagnosed HLH were included, and serum concentrations of 6 cytokines were tested before treatment began. Absolute cytokine levels and ratios between them were then studied in the HLH groups collectively and separately RESULTS: In general, IFN-γ, IL-10 and IL-6 showed differences among 5 HLH groups. Specifically, relative levels of these three cytokines to each other were meaningful in distinguishing 4 types of HLH. Level of IL-6 was higher than those of IFN-γ or IL-10 in HLH driven by Systemic auto-inflammatory disorders (SAIDs) or Langerhans Cell Histiocytosis (LCH), while primary HLH and EBV-HLH shared elevated ratio of IL-10 to IL-6. Although more than one distinctive ratios were found in 3 HLH groups, combination of these parameters didn't offer optimal balance between sensitivity and specificity. CONCLUSION: As a group of easily gained laboratory findings, cytokine levels were reliable in the procedure of roughly classifying HLH cases with the help of patients' clinical phenotype. However, adequate data is still needed to explore the significance of these indicators in identifying one particular underlying disease accurately.

Atrial Fibrillation Ablation Using Robotic Magnetic Navigation Reduces the Incidence of Silent Cerebral Embolism.

Background: The incidence of silent cerebral embolisms (SCEs) has been documented after pulmonary vein isolation using different ablation technologies; however, it is unreported in patients undergoing with atrial fibrillation (AF) ablation using Robotic Magnetic Navigation (RMN). The purpose of this prospective study was to investigate the incidence, risk predictors and probable mechanisms of SCEs in patients with AF ablation and the potential impact of RMN on SCE rates. Methods and Results: We performed a prospective study of 166 patients with paroxysmal or persistent AF who underwent pulmonary vein isolation. Patients were divided into RMN group (n = 104) and manual control (MC) group (n = 62), and analyzed for their demographic, medical, echocardiographic, and risk predictors of SCEs. All patients underwent cerebral magnetic resonance imaging within 48 h before and after the ablation procedure to assess cerebral embolism. The incidence and potential risk factors of SCEs were compared between the two groups. There were 26 total cases of SCEs in this study, including 6 cases in the RMN group and 20 cases in the MC group. The incidences of SCEs in the RMN group and the MC group were 5.77 and 32.26%, respectively (X2 = 20.63 P < 0.05). Univariate logistic regression analysis demonstrated that ablation technology, CHA2DS2-VASc score, history of cerebrovascular accident/transient ischemic attack, and low ejection fraction were significantly associated with SCEs, and multivariate logistic regression analysis showed that MC ablation was the only independent risk factor of SCEs after an AF ablation procedure. Conclusions: Ablation technology, CHA2DS2-VASc score, history of cerebrovascular accident/transient ischemic attack, and low ejection fraction are associated with SCEs. However, ablation technology is the only independent risk factor of SCEs and RMN can significantly reduce the incidence of SCEs resulting from AF ablation. Clinical Trial Registration: ChiCTR2100046505.

Effectiveness and Safety of Dabrafenib in the Treatment of 20 Chinese Children with BRAFV600E-Mutated Langerhans Cell Histiocytosis.

PURPOSE: We sought to investigate the effectiveness and safety of dabrafenib in children with BRAFV600E-mutated Langerhans cell histiocytosis (LCH). MATERIALS AND METHODS: A retrospective analysis was performed on 20 children with BRAFV600E-mutated LCH who were treated with dabrafenib. RESULTS: The median age at which the patients started taking dabrafenib was 2.3 years old (range, 0.6 to 6.5 years). The ratio of boys to girls was 2.3:1. The median follow-up time was 30.8 months (range, 18.9 to 43.6 months). There were 14 patients (70%) in the risk organ (RO)+ group and six patients (30%) in the RO- group. All patients were initially treated with traditional chemotherapy and then shifted to targeted therapy due to poor control of LCH or intolerance to chemotherapy. The overall objective response rate and the overall disease control rate were 65% and 75%, respectively. During treatment, circulating levels of cell-free BRAFV600E (cfBRAFV600E) became negative in 60% of the patients within a median period of 3.0 months (range, 1.0 to 9.0 months). Grade 2 or 3 adverse effects occurred in five patients. CONCLUSION: Some children with BRAFV600E-mutated LCH may benefit from monotherapy with dabrafenib, especially high-risk patients with concomitant hemophagocytic lymphohistiocytosis and intolerance to chemotherapy. The safety of dabrafenib is notable. A prospective study with a larger sample size is required to determine the optimal dosage and treatment duration.

Combined analysis of IKZF1 deletions and CRLF2 expression on prognostic impact in pediatric B-cell precursor acute lymphoblastic leukemia.

This study aimed to investigate the combined impact of IKZF1 deletions/high expression of CRLF2 on the prognosis of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). IKZF1 deletions and CRLF2 expression were assessed in bone marrow samples from 117 children with newly diagnosed BCP-ALL. Sixteen (13.7%) patients were found to harbor IKZF1 deletions, which was associated with inferior outcomes. The event-free survival (EFS) for patients with high -CRLF2 expression was significantly worse than that for low -CRLF2 expression. Moreover, combined modeling of IKZF1+ /CRLF2high identified 7.8% of cases as the highest risk subgroup (7-year EFS 33.3 ± 15.7%). In a multivariate analysis, IKZF1+ /CRLF2high remained a strong independent prognostic factor for EFS (HR: 14.263, p = 0.019). IKZF1 deletions and high -CRLF2 expression were associated with inferior outcomes, and the coexistence of IKZF1+ /CRLF2high had a significant impact on an integrated prognostic model for high-risk BCP-ALL.

[Qualitative study on the cognition of acquired immunodeficiency syndrome occupational protection among the managers of multi-level stomatology medical institutions].

OBJECTIVE: To understand the current cognition of acquired immunodeficiency syndrome (AIDS) occupational protection among the managers of multi-level stomatology medical institutions in efforts to provide a reference for formulating technical standards for occupational protection. METHODS: Eighteen managers of oral medical institutions were individually interviewed in-depth using asemi-structured questionnaire on issues related to AIDS occupational protection using the phenomenological research method. Nvivo 12.0 software was used to code and analyze the interview data, and relevant themes were extracted. RESULTS: Three themes were extracted from the data. Occupational protection measures for AIDS in dental medical institutions mainly based on the aspects of standardized operation, standardized prevention, and post-exposure treatment. However, the implementation of these protective measures was often inadequate. Occupational protection training for AIDS was carried out regularly at dental medical institutions, but the training effect was not generally tracked. Several limitations in AIDS occupational protection management; these limitations included the lack of a specific occupational protection system, the difficulty of AIDS screening for outpatients, and the difficulty of AIDS occupational protection supervision. CONCLUSIONS: Oral medical institutions should strengthen their occupational protection training and supervision approaches and formulate unified occupational protection standards to reduce occupational exposure and improve hospital management quality and efficiency.

Downregulating CREBBP inhibits proliferation and cell cycle progression and induces daunorubicin resistance in leukemia cells.

Low expression levels of CREB­binding protein (CREBBP) have been demonstrated to be associated with high minimal residual disease at the end of induction therapy and adverse long­term outcomes in pediatric patients with acute lymphoblastic leukemia (ALL). However, the effect of low CREBBP expression on the prognosis of ALL has not yet been investigated. In the present study, CREBBP was downregulated and overexpressed in ALL cell lines (Jurkat and Reh). Sensitivity to chemotherapy and cell proliferation activity was determined via a Cell Counting Kit­8 assay. Cell cycle analysis was performed using flow cytometry. Immunofluorescence confocal microscopy and co­immunoprecipitation (Co­IP) assays were performed to determine the interaction between CREBBP and E2F transcription factor 3a (E2F3a). The binding of CREBBP to downstream gene caspase 8 associated protein 2 (CASP8AP2) promoters was assessed using a chromatin immunoprecipitation assay, and mRNA expression levels were detected via reverse transcription­quantitative PCR. Western blot analysis was performed to detect protein expression of CREBBP, E2F3a and CASP8AP2. Downregulation of CREBBP increased the IC50 value of daunorubicin; however, no significant affects were observed on the IC50 values of vincristine and L­asparaginase. Furthermore, downregulation of CREBBP notably inhibited leukemia cell proliferation, accumulated cells in the G0/G1 phase and decreased cell proportions in the S and G2/M phases. Co­IP analysis demonstrated that CREBBP interacted with E2F3a, a transcription factor involved in G1/S transition. Immunofluorescence confocal microscopy indicated co­localization of CREBBP and E2F3a at the cell nucleus. Furthermore, E2F3a protein expression decreased in CREBBP RNA interference treated Jurkat and Reh cells. CASP8AP2, a target gene of E2F3a, was also identified to be a downstream gene of CREBBP. In addition, decreased IC50 value and cell proportions in the G0/G1 phase, accelerated cell proliferation and upregulated E2F3a and CASP8AP2 expression were exhibited in CREBBP overexpressed cells. Taken together, the results of the present study suggested that CREBBP downregulation affects proliferation and cell cycle progression in leukemia cells, potentially via the interaction and regulation of E2F3a, resulting in chemotherapy resistance. Thus, targeting CREBBP may be a therapeutic strategy for treating pediatric patients with ALL.

ß-catenin promotes MTX resistance of leukemia cells by down-regulating FPGS expression via NF-κB.

BACKGROUND: Aberrant activation of ß-catenin has been shown to play important roles in the chemoresistance of acute lymphoblastic leukemia (ALL), but the involvement and mechanism of ß-catenin in methotrexate (MTX) resistance is poorly understood. In the present study, we demonstrate a critical role of ß-catenin-NF-κB-FPGS pathway in MTX resistance in the human T-lineage ALL cell lines. METHODS: Lentivirus sh-ß-catenin was used to silence the expression of ß-catenin. Flow cytometry was performed to detect apoptosis after MTX treatment. Western blot, real-time PCR, Co-immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP), Re-ChIP, and Luciferase assay were utilized to investigate the relationship among ß-catenin, nuclear factor (NF)-κB, and folypoly-γ-glutamate synthetase (FPGS). RESULTS: Depletion of ß-catenin significantly increased the cytotoxicity of MTX. At the molecular level, knockdown of ß-catenin caused the increase of the protein level of FPGS and NF-κB p65. Furthermore, ß-catenin complexed with NF-κB p65 and directly bound to the FPGS promoter to regulate its expression. In addition, ß-catenin repression prolonged the protein turnover of FPGS. CONCLUSIONS: Taken together, our results demonstrate that ß-catenin may contribute to MTX resistance in leukemia cells via the ß-catenin-NF-κB-FPGS pathway, posing ß-catenin as a potential target for combination treatments during ALL therapy.

Associations between PRF1 Ala91Val polymorphism and risk of hemophagocytic lymphohistiocytosis: a meta-analysis based on 1366 subjects.

BACKGROUND: Perforin (PRF1) gene mutation can cause the onset of hemophagocytic lymphohistiocytosis (HLH). It has reported that PRF1 Ala91Val polymorphism was related with HLH risk. In the meta-analysis, we aim to evaluate the association between PRF1 Ala91Val polymorphism and HLH risk. METHODS: We accomplished a meta-analysis of six published case-control studies including 391 patients with HLH and 975 controls. We evaluated the quality of each study through Newcastle-Ottawa Scale (NOS). Data analysis was performed with Stata software. RESULTS: In general, all studies were of high quality (NOS score higher than 7). There were statistically significant between the PRF1 Ala91Val polymorphism and HLH risk though the pooled analysis [for Ala/Val vs. Ala/Ala: pooled odds ratio (OR) = 3.22, 95% confidence interval (CI) 1.08-9.56, P = 0.035, random model; for Ala/Val + Val/Val vs. Ala/Ala: pooled OR = 2.96, 95% CI 1.14-7.69, P = 0.025, random model]. Furthermore, sensitivity analysis also revealed a relationship between PRF1 Ala91Val polymorphism and HLH risk (for Ala/Val vs. Ala/Ala: pooled OR = 5.236, 95% CI 2.72-10.08, P < 0.000, I2 = 12.1%, Pheterogeneity = 0.332; for Ala/Val + Val/Val vs. Ala/Ala, pooled OR = 4.856, 95% CI 2.66-8.85, P < 0.000, I2 = 5.9%, Pheterogeneity = 0.373). Funnel plot and Egger's test did not indicate obvious published bias (P = 0.841 for Ala/Val vs. Ala/Ala; P = 0.284 for Ala/Val + Val/Val vs. Ala/Ala). CONCLUSION: This meta-analysis indicated that PRF1 Ala91Val polymorphism affects the factor for developing HLH and future studies of PRF1 Ala91Val on the onset of HLH will be guaranteed.

Blockade of ß-adrenergic signaling suppresses inflammasome and alleviates cardiac fibrosis.

BACKGROUND: Heart failure (HF) is an end-stage syndrome of all structural heart diseases which accompanies the loss of myocardium and cardiac fibrosis. Although the role of inflammasome in cardiac fibrosis has recently been a point of focus, the mechanism of inflammasome activation in HF has not yet been elucidated. METHODS: In this study, we investigated the expression of inflammasome proteins in a rat thoracic aorta constriction (TAC) model and cultured cardiac fibroblasts with stimulation of norepinephrine (NE). RESULTS: Our results showed that levels of inflammasome proteins in the myocardial of TAC rats were elevated. By blocking ß-adrenergic signaling in the rats, inflammasome activation was suppressed and heart function was improved. The stimulation of cultured cardiac fibroblasts with NE activated inflammasome in vitro, which was abrogated by the inhibition of the calcium channels and reactive oxygen species (ROS). The activation of inflammasome by NE promoted cardiac fibrosis, whereas the inhibition of the calcium channels, ROS, and inflammasome reduced this effect. CONCLUSIONS: The present study indicated that activation of inflammasome by ß-adrenergic signaling promotes cardiac fibrosis. Therefore, modulation of inflammasome during HF might provide a novel strategy to treat this disease.

Correlation between aneuploidy pregnancy and the concentration of various hormones and vascular endothelial factor in follicular fluid as well as the number of acquired oocytes.

Objective To investigate the correlation between aneuploidy pregnancy and the concentration of various hormones and vascular endothelial factor in follicular fluid as well as the number of acquired oocytes and to provide a scientific basis for improving ovulation induction programs. Methods In total, we collected 277 follicular fluid specimens from patients undergoing in vitro fertilization (IVF) treatment in our hospital. Eighteen cases of aneuploidy embryos were identified. The follicular fluid of these aneuploidy embryos was used for the study. According to the case and control 1:5 paired design, we selected five age-matched controls with healthy births following IVF for each aneuploidy case. Concentrations of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2) and vascular endothelial growth factor (VEGF) in the follicular fluid were measured. Conditional logistic regression was used to analyze the relationship between aneuploidy pregnancy and the concentrations of various hormones and VEGF in the follicular fluid as well as the number of acquired oocytes. Results Multivariate conditional logistic regression showed that of all the factors analyzed, only FSH [odds ratio (OR) = 1.300, 95% confidence interval (CI), 1.091-1.548, P = 0.003] level in the follicular fluid and the number of acquired oocytes (OR = 1.179, 95% CI, 1.070-1.299, P = 0.001) were closely related to aneuploidy pregnancy. No other factors were found to be associated with aneuploidy pregnancy. Conclusion FSH concentrations in the follicular fluid are risk factors for aneuploidy pregnancies. The higher the number of eggs, the higher the risk of aneuploidy. These findings may help improve ovulation induction programs.

Baseline Red Blood Cell Distribution Width as a Predictor of Stroke Occurrence and Outcome: A Comprehensive Meta-Analysis of 31 Studies.

Background: Red blood cell distribution width (RDW) may be a potential biomarker of inflammation in patients with stroke. Elevated RDW is associated with higher incidence of stroke, unfavorable functional outcome, and increased mortality, although results are inconsistent in the reported literature. This study aims to evaluate the predictive power of RDW regarding stroke occurrence and outcome. Methods: A thorough literature search was conducted utilizing the PubMed Central (PMC) and EMBASE databases to identify studies up to May 2019. Data from these studies were pooled, and combined odds ratios/risk ratios (ORs/RRs) were estimated for the risk of stroke, functional outcome, and mortality. A subgroup analysis was also performed to explore heterogeneity in terms of population status, demographic factors (age, gender distribution, and country), and vascular risk factors (hypertension, diabetes mellitus, and current smoking). Results: A total of 31 studies with 3,487,896 patients were included in the analysis. Elevated RDW was found to be a risk factor in ischemic stroke (OR/RR 1.528; 95% confidence interval [CI] = 1.372-1.703), whereas combined OR in subarachnoid hemorrhage (SAH) was not statistically significant (OR/RR 1.835; 95% CI = 0.888-3.792). Elevated RDW posed increased risk in populations with conventionally higher risk of stroke, such as atrial fibrillation (AF) (OR/RR 1.292; 95% CI = 1.107-1.508) and diabetes mellitus (OR/RR 2.101; 95% CI = 1.488-2.968), and in community cohorts (OR/RR 1.245; 95% CI = 1.216-1.275). In addition, higher RDW was associated with unfavorable functional outcome, either at discharge (OR/RR 1.220; 95% CI = 1.070-1.39) or at 90 days (OR/RR 1.277; 95% CI = 1.155-1.413). Higher mortality was found in patients with increased RDW (OR/RR 1.278; 95% CI = 1.221-1.337), independent of demographic factors (age, gender distribution, and country). Conclusions: Baseline RDW should be integrated into clinical practice as a predictor of ischemic stroke occurrence and outcome. Future studies should also explore the dynamic change of RDW in post-stroke patients to evaluate the clinical significance of RDW and its impact on the inflammatory state of ischemic stroke.

Clinical Significance of Baseline Neutrophil-to-Lymphocyte Ratio in Patients With Ischemic Stroke or Hemorrhagic Stroke: An Updated Meta-Analysis.

Background and purpose: Stroke is a leading cause of death and acquired disability in adults today. Inflammation plays an important role in the pathophysiology of stroke. The peripheral neutrophil-to-lymphocyte ratio (NLR) is an important global inflammatory indicator becoming more mainstream in stroke care. This meta-analysis aims to evaluate the relationship between the baseline NLR and acute ischemic and hemorrhagic stroke, as well as define the clinical significance of NLR in subtypes of ischemic stroke. Methods: This meta-analysis was registered in PROSPERO with the number CRD42018105305. We went through relevant articles from PubMed Central (PMC) and EMBASE. Prospective and retrospective studies were included if related to baseline NLR levels prior to treatment in patients with ischemic or hemorrhagic stroke. Studies were identified up until April 2019. The cutoff value for NLR and the sources of odds ratios (ORs)/risk ratios (RRs) were measured. Modified Rankin Scale (mRS) was used to investigate the outcomes during clinical follow-up. Predefined criteria were used to evaluate the risk of bias in eligible studies. P-values < 0.05 were considered statistically significant. STATA version 14.0 (STATA, College Station, TX) was used in all statistical analyses. Results: Thirty-seven studies with 43,979 individuals were included in the final analysis. Higher NLR levels were correlated with increased risk of ischemic stroke (ORs/RRs = 1.609; 95% CI = 1.283-2.019), unfavorable functional outcome at 3 months (ORs/RRs = 1.851; 95% CI = 1.325-2.584), and increased mortality in patients with ischemic stroke (ORs/RRs = 1.068; 95% CI = 1.027-1.111). While in terms of hemorrhagic stroke (including SAH and ICH), elevated NLR levels only had deleterious effects on mortality (ORs/RRs = 1.080; 95% CI = 1.018-1.146). Conclusions: Baseline NLR level is a promising predictor of the clinical outcomes in both ischemic and hemorrhagic stroke. In addition, elevated NLR is also associated with a high risk of ischemic stroke occurrence. However, future studies are needed to demonstrate the underlying mechanisms and further explain this association.

Significance of serum ferritin level in hemophagocytic lymphohistiocytosis diagnosis.

INTRODUCTION: The threshold of serum ferritin (SF) level listed in diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH) of HLH-2004 has a low specificity. The goal of this research was to evaluate the role of admission SF in HLH diagnostic procedure and to find an appropriate threshold for a HLH suspected cohort with fever. METHODS: All patients admitted to Beijing Children's Hospital during the period of September 1, 2015 and July 31, 2016 with fever and SF tested at admission were included in this study. The significance of SF in HLH diagnosis and its relationships with HLH-relevant clinical characteristics were studied. RESULTS: Among 357 patients, 39 HLH cases were diagnosed (24 EBV-related HLH, 13 unknown etiologies triggered HLH, and two familial HLH). The best cutoff value of admission SF was 934 ng/mL, with sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) being 87.2%, 88.4%, 47.9%, and 98.3%, respectively. Compared to 500 ng/mL, specificity and PPV of the new SF standard in HLH diagnose increased by 11.7% and 14.0%, which indicated improvements in diagnostic ability of "non-HLH" and in veracity of "HLH" identification. Among four HLH patients whose admission SF was between 500 ng/mL and 934 ng/mL, HLH diagnosis was guaranteed by other laboratory results in two patients; however, possible misdiagnosis was made in the rest two patients. CONCLUSION: Elevated cutoff value of admission SF level seems to be more appropriate for distinguishing HLH in patients with fever. The exact cutoff value of SF level at diagnosis needs to be determined.

Comparisons of efficacy, safety, and recurrence risk factors of paroxysmal and persistent atrial fibrillation catheter ablation using robotic magnetic navigation system.

BACKGROUND: No data exist on comparisons of efficacy, safety, and recurrence risk factors of paroxysmal and persistent atrial fibrillation (AF) ablation using robotic magnetic navigation system (MNS), respectively. METHODS: About 151 AF patients were prospectively enrolled and divided into paroxysmal AF group (n = 102) and persistent AF group (n = 49). Circumferential pulmonary vein antrum isolation (CPVI) was performed in all patients. Linear ablation at the left atrial roof and mitral isthmus was performed in patients with persistent AF in addition to CPVI. The procedural time, X-ray exposure time, acute and long-term success rates of CPVI, and procedure-related complications were analyzed. The AF recurrence rates in the two groups were compared during 1 year, and Cox regression was used to analyze the recurrence risk factors. RESULTS: The acute success rates of CPVI in the two groups were 98.04% and 97.96%, respectively. There were no significant differences in the procedural time, X-ray exposure time, and ablation time between the two groups (P > 0.05). No serious complications appeared in either group. The AF ablation success rates were 70.6% and 57.1% for the paroxysmal and persistent groups respectively at 12-month follow-up (P = 0.102). AF duration and coronary heart disease prior to ablation were associated with the higher AF recurrence in patients with persistent AF. CONCLUSION: Ablation using MNS is effective and safe both in patients with paroxysmal and persistent AF. AF duration and coronary heart disease prior to ablation are two independent risk factors of AF recurrence in patients with persistent AF postoperatively.