The prevention effect of Limosilactobacillus reuteri on acute kidney injury by regulating gut microbiota.

Acute kidney injury (AKI) has considerably high morbidity and mortality but we do not have proper treatment for it. There is an urgent need to develop new prevention or treatment methods. Gut microbiota has a close connection with renal diseases and has become the new therapy target for AKI. In this study, we found the oral administration of the probiotic Limosilactobacillus reuteri had a prevention effect on the AKI induced by lipopolysaccharide (LPS). It reduced serum concentration of creatinine and urea nitrogen and protected the renal cells from necrosis and apoptosis. Meanwhile, L. reuteri improved the gut barrier function, which is destroyed in AKI, and modulated the gut microbiota and relevant metabolites. Compared with the LPS group, L. reuteri increased the proportion of Proteobacteria and reduced the proportion of Firmicutes, changing the overall structure of the gut microbiota. It also influenced the fecal metabolites and changed the metabolite pathways, such as tyrosine metabolism, pentose and glucuronate interconversions, galactose metabolism, purine metabolism, and insulin resistance. These results showed that L. reuteri is a potential therapy for AKI as it helps in sustaining the gut barrier integrity and modulating gut microbiota and related metabolites.

Association between postpartum depression and postpartum hemorrhage: A systematic review and meta-analysis.

INTRODUCTION: Postpartum depression (PPD) is a growing mental health concern worldwide and has detrimental effects on the social and cognitive health of both mothers and infants. This review was performed to assess the risk of PPD in women with postpartum hemorrhage (PPH) and to identify potential moderators. MATERIAL AND METHODS: The review protocol was registered in the PROSPERO database on June 17, 2023 (registration number: CRD42023432955). Two researchers independently performed a literature search of the PubMed, Embase, and Web of Science databases for articles published before May 25, 2023, with no filters and no language or location restrictions. Study quality was evaluated using the Newcastle-Ottawa Scale. The primary outcome was the odds ratio (OR) and 95% confidence interval (CI) of PPD in women with vs. without PPH. We performed sensitivity analyses and meta-regression analyses to resolve heterogeneity. Meta-regression analyses included the effects of age, maternal smoking, marital status, preterm labor, maternal education level, preeclampsia, anemia during pregnancy, and cesarean section. RESULTS: In total, seven studies involving 540 558 participants met the eligibility criteria and were included in the meta-analysis. Women with PPH were at increased risk of PPD compared with women without PPH (OR 1.10; 95% CI 1.03-1.16), and heterogeneity was low (I2 = 23%; τ2 = 0.0007; p = 0.25). Moreover, the results of the sensitivity analyses showed that the I2 value decreased from 23% to 0% after excluding one particular study, which may have been a source of heterogeneity. In the meta-regression analyses, the OR of PPD was greatly affected by maternal smoking (OR -0.26; 95% CI -0.30 to -0.22; p < 0.001). However, we did not observe any effects for maternal age, marital status, preterm labor, maternal education level, preeclampsia, anemia during pregnancy, or cesarean section. CONCLUSIONS: Women with PPH must be closely monitored because they have a higher risk of PPD than women without PPH. Early recognition and management of these patients will improve treatment outcomes, maternal health, and newborn development.

An Obstacle Detection Method Based on Longitudinal Active Vision.

The types of obstacles encountered in the road environment are complex and diverse, and accurate and reliable detection of obstacles is the key to improving traffic safety. Traditional obstacle detection methods are limited by the type of samples and therefore cannot detect others comprehensively. Therefore, this paper proposes an obstacle detection method based on longitudinal active vision. The obstacles are recognized according to the height difference characteristics between the obstacle imaging points and the ground points in the image, and the obstacle detection in the target area is realized without accurately distinguishing the obstacle categories, which reduces the spatial and temporal complexity of the road environment perception. The method of this paper is compared and analyzed with the obstacle detection methods based on VIDAR (vision-IMU based detection and range method), VIDAR + MSER, and YOLOv8s. The experimental results show that the method in this paper has high detection accuracy and verifies the feasibility of obstacle detection in road environments where unknown obstacles exist.

A cross-sectional survey on the relationship between workplace psychological violence and empathy among Chinese nurses: the mediation role of resilience.

BACKGROUND: Workplace violence is one of the most serious public health issues worldwide in healthcare occupations, nurse is a profession which faces the greatest risk of exposure to workplace violence among healthcare occupations. OBJECTIVE: The present study aimed to explore the relationship between workplace psychological violence and empathy among Chinese nurses, and further examine the mediation role of resilience in this relationship. METHOD: A cross-sectional survey was conducted among a convenience sample of clinical registered nurses in Xinjiang China from 29 September 2023 to 19 October 2023.The online questionnaire, contained the general information form, the Workplace Psychologically Violent Behaviors Instrument, the Jefferson Scale of Empathy-Healthcare Professionals Version, and the Connor-Davidson Resilience Scale, was used to collect data. The IBM SPSS statistics software version 22.0 was used to perform data analyses in forms of descriptive statistics, correlation analysis, and mediation analysis. RESULT: This survey recruited a convenience sample of 1613 clinical registered nurses aged 22 to 55 years who come from diverse ethnicities and worked in different departments. A total of 534 nurse experienced psychological violent, which yielded a positive rate of 33.1% for psychological violent among nurses. Pearson analysis reported a negative correlation between psychological violences and empathy (r=-0.724, P < 0.01) as well as a negative correlation between psychological violences and resilience (r=-0.681, P < 0.01). Mediation analysis reported that resilience mediated the negative relationship between psychological violence and empathy, the mediation effect accounted for ab/(ab + c') = 23.40% of the total effect. CONCLUSION: This study supported an inverse ralationship between psychological violence and empathy among Chinese nurses where resilience acted as a protective factor to mediated the negative impacts of psychological violences on empathy These results directed health policies and clinical interventions to equip nurses with resilience to copy with and recover from workplace psychological violence.

Effects of folate on telomere length and chromosome stability of human fibroblasts and melanoma cells in vitro: a comparison of folic acid and 5-methyltetrahydrofolate.

Telomere length (TL), which is maintained by human telomerase reverse transcriptase (hTERT; component of telomerase) and/or TRF1/TRF2 (core components of shelterin) via different mechanisms, is essential for chromosomal stability and cell survival. Folates comprise a group of essential B9 vitamin that involve in DNA synthesis and methylation. This study aimed to evaluate the effects of folic acid (FA) and 5-methyltetrahydrofolate (5-MeTHF) on TL, chromosome stability, and cell survival of telomerase-negative BJ and telomerase-positive A375 cells in vitro. BJ and A375 cells were cultured in modified medium with FA or 5-MeTHF (22.6 or 2260 nM) for 28 days. TL and mRNA expression were determined by RT-qPCR. Chromosome instability (CIN) and cell death were measured by CBMN-Cyt assay. Results showed that abnormal TL elongation was observed in FA- and 5-MeTHF-deficient BJ cells. The TL of A375 cells showed no obvious alterations under the FA-deficient condition but was significantly elongated under the 5-MeTHF-deficient condition. In both BJ and A375 cells, FA and 5-MeTHF deficiency caused decreased TRF1, TRF2, and hTERT expression, increased CIN and cell death; while a high concentration of 5-MeTHF induced elongated TL, elevated CIN, increased TRF1 and TRF2 expression, and decreased hTERT expression, when compared with the FA counterpart. These findings concluded that folate deficiency induced TL instability in both telomerase-negative and -positive cells, and FA was more efficient in maintaining TL and chromosome stability compared with 5-MeTHF.

Effects of folate on telomere length and chromosome stability of human fibroblasts and melanoma cells in vitro: a comparison of folic acid and 5-methyltetrahydrofolate.

Telomere length (TL), which is maintained by human telomerase reverse transcriptase (hTERT; component of telomerase) and/or TRF1/TRF2 (core components of shelterin) via different mechanisms, is essential for chromosomal stability and cell survival. Folates comprise a group of essential B9 vitamin that involve in DNA synthesis and methylation. This study aimed to evaluate the effects of folic acid (FA) and 5-methyltetrahydrofolate (5-MeTHF) on TL, chromosome stability, and cell survival of telomerase-negative BJ and telomerase-positive A375 cells in vitro. BJ and A375 cells were cultured in modified medium with FA or 5-MeTHF (22.6 or 2260 nM) for 28 days. TL and mRNA expression were determined by RT-qPCR. Chromosome instability (CIN) and cell death were measured by CBMN-Cyt assay. Results showed that abnormal TL elongation was observed in FA and 5-MeTHF deficient BJ cells. The TL of A375 cells showed no obvious alterations under the FA-deficient condition but was significantly elongated under the 5-MeTHF-deficient condition. In both BJ and A375 cells, FA and 5-MeTHF deficiency caused decreased TRF1, TRF2, and hTERT expression, increased CIN and cell death; while a high concentration of 5-MeTHF induced elongated TL, elevated CIN, increased TRF1 and TRF2 expression and decreased hTERT expression, when compared with the FA counterpart. These findings concluded that folate deficiency induced TL instability in both telomerase-negative and -positive cells, and FA was more efficient in maintaining TL and chromosome stability compared with 5-MeTHF.

Exploring the predictive value of combined ultrasound parameters for spinal anesthesia-induced hypotension in cesarean section: a prospective observational study.

BACKGROUND: Prophylactic vasopressor infusion can effectively assist with fluid loading to prevent spinal anesthesia-induced hypotension. However, the ideal dose varies widely among individuals. We hypothesized that hypotension-susceptible patients requiring cesarean section (C-section) could be identified using combined ultrasound parameters to enable differentiated prophylactic medical interventions. METHODS: This prospective observational trial was carried out within a regional center hospital for women and children in Sichuan Province, China. Singleton pregnant women undergoing combined spinal-epidural anesthesia for elective C-sections were eligible. Women with contraindications to spinal anesthesia or medical comorbidities were excluded. Velocity time integral (VTI) and left ventricular end-diastolic area (LVEDA) in the supine and left lateral positions were measured on ultrasound before anesthesia. Stroke volume, cardiac output, and the percentage change (%) in each parameter between two positions were calculated. Vital signs and demographic data were recorded. Spinal anesthesia-induced hypotension was defined as a mean arterial pressure decrease of > 20% from baseline. The area under the receiver operating characteristic curve (AUROC) was used to analyze the associations of ultrasound measurements, vital signs, and demographic characteristics with spinal anesthesia-induced hypotension. This exploratory study did not have a predefined outcome; however, various parameter combinations were compared using the AUROC to determine which combined parameters had better predictive values. RESULTS: Patients were divided into the normotension (n = 31) and hypotension groups (n = 57). A combination of heart rate (HR), LVEDAs, and VTI% was significantly better at predicting hypotension than was HR (AUROC 0.827 vs. 0.707, P = 0.020) or LVEDAs (AUROC 0.827 vs. 0.711, P = 0.039) alone, but not significantly better than VTI% alone (AUROC 0.827 vs. 0.766, P = 0.098). CONCLUSION: The combined parameters of HR and LVEDAs with VTI% may predict spinal anesthesia-induced hypotension more precisely than the single parameters. Future research is necessary to determine whether this knowledge improves maternal and neonatal outcomes. TRIAL REGISTRATION: ChiCTR1900025191.

The height of the operating table affects the performance of residents in combined spinal and epidural anesthesia training by affecting the vision of the puncture needle: a randomized controlled trial.

BACKGROUND: The present study aimed to evaluate whether the operating table height affected the success rate and incidences of complications of combined spinal-epidural anesthesia administered by residents during training. METHODS: One-hundred-and-eighty patients were randomly allocated according to landmarks on the resident's body: umbilicus (group U), lowest rib margin (R), and xiphoid process (X). The success rates of combined spinal-epidural anesthesia, and the incidences of paresthesia and vessel trauma were recorded. RESULTS: There were no differences between the three groups in the success rates of combined spinal-epidural anesthesia, and the incidences of paresthesia and vessel trauma. However, paresthesia during epidural catheter advancement was more common on the left side (66.7%) than the right side (33.3%) (P = 0.03). In group R, the success rate of epidural anesthesia was higher during the residents' third time (100%) than their first time (50%; P = 0.01). Most residents (83%) preferred the table height at which the needle insertion point was at the level of their lowest rib margin. CONCLUSIONS: Neither the success nor the complication of combined spinal-epidural anesthesia in lateral decubitus position during residents' training affected by the operating table height. However, paresthesia was more likely to occur on the left side when a stiff catheter was inserted into the epidural space. It may be better to keep the table height at residents' lowest rib margin. It was not just preferred by most of residents but also better for their training of performing epidural anesthesia. TRIAL REGISTRATION: The trial was registered prior to patient enrollment at Chinese Clinical Trial Registry (NCT: ChiCTR1800016078, Principal investigator: Juan Gu, Date of registration: 9 May 2018). Registry URL http://www.chictr.org.cn.

Discharge Against Medical Advice After Hospitalization for Sepsis: Predictors, 30-Day Readmissions, and Outcomes.

BACKGROUND: Sepsis is a leading cause of death worldwide. However, little has been known concerning the status of discharge against medical advice (DAMA) in sepsis patients. OBJECTIVE: To identify factors associated with DAMA, evaluate the association of DAMA with 30-day unplanned readmission and readmitted outcomes after sepsis hospitalization. METHODS: Using the National Readmission Database, we identified sepsis patients who discharged routinely or DAMA in 2017. Multivariable models were used to identify factors related to DAMA, evaluate the association between DAMA and readmission, and elucidate the relationship between DAMA and outcomes in patients readmitted within 30 days. RESULTS: Among 1,012,650 sepsis cases, patients with DAMA accounted for 3.88% (n = 39,308). The unplanned 30-day readmission rates in patients who discharged home and DAMA were 13.08% and 27.21%, respectively. Predictors of DAMA in sepsis included Medicaid, diabetes, smoking, drug abuse, alcohol abuse, and psychoses. DAMA was statistically significantly associated with 30-day (odds ratio [OR] 2.18, 95% confidence interval [CI] 2.09-2.28), 60-day (OR 1.98, 95% CI 1.90-2.06), and 90-day (OR 1.88, 95% CI 1.81-1.96) readmission. DAMA is also associated with higher mortality in patients readmitted within 30 days (OR 1.38, 95% CI 1.17-1.63), whereas there were no statistically significant differences in length of stay and costs between patients who discharged home or DAMA. CONCLUSIONS: DAMA occurs in nearly 3.88% of sepsis patients and is linked to higher readmission and mortality. Those at high risk of DAMA should be early identified to motivate intervention to avoid premature discharges and associated adverse outcomes.

VIDAR-Based Road-Surface-Pothole-Detection Method.

This paper presents a VIDAR (a Vision-IMU based detection and ranging method)-based approach to road-surface pothole detection. Most potholes on the road surface are caused by the further erosion of cracks in the road surface, and tires, wheels and bearings of vehicles are damaged to some extent as they pass through the potholes. To ensure the safety and stability of vehicle driving, we propose a VIDAR-based pothole-detection method. The method combines vision with IMU to filter, mark and frame potholes on flat pavements using MSER to calculate the width, length and depth of potholes. By comparing it with the classical method and using the confusion matrix to judge the correctness, recall and accuracy of the method proposed in this paper, it is verified that the method proposed in this paper can improve the accuracy of monocular vision in detecting potholes in road surfaces.

Obstacle Detection Method Based on RSU and Vehicle Camera Fusion.

Road obstacle detection is an important component of intelligent assisted driving technology. Existing obstacle detection methods ignore the important direction of generalized obstacle detection. This paper proposes an obstacle detection method based on the fusion of roadside units and vehicle mounted cameras and illustrates the feasibility of a combined monocular camera inertial measurement unit (IMU) and roadside unit (RSU) detection method. A generalized obstacle detection method based on vision IMU is combined with a roadside unit obstacle detection method based on a background difference method to achieve generalized obstacle classification while reducing the spatial complexity of the detection area. In the generalized obstacle recognition stage, a VIDAR (Vision-IMU based identification and ranging) -based generalized obstacle recognition method is proposed. The problem of the low accuracy of obstacle information acquisition in the driving environment where generalized obstacles exist is solved. For generalized obstacles that cannot be detected by the roadside unit, VIDAR obstacle detection is performed on the target generalized obstacles through the vehicle terminal camera, and the detection result information is transmitted to the roadside device terminal through the UDP (User Data Protocol) protocol to achieve obstacle recognition and pseudo-obstacle removal, thereby reducing the error recognition rate of generalized obstacles. In this paper, pseudo-obstacles, obstacles with a certain height less than the maximum passing height of the vehicle, and obstacles with a height greater than the maximum passing height of the vehicle are defined as generalized obstacles. Pseudo-obstacles refer to non-height objects that appear to be "patches" on the imaging interface obtained by visual sensors and obstacles with a height less than the maximum passing height of the vehicle. VIDAR is a vision-IMU-based detection and ranging method. IMU is used to obtain the distance and pose of the camera movement, and through the inverse perspective transformation, it can calculate the height of the object in the image. The VIDAR-based obstacle detection method, the roadside unit-based obstacle detection method, YOLOv5 (You Only Look Once version 5), and the method proposed in this paper were applied to outdoor comparison experiments. The results show that the accuracy of the method is improved by 2.3%, 17.4%, and 1.8%, respectively, compared with the other four methods. Compared with the roadside unit obstacle detection method, the speed of obstacle detection is improved by 1.1%. The experimental results show that the method can expand the detection range of road vehicles based on the vehicle obstacle detection method and can quickly and effectively eliminate false obstacle information on the road.

MicroRNA-22-3p and MicroRNA-149-5p Inhibit Human Hepatocellular Carcinoma Cell Growth and Metastasis Properties by Regulating Methylenetetrahydrofolate Reductase.

microRNAs are small endogenous noncoding RNAs that have emerged as key negative regulators that target gene expression through RISC. Our previous study showed that the methylenetetrahydrofolate reductase gene (MTHFR) plays a key role in one carbon metabolism, which is downregulated by miR-22-3p and miR-149-5p, and that it could exert a potential anti-cancer effect. Whether miR-22-3p/miR-149-5p can regulate MTHFR to exert anti-cancer effects has become the focus of our research. Normal (HL-7702 cells) and cancerous (QGY-7703/HepG2 cells) human hepatocellular cells were transfected with 100 nM hsa-miR-22-3p/hsa-miR-149-5p mimic or controls. After 24, 48, and 72 h, cell proliferation ability was tested using CCK-8. The changes in MTHFR expression at both the transcriptional and translational levels were determined by RT-qPCR and Western blotting, respectively. Cancerous cell invasion and migration ability were confirmed by means of a transwell assay. We found that ectopic miR-22-3p/miR-149-5p inhibits hepatocellular carcinoma cell proliferation but does not inhibit normal human hepatocyte proliferation. The transfection of ectopic miR-22-3p/miR-149-5p downregulated the MTHFR expression in QGY-7703 and HepG2 but not in HL-7702. QGY-7703 and HepG2 migration and invasion were inhibited by ectopic miR-22-3p/miR-149-5p. Additionally, we found that ectopic miR-22-3p/miR-149-5p significantly increased the expression of TP53INP1 and PDCD4 in QGY-7703. The results of the study suggest that miRNA-22-3p and miRNA-149-5p inhibit tumor growth and metastasis properties may be by regulating MTHFR and that they exert anticancer effects in hepatocellular carcinoma cells.

Plasma Diaphanous Related Formin 1 Levels Are Associated with Altered Glucose Metabolism and Insulin Resistance in Patients with Polycystic Ovary Syndrome: A Case Control Study.

BACKGROUND: Diaphanous related formin 1 (DIAPH1) is a novel component of advanced glycation end product (AGE) signal transduction that was recently found to participate in diabetes-related disorders, obesity, and androgen hormones. We investigated whether plasma DIAPH1 levels were a potential prognostic predictor for polycystic ovary syndrome (PCOS). METHODS: The levels of circulating plasma DIAPH1 and indicators of glucose, insulin, lipid metabolism, liver enzymes, kidney function, sex hormones, and inflammation were measured in 75 patients with PCOS and 77 healthy participants. All of the participants were divided into normal-weight (NW) and overweight/obese (OW) subgroups. Statistical analyses were performed with R studio. RESULTS: PCOS patients manifested hyperandrogenism, increased luteinizing hormone/follicle-stimulating hormone (LH/FSH), and accumulated body fat and insulin resistance. Plasma DIAPH1 levels were significantly decreased in women with PCOS compared to control participants, and DIAPH1 levels were distinctly reduced in OW PCOS compared to OW control subjects (P < 0.001). DIAPH1 levels correlated with fasting blood glucose (FBG), total cholesterol (TC), the homeostasis model assessment of ß-cell function (HOMA-ß), and LH/FSH in all participants (FBG: r = 0.351, P < 0.0001; TC: r = 0.178, P = 0.029; HOMA-ß: r = -0.211, P = 0.009; LH/FSH: r = -0.172, P = 0.040). Multivariate logistic regression analysis revealed that plasma DIAPH1 levels were an independent risk factor for PCOS. A model containing DIAPH1, BMI, FBG, and testosterone was constructed to predict the risk of PCOS, with a sensitivity of 92.0% and a specificity of 80.9%. A nomogram was constructed to facilitate clinical diagnosis. CONCLUSIONS: These findings suggest the association of plasma DIAPH1 with glucose metabolism, insulin resistance, and sex hormones and support DIAPH1 as a potential predictive factor for PCOS.

Worse Outcomes After Readmission to a Different Hospital After Sepsis: A Nationwide Cohort Study.

BACKGROUND: In the United States, sepsis accounts for 13% of the total hospital expenses and > 50% of hospital deaths. Moreover, people with sepsis are more likely to be readmitted. OBJECTIVE: The aim of this study was to assess the prevalence and outcomes of different hospital readmissions (DHRs) in patients with sepsis, and the factors associated with DHR. METHODS: We used data from the Nationwide Readmissions Database of the United States in 2017 to identify patients admitted for sepsis. Multivariable logistic regression analysis was used to evaluate the factors associated with DHR; five models were constructed to elucidate the relationship between DHR and in-hospital outcomes. RESULTS: In 2017, 85,120 (21.97%) of all patients with sepsis readmitted within 30 days in the United States were readmitted to a different hospital. The most common reason for readmission was infection irrespective of hospital status. Compared with the patients with sepsis who were readmitted to the same hospital, DHR was associated with higher hospitalization costs ($2264; 95% CI $1755-$2772; p < 0.001), longer length of stay (0.58 days; 95% CI 0.44-0.71 days; p < 0.001), and higher risk of in-hospital mortality (odds ratio 1.63; 95% CI 1.55-1.72; p < 0.001). CONCLUSIONS: DHR occurred in one-fifth of patients with sepsis in the United States. Our findings suggest that patients readmitted to a different hospital within 30 days may experience higher in-hospital mortality, longer length of stay, and higher hospitalization costs. Future studies need to examine whether continuity of care can improve the prognosis of patients with sepsis.

Understanding the birth of rupture-prone and irreparable micronuclei.

Micronuclei are extra-nuclear bodies mainly derived from ana-telophase lagging chromosomes/chromatins (LCs) that are not incorporated into primary nuclei at mitotic exit. Unlike primary nuclei, most micronuclei are enclosed by nuclear envelope (NE) that is highly susceptible to spontaneous and irreparable rupture. Ruptured micronuclei act as triggers of chromothripsis-like chaotic chromosomal rearrangements and cGAS-mediated innate immunity and inflammation, raising the view that micronuclei play active roles in human aging and tumorigenesis. Thus, understanding the ways in which micronuclear envelope (mNE) goes awry acquires increased importance. Here, we review the data to present a general framework for this question. We firstly describe NE reassembly after mitosis and NE repair during interphase. Simultaneously, we briefly discuss how mNE is organized and how mNE rupture controls the fate of micronuclei and micronucleated cells. As a focus of this review, we highlight current knowledge about why mNE is rupture-prone and irreparable. For this, we survey observations from a series of elegant studies to provide a systematic overview. We conclude that the birth of rupture-prone and irreparable micronuclei may be the cumulative effects of their intracellular geographic origins, biophysical properties, and specific mNE features. We propose that DNA damage and immunogenicity in micronuclei increase stepwise from altered mNE components, mNE rupture, and refractory to repair. Throughout our discussion, we note interesting issues in mNE fragility that have yet to be resolved.

Extract of bulbus of Fritillaria cirrhosa induces spindle multipolarity in human-derived colonic epithelial NCM460 cells through promoting centrosome fragmentation.

Bulbus of Fritillaria cirrhosa D. Don (BFC), an outstanding antitussive and expectorant herbal drug used in China and many other countries, has potential but less understood genotoxicity. Previously, we have reported that aqueous extract of BFC compromised the spindle assembly checkpoint and cytokinesis in NCM460 cells. Here, we found that one remarkable observation in BFC-treated NCM460 cells was multipolar mitosis, a trait classically compromises the fidelity of chromosome segregation. More detailed investigation revealed that BFC-induced spindle multipolarity in metaphases and ana-telophases in a dose- and time-dependent manner, suggesting BFC-induced multipolar spindle conformation was not transient. The frequency of multipolar metaphase correlated well to that of multipolar ana-telophases, indicating that BFC-induced multipolar metaphases often persisted through anaphase. Unexpectedly, BFC blocked the proliferation of binucleated cells, suggesting spindle multipolarity was not downstream of BFC-induced cytokinesis failure. Exposure of BFC to early mitotic cells, rather than S/G2 cells, contributed greatly to spindle multipolarity, indicating BFC might disrupt centrosome integrity rather than induce centrosome overduplication. The immunofluorescence results showed that the centrosomes were severely fragmented by a short-term treatment of BFC and the extent of centrosome fragmentation in early mitotic cells was larger than this in S/G2 cells. Consistently, several genes (e.g. p53, Rb centrin-2, Plk-4, Plk-1 and Aurora-A) involved in regulating centrosome integrity were significantly deregulated by BFC. Together, our results suggest that BFC causes multipolar spindles primarily by inducing centrosome fragmentation. Coupling these results to our previous observations, we recommend the risk/benefit ratio should be considered in the practical use of BFC.

Mosaic loss of human Y chromosome: what, how and why.

Y chromosome (ChrY), the male-specific sex chromosome, has been considered as a genetic wasteland. Aging-related mosaic loss of ChrY (LOY) has been known for more than half a century, but it was constantly considered as a neutral karyotype related to normal aging. These views have been challenged with genome-wide association studies identifying mosaic LOY in human somatic cells is the most commonly acquired mutation in male's genome and is associated with a wide spectrum of human diseases including cancer, Alzheimer's disease, and cardiovascular disease. These previously undescribed clinical significances deeply modify our perception on ChrY and open up a range of new questions. Here, we review the latest advances in our knowledge of the biological origins and clinical consequences of mosaic LOY. We highlight the association of mosaic LOY to pathogenic conditions and evaluate the cause-and-consequence relationships between mosaic LOY and pathogenesis. The known risk factors of mosaic LOY including age, genetic variants, ChrY structural aberrations and environmental stressors are discussed. In light of evidence from pioneering and more recent studies, we propose the micronucleation hypothesis and centromere-dysfunction and telomere-attrition models to explain how mosaic LOY occurs and why ChrY is prone to lose. We believe it is importantly and timely to extend mosaic LOY research from epidemiological associations to mechanistic studies. In this regard, we outline important gaps and assess several future directions from a biological and clinical perspective. An improved understanding of mosaic LOY will open new pathways to modify and increase healthy aging in males.

Efficacy of premedication with intranasal dexmedetomidine for removal of inhaled foreign bodies in children by flexible fiberoptic bronchoscopy: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Tracheobronchial foreign body aspiration in children is a life-threatening, emergent situation. Currently, the use of fiberoptic bronchoscopy for removing foreign bodies is attracting increasing attention. Oxygen desaturation, body movement, laryngospasm, bronchospasm, and breath-holding are common adverse events during foreign body removal. Dexmedetomidine, as a highly selective α2-adrenergic agonist, produces sedative and analgesic effects, and does not induce respiratory depression. We hypothesized that intranasal dexmedetomidine at 1 µg kg - 1 administered 25 min before anesthesia induction can reduce the incidence of adverse events during fiberoptic bronchoscopy under inhalation general anesthesia with sevoflurane. METHODS: In all, 40 preschool-aged children (6-48 months) with an American Society of Anesthesiologists physical status of I or II were randomly allocated to receive either intranasal dexmedetomidine at 1 µg·kg - 1 or normal saline at 0.01 ml kg- 1 25 min before anesthesia induction. The primary outcome was the incidence of perioperative adverse events. Heart rate, respiratory rate, parent-child separation score, tolerance of the anesthetic mask, agitation score, consumption of sevoflurane, and recovery time were also recorded. RESULTS: Following pre-anesthesia treatment with either intranasal dexmedetomidine or saline, the incidences of laryngospasm (15% vs. 50%), breath-holding (10% vs. 40%), and coughing (5% vs. 30%) were significantly lower in patients given dexmedetomidine than those given saline. Patients who received intranasal dexmedetomidine had a lower parent-child separation score (P = 0.017), more satisfactory tolerance of the anesthetic mask (P = 0.027), and less consumption of sevoflurane (38.18 ± 14.95 vs. 48.03 ± 14.45 ml, P = 0.041). The frequency of postoperative agitation was significantly lower in patients given intranasal dexmedetomidine (P = 0.004), and the recovery time was similar in the two groups. CONCLUSIONS: Intranasal dexmedetomidine 1 µg·kg- 1, with its sedative and analgesic effects, reduced the incidences of laryngospasm, breath-holding, and coughing during fiberoptic bronchoscopy for FB removal. Moreover, it reduced postoperative agitation without a prolonged recovery time. TRAIL REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800017273) on July 20, 2018.

Amide-linked local anesthetics preferentially target leukemia stem cell through inhibition of Wnt/ß-catenin.

The anti-cancer activities of amide-linked local anesthetics have been demonstrated in various types of bulky/differentiated cancer cells. However, whether these anesthetics also affect biological functions of cancer stem cells is largely unknown. In this study, we systematically investigated the effects of three commonly used amide-linked local anesthetics (ropivacaine, lidocaine and bupivacaine) on leukemia stem cell (LSC) derived from two different leukemia diseases (acute myeloid leukemia, n = 8 and chronic myeloid leukemia, n = 8) as well as normal hematopoietic stem cell (HSC) derived from cord blood donors (n = 8) as comparison. We show that all three local anesthetics at clinically achievable concentrations significantly inhibit colony formation and serial replating of LSC in a dose-dependent manner, suggesting their inhibitory effects on LSC differentiation, proliferation and self-renewal. In addition, lidocaine and bupivacaine are more potent than ropivacaine. However, local anesthetics at the same concentrations do not affect LSC and HSC survival, demonstrating the differentiation and self-renewal as the primary effects of local anesthetics on LSC and HSC. Interestingly, local anesthetics display certain selectivity between LSC and HSC by having higher efficacy on LSC than HSC. Mechanism studies using both pharmacological and genetic approaches demonstrate that these local anesthetics target LSC via inhibiting Wnt/ß-catenin but not Hedgehog or NF-ĸB signaling. Our work is the first to demonstrate the possible influence of amide-linked local anesthetics on cancer as well as normal stem cells via inhibiting Wnt/ß-catenin signaling. Our findings contribute to the comprehensive understanding of potential implication of amide-linked local aesthesis in tumor biology.

Shelterin differentially respond to oxidative stress induced by TiO2-NPs and regulate telomere length in human hepatocytes and hepatocarcinoma cells in vitro.

Titanium dioxide nanoparticles (TiO2-NPs) have raised serious attention for their widely use and potential adverse effects on human mainly due to producing ROS. However, the influence of TiO2-NPs on telomere maintaining has not been studied clearly. Shelterin plays core roles in telomere length (TL) regulation. Abnormal TL are associated with chromosome instability (CIN) and high risk of diseases. This study investigated whether TiO2-NPs affect TL to induce CIN through ROS generation and the possible mechanisms. Human hepatocyte L-02 and hepatocarcinoma cells QGY were exposed to TiO2-NPs (0, 40, 80 µg/mL) for 72 h. The intracellular hydrogen dioxide (H2O2) concentration were measured. The TL, Nrf-2, and three core shelterin components (TRF1, TRF2, and POT1) transcription level were determined by quantitative real-time PCR. CIN was measured by cytokinesis-block micronucleus assay. TiO2-NPs exposure increased intracellular H2O2 in both L-02 and QGY cells, and induced Nrf-2, TRF1, TRF2, POT1 downregulated transcription compared with control (P < 0.001) in L-02 but all upregulated (P < 0.05) in QGY. Significant TL shortening (P < 0.001) and CIN increase (P < 0.01) in L-02 cells were observed but not in QGY cells. The differentially responses of the tested components of shelterin and Nrf-2 to oxidative stress induced by TiO2-NPs led to the weakened telomere protection in normal cells and effective telomere maintenance in cancer cells, respectively. The upregulation of Nrf-2 and shelterin could protect TL and chromosome stability against TiO2-NPs exposure.