Machine learning approach for predicting post-intubation hemodynamic instability (PIHI) index values: towards enhanced perioperative anesthesia quality and safety.

BACKGROUND: Adequate preoperative evaluation of the post-intubation hemodynamic instability (PIHI) is crucial for accurate risk assessment and efficient anesthesia management. However, the incorporation of this evaluation within a predictive framework have been insufficiently addressed and executed. This study aims to developed a machine learning approach for preoperatively and precisely predicting the PIHI index values. METHODS: In this retrospective study, the valid features were collected from 23,305 adult surgical patients at Peking Union Medical College Hospital between 2012 and 2020. Three hemodynamic response sequences including systolic pressure, diastolic pressure and heart rate, were utilized to design the post-intubation hemodynamic instability (PIHI) index by computing the integrated coefficient of variation (ICV) values. Different types of machine learning models were constructed to predict the ICV values, leveraging preoperative patient information and initiatory drug infusion. The models were trained and cross-validated based on balanced data using the SMOTETomek technique, and their performance was evaluated according to the mean absolute error (MAE), root mean square error (RMSE), mean absolute percentage error (MAPE) and R-squared index (R2). RESULTS: The ICV values were proved to be consistent with the anesthetists' ratings with Spearman correlation coefficient of 0.877 (P < 0.001), affirming its capability to effectively capture the PIHI variations. The extra tree regression model outperformed the other models in predicting the ICV values with the smallest MAE (0.0512, 95% CI: 0.0511-0.0513), RMSE (0.0792, 95% CI: 0.0790-0.0794), and MAPE (0.2086, 95% CI: 0.2077-0.2095) and the largest R2 (0.9047, 95% CI: 0.9043-0.9052). It was found that the features of age and preoperative hemodynamic status were the most important features for accurately predicting the ICV values. CONCLUSIONS: Our results demonstrate the potential of the machine learning approach in predicting PIHI index values, thereby preoperatively informing anesthetists the possible anesthetic risk and enabling the implementation of individualized and precise anesthesia interventions.

Prenatal co-exposure to diisodecyl phthalate and ozone contribute to depressive behavior in offspring mice through oxidative stress and TWIST1 participation.

Exposure to diisodecyl phthalate (DIDP) during early pregnancy may be a risk factor for depressive behavior in offspring. While ozone (O3) exposure also raises the probability of depressive behavior during the preceding DIDP-induced process. In the present study, we investigated the effects of prenatal exposure to DIDP and O3 on the development of depressive-like behavior in offspring mice. The study found that prenatal exposure to both DIDP and O3 significantly increased depressive-like behavior in the offspring mice compared to either DIDP or O3 alone. Prenatal exposure to DIDP and O3 obviously increased the levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol, and decreased the levels of brain-derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) in the brain tissues of offspring mice. Transcriptome analysis further revealed significant alterations in genes related to oxidative stress and TWIST1 (a helix-loop-helix transcription factor) in response to the combined exposure to DIDP and O3. HPA axis activation, dysregulation of neurodevelopmental factors, oxidative stress and TWIST1 involvement, collectively contributed to the development of depression-like behaviors in offspring mice following prenatal exposure to DIDP and O3. Moreover, the study also verified the potential role of oxidative stress using vitamin E as an antioxidant. The findings provide valuable evidence for the relationship between co-exposure to DIDP and O3 and depression, highlighting the importance of considering the combined effects of multiple environmental pollutants in assessing their impact on mental health outcomes.

Curcumin relieves oxaliplatin-induced neuropathic pain via reducing inflammation and activating antioxidant response.

Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK-3ß activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR-treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4-mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK-3ß through four covalent bonds and reduced GSK-3ß activity. In conclusion, our findings suggest that CUR treatment inhibits GSK-3ß activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA-induced neuropathic pain.

Anemoside B4 alleviates arthritis pain via suppressing ferroptosis-mediated inflammation.

Chronic pain is the key manifestations of rheumatoid arthritis. Neuroinflammation in the spinal cord drives central sensitization and chronic pain. Ferroptosis has potentially important roles in the occurrence of neuroinflammation and chronic pain. In the current study, mouse model of collagen-induced arthritis was established by intradermal injection of type II collagen in complete Freund's adjuvant (CFA) solution. CFA inducement resulted in swollen paw and ankle, mechanical and spontaneous pain, and impaired motor coordination. The spinal inflammation was triggered, astrocytes were activated, and increased NLRP3-mediated inflammatory signal was found in CFA spinal cord. Oxidative stress and ferroptosis in the spinal cord were manifested. Meanwhile, enhancive spinal GSK-3ß activity and abnormal phosphorylated Drp1 were observed. To investigate the potential therapeutic options for arthritic pain, mice were intraperitoneally injected with AB4 for three consecutive days. AB4 treatment reduced pain sensitivity and increased the motor coordination. In the spinal cord, AB4 treatment inhibited NLRP3 inflammasome-mediated inflammatory response, increased antioxidation, decreased mitochondrial reactive oxygen species and ferroptosis. Furthermore, AB4 decreased GSK-3ß activity by binding with GSK-3ß through five electrovalent bonds. Our findings indicated that AB treatment relieves arthritis pain by inhibiting GSK-3ß activation, increasing antioxidant capability, reducing Drp1-mediated mitochondrial dysfunction and suppressing neuroinflammation.

Mediation of the JNC/ILC2 pathway in DBP-exacerbated allergic asthma: A molecular toxicological study on neuroimmune positive feedback mechanism.

BACKGROUND: Dibutyl phthalate (DBP), a commonly used plasticizer, has been found to be strongly linked to a consistently high prevalence of allergic diseases, particularly allergic asthma. Previous animal experiments have demonstrated that exposure to DBP can worsen asthma by triggering the production of calcitonin gene-related peptide (CGRP), a neuropeptide in the lung tissue. However, the precise neuroimmune mechanism and pathophysiology of DBP-exacerbated allergic asthma with the assistance of CGRP remain unclear. OBJECTIVE: The present study was to investigate the potential pathophysiological mechanism in DBP-exacerbated asthma from the perspective of neural-immune interactions. METHODS AND RESULTS: C57BL/6 mice were orally exposed to different concentrations (0.4, 4, 40 mg/kg) of DBP for 28 days. They were then sensitized with OVA and nebulized with OVA for 7 consecutive excitations. To investigate whether DBP exacerbates allergic asthma in OVA induced mice, we analyzed airway hyperresponsiveness and lung histopathology. To investigate the activation of JNC and TRPV1 neurons and the release of CGRP by JNC cells, we measured the levels of TRPV1 channels, calcium inward flow, and downstream neuropeptide CGRP. Results showed that TRPV1 expression, inward calcium flux, and CGRP levels were significantly elevated in the lung tissues of the 40DBP + OVA group, suggesting the release of CGRP by JNC cells. To counteract the detrimental effects of DBP mediated by CGRP, we employed olcegepant (also known as BIBN-4096), a CGRP receptor specific antagonist. Results revealed that 40DBP + OVA + olcegepant led to notable decreases in TRPV1, calcium inward flow, and CGRP expression in lung tissues compare with 40DBP + OVA, further supporting the efficacy of olcegepant. Additionally, we also conducted ILC2 flow sorting and observed that neuropeptide CGRP-activated ILC2 cells have a crucial role as key effector cells in DBP-induced neuroimmune positive feedback regulation. Finally, we examined the protein expression of CGRP, GATA3 and P-GATA3, and found that significant upregulations of CGRP and P-GATA3 in the 40DBP + OVA group, suggest that GATA3 acted as a key regulator of CGRP-activated ILC2. CONCLUSION: The aforementioned studies indicate that exposure to DBP can exacerbate allergic asthma, leading to airway inflammation. This exacerbation occurs through the activation of TRPV1 in JNC, resulting in the release of CGRP. The excessive release of CGRP further promotes the release of Th2 cytokines by inducing the activation of ILC2 through GATA phosphorylation. Consequently, this process contributes to the development of airway inflammation and allergic asthma. The increased production of Th2 cytokines also triggers the production of IgE, which interacts with FcεRI on JNC neurons, thereby mediating neuro-immune positive feedback regulation.

The IL-31/TRPV1 pathway mediates allergic asthma exacerbated by DINP dermal exposure in OVA-sensitized Balb/c mice.

BACKGROUND: The potential role of dermal exposure diisononyl phthalate (DINP) as an adjuvant in allergic inflammation and asthma has been suggested. However, the current findings do not provide enough evidence to support this claim. OBJECTIVES: The purpose of this investigation was to examine the impact and mechanisms of allergic asthma exacerbation through the dermal exposure to DINP. METHODS: The study was undertaken using OVA-sensitized mice. Lung histopathology and airway hyperreactivity (AHR) were assessed. Expression levels of immunoglobulins (t-IgE, OVA-IgE and OVA-IgG1), cytokines (IL-31, IL-4, IL-5, IL-6, IL-13 and INF-γ), and TRPV1 were measured. To investigate the mechanism by which allergic asthma worsens due to dermal exposure to DINP, the blockade analysis using the IL-31 antagonist SB-431542 and the TRPV1 antagonist capsazepine (CZP) were performed. RESULTS: The findings of the study revealed that the simultaneous exposure to DINP and OVA resulted in an increase in inspiratory resistance (Ri) and expiratory resistance (Re), a decrease in the minimum value of lung dynamic compliance (Cldyn), and worsened airway remodeling. Additionally, it was found that this exposure led to an increase in the levels of IL-31 and TRPV1, which are biomarkers of Th2 cytokines (IL-4, IL-5, IL-6, and IL-13), as well as immunoglobulins (Total IgE, OVA-lgE, and OVA-IgG1), while decreasing the biomarker of Th1 cytokines (IFN-γ). However, these impairments showed improvement after the administration of SB-431542 or CZP. CONCLUSION: The findings of this research indicate that the IL-31/TRPV1 pathway plays a moderating function in OVA-induced allergic asthma worsened by dermal exposure to DINP.

Spatiotemporal variation in sensitivity of urban vegetation growth and greenness to vegetation water content: Evidence from Chinese megacities.

Understanding the sensitivity of vegetation growth and greenness to vegetation water content change is crucial for elucidating the mechanism of terrestrial ecosystems response to water availability change caused by climate change. Nevertheless, we still have limited knowledge of such aspects in urban in different climatic contexts under the influence of human activities. In this study, we employed Google Earth Engine (GEE), remote sensing satellite imagery, meteorological data, and Vegetation Photosynthesis Model (VPM) to explore the spatiotemporal pattern of vegetation growth and greenness sensitivity to vegetation water content in three megacities (Beijing, Shanghai, and Guangzhou) located in eastern China from 2001 to 2020. We found a significant increase (slope > 0, p < 0.05) in the sensitivity of urban vegetation growth and greenness to vegetation water content (SLSWI). This indicates the increasing dependence of urban vegetation ecosystems on vegetation water resources. Moreover, evident spatial heterogeneity was observed in both SLSWI and the trends of SLSWI, and spatial heterogeneity in SLSWI and the trends of SLSWI was also present among identical vegetation types within the same city. Additionally, both SLSWI of vegetation growth and greenness and the trend of SLSWI showed obvious spatial distribution differences (e.g., standard deviations of trends in SLSWI of open evergreen needle-leaved forest of GPP is 14.36 × 10-2 and standard deviations of trends in SLSWI of open evergreen needle-leaved forest of EVI is 10.16 × 10-2), closely associated with factors such as vegetation type, climatic conditions, and anthropogenic influences.

Xanthohumol relieves arthritis pain in mice by suppressing mitochondrial-mediated inflammation.

Chronic pain is the most common symptom for people who suffer from rheumatoid arthritis and it affects approximately 1% of the global population. Neuroinflammation in the spinal cord induces chronic arthritis pain. In this study, a collagen-induced arthritis (CIA) mice model was established through intradermally injection of type II collagen in complete Freund's adjuvant solution. Following CIA inducement, the paws and ankles of mice were found to swell, mechanical pain and spontaneous pain were induced, and their motor coordination was impaired. The spinal inflammatory reaction was triggered, which presented as severe infiltration of inflammatory cells, and the expression levels of GFAP, IL-1ß, NLRP3, and cleaved caspase-1 increased. Oxidative stress in the spinal cord of CIA mice was manifested as reduced Nrf2 and NDUFB11 expression and SOD activity, and increased levels of DHODH and Cyto-C. At the same time, spinal AMPK activity was decreased. In order to explore the potential therapeutic options for arthritic pain, Xanthohumol (Xn) was intraperitoneally injected into mice for three consecutive days. Xn treatment was found to reduce the number of spontaneous flinches, in addition to elevating mechanical pain thresholds and increasing latency time. At the same time, Xn treatment in the spinal cord reduced NLRP3 inflammasome-mediated inflammation, increased the Nrf2-mediated antioxidant response, and decreased mitochondrial ROS level. In addition, Xn was found to bind with AMPK via two electrovalent bonds and increased AMPK phosphorylation at Thr174. In summary, the findings indicate that Xn treatment activates AMPK, increases Nrf2-mediated antioxidant response, reduces Drp1-mediated mitochondrial dysfunction, suppresses neuroinflammation, and can serve to relieve arthritis pain.

Mediation of endoplasmic reticulum stress and NF-κB signaling pathway in DINP-exacerbated allergic asthma: A toxicological study with Balb/c mice.

Epidemiological evidence indicates a significant relationship between exposure to diisononyl phthalate and allergic asthma. Despite this, the mechanism underlying this association remains unclear. Previous toxicological researches have suggested that the development of allergic asthma may involve the activation of endoplasmic reticulum stress (ERS) and the nuclear factor κ-B (NF-κB) pathways. Nevertheless, it is currently unknown whether these specific signaling pathways are implicated in diisononyl phthalate (DINP)-induced allergic asthma. The objective of this research was to understand how DINP exacerbates allergic asthma in Balb/c mice through ERS and NF-κB pathways. To systematically examine the aggravated effects of DINP in Balb/c mice, we measured airway hyperresponsiveness (AHR), lung tissue pathology, cytokines, and ERS and NF-κB pathway biomarkers. Additionally, we applied the ERS antagonist phenylbutyric acid (4-PBA) or the NF-κB antagonist pyrrolidine dithiocarbamate (PDTC) to verify the mediating effects of ERS and NF-κB on DINP-exacerbated allergic asthma. The results of our experiment show that oral DINP exposure may exacerbate airway hyperresponsiveness and airway remodeling. This deterioration is accompanied by an imbalance in immunoglobulin levels, Th17/Treg cells, ERS, and NF-κB biomarkers, leading to the activation of pro-inflammatory pathways. Furthermore, our study found that the blocking effect of 4-PBA or PDTC can inhibit the Th17/Treg imbalance and effectively alleviate symptoms resembling allergic asthma. In conclusion, ERS and NF-κB signaling pathways play an important role in regulating DINP-induced allergic asthma exacerbations.

Efficacy of continuous intravenous remimazolam versus midazolam in the extraction of impacted wisdom teeth: protocol of a randomised controlled trial.

INTRODUCTION: Benzodiazepines such as midazolam are widely used to moderately sedate patients during impacted wisdom tooth extraction to reduce anxiety in outpatient surgery. This present protocol was designed to determine whether continuous intravenous remimazolam, a new ultrashort-acting benzodiazepine, produces superior postoperative recovery quality to that of midazolam in patients undergoing extraction of impacted wisdom teeth. METHODS AND ANALYSIS: This study is a multicentre randomised controlled trial conducted at Peking Union Medical College Hospital, Beijing Anzhen Hospital and Beijing Shijitan Hospital in China. Approximately 150 participants undergoing extraction of impacted mandibular wisdom teeth will be randomly allocated to two groups (remimazolam and midazolam). The participants will be administered standard interventions to ensure they achieve a sedation level of III on the Ramsay sedation scale during the treatment. Preoperative and anaesthesia management and surgical techniques will be standardised for all participants. The primary outcome is recovery time for complete alertness and the secondary outcomes are anterograde amnesia during and after surgery, and interruption during operation for poor compliance or safety concerns. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Review Committee of Peking Union Medical College Hospital (approval number: ZS-3142), Beijing Anzhen Hospital (approval number: KS2022082) and Beijing Shijitan Hospital (approval number: 2023-4). TRIAL REGISTRATION NUMBER: NCT05350085.

Composite dietary antioxidant index negatively correlates with osteoporosis among middle-aged and older US populations.

OBJECTIVE: To assess whether the composite dietary antioxidant index (CDAI) is associated with osteoporosis (OP) in middle-aged and older US populations. METHODS: We conducted a cross-sectional survey and identified individuals aged 40-85 years (n=11,664) from secondary datasets from the 2007-2010, 2013-2014, and 2017-2018 National Health and Nutrition Examination Survey (NHANES). Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD), and OP was defined as a BMD T-score ≤-2.5 at the femoral neck or lumbar spine. The CDAI score was calculated based on dietary data from the first NHANES 24-hour dietary recall. Multivariate logistic regression models were used to evaluate the association between CDAI and OP. RESULTS: Among the 11,664 participants, the average age was 60.3 (11.8), 5,898 (50.6%) were female, and 925 (7.9%) had OP. The median CDAI was -2.0 (interquartile range, -6.9 to 4.2). After adjusting for age, sex, race, family income, body mass index, physical activity, calorie intake, estimated glomerular filtration rate, smoking and drinking status, hypertension, and diabetes, the CDAI was associated with OP (odds ratio (OR), 0.98; 95% CI: 0.96-0.99). Participants in the highest CDAI quantile were at low risk of osteoporosis (OR, 0.61; 95% CI: 0.44-0.85) versus those in the lowest quantile. Moreover, this association was stable in the subgroup and sensitivity analyses. CONCLUSION: Dietary antioxidant ability assessed by using the CDAI was inversely associated with OP among US adults aged 40-85 years.

Driving forces of UHI changes in China's major cities from the perspective of land surface energy balance.

As remarkable human-induced temperature anomalies on the land surface, variations of urban heat island (UHI) and its driving factors have been investigated in numerous studies. However, few studies discussed the spatiotemporal heterogeneity of the driving forces exerted by land surface energy fluxes, i.e., net radiation, sensible heat, latent heat and heat storage, on UHI behaviors at large scale and long term. In this study, a comprehensive application of multisource datasets and statistical methods have been implemented based on land surface energy balance theory, the spatiotemporal variations of surface UHI intensity (urban-rural temperature difference) and changes of their driving forces have been quantified. The results demonstrate the dynamics of UHI intensity in 32 major cities of China from 2003 to 2017 are generally coherent with the common perception, the overall surface UHI intensity is 4.57 K higher in summer than in winter. The spatial variations of the fluxes that alter UHI intensity can be largely attributed to the varied energy interactions between vegetated/paved surface and atmosphere and the differences of background temperature and precipitation, the contribution of latent heat to UHI changes declines nearly 40% from semiarid/arid climate at the north to subtropical humid climate at the south, while the contributions of other fluxes are stable. The temporal changes of the effect of these fluxes, however, imply more complex mechanisms. The contributions of sensible heat and latent heat to UHI intensity variations are three times and eight times larger in the warm season than in the cold season respectively, indicating the influence of seasonality of background temperature, precipitation and vegetation. The low contributions of these fluxes in the cold season also suggest the significant effect of other driving forces such as anthropogenic heat, especially in semiarid/semihumid climate zones. This study highlights the temporal shifts of major driving forces of UHI intensity, the mitigation tactics for UHI in different cities and seasons should be customized for better validity.

Novel compound heterozygous missense mutations in GDAP1 cause Charcot-Marie-Tooth type 4A.

Homozygous or compound heterozygous mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT4A) that are consistent with an autosomal recessive mode of inheritance. The case reported in this study is clinically and genetically diagnosed with recessive CMT4A that is caused by a compound novel heterozygous GDAP1 mutation. The genomic DNA of the proband with the clinical diagnosis of CMT was screened for GDAP1 mutations using a targeted next-generation sequencing (NGS) gene-panel that comprised of 27 CMT genes. Two novel compound heterozygous amino acid changing variants were identified in the GDAP1 gene, c.246C>G p.His82Gln in exon 2 and c.614T>G p.Leu205Trp in exon 5. The two amino acid changing variants were not previously reported in the 1000 Genome, Mutation Taster and gnomAD. Our findings expand the phenotypic characterization of the two novel heterozygous mutations associated with CMT4A (AR-CMT1A) and add to the repertoire of GDAP1 mutations related to autosomal recessive CMT in Chinese populations.

Induction and maintenance of procedural sedation in adults: focus on remimazolam injection.

Introduction: Procedural sedation (PS) is a humane way to help patients get through painful medical procedures by the administration of sedative drugs combined with analgesics. However, each of the currently used medications has certain shortcomings, urging the search for a new drug. Remimazolam, a novel benzodiazepine, is an ultra-short-acting hypnotic agent invented out of the 'soft drug' development.Areas covered: This presented review provides an overview of the drugs used in clinical practice for the induction and maintenance of procedural sedation in adults, focusing on the newly investigated benzodiazepine remimazolam. Literature search was conducted using the MEDLINE and ClinicalTrial.gov databases from January 2007 to December 2020.Expert opinion: Based on the reported clinical trials so far, remimazolam has demonstrated its effectiveness and safety with promising properties including rapid onset, short duration of action, predictable and consistent recovery profile, metabolism almost unaffected by liver or renal function, with non or minimal cardiorespiratory depression, and availability with a reversal drug. With marketing approval received recently, remimazolam is expected to have a place in the practice for procedural sedation in the near future if its efficacy and safety are further confirmed by more clinical trials and post-market analyses.

Continuous artificial light at night exacerbates diisononyl phthalate-induced learning and memory impairment in mice: Toxicological evidence.

Previously, we reported that exposure to diisononyl phthalate (DINP) resulted in cognitive deficits and anxiety in mice (https://doi.org/10.1038/srep14676). Artificial light at night (ALAN) is now recognized as being a potential threat to human health. However, toxicological evidence concerning exposure to a combination of ALAN and DINP in vivo is limited. To this end, mice were orally exposed to different concentrations of DINP for 28 consecutive days, and ALAN (intensity 150 lux, every night for 12 h). The results showed that oxidative stress levels increased with increasing DINP exposure concentrations, which triggered apoptosis (Bcl-2 levels decreased, Bax levels increased), resulting in nerve cell damage and a decline in the learning and memory abilities of mice. The combined effects of ALAN and DINP exposure on the learning ability and memory of mice are more serious than for DINP exposure alone. The antioxidant vitamin E was shown to have a certain antagonistic effect on the oxidative damage caused by ALAN and DINP exposure. These results highlight a previously unknown relationship between exposure to ALAN and DINP-induced learning and memory impairment, and provide evidence that ALAN may be exacerbating the effects of DINP.

Remimazolam tosilate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial.

BACKGROUND AND AIM: Remimazolam tosilate (RT) is a new short-acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy. METHODS: This positive-controlled, non-inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety. RESULTS: The success rate of sedation in the RT group was non-inferior to that in the propofol group (97.34% vs 100.00%; difference in rate -2.66%, 95% CI -4.96 to -0.36, meeting criteria for non-inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment-related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001). CONCLUSION: This trial established non-inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.

Nimodipine attenuates dibutyl phthalate-induced learning and memory impairment in kun ming mice: An in vivo study based on bioinformatics analysis.

Dibutyl phthalate (DBP), a typical representative of phthalate esters (PAEs), is used as a plasticizer in various industrial applications and has been reported to be responsible for neurobehavioral changes. Despite mounting evidence showing that nimodipine (Nim) palys a neuropharmacological and psychopharmacological role in neurons, the attenuating effects of Nim on learning and memory impairment induced by DBP exposure remain unknown. Based on bioinformatics analysis we found that the biological processes affected by both DBP and Nim may involve the calcium signaling pathway, the MAPK signaling pathway and the apoptosis pathway. The results of an in vivo study confirmed that DBP affects the levels of Ca2+ -related proteins, up-regulates phosphorylated -ERK1/2 expression and results in hippocampal neuronal damage and apoptosis, whereas Nim as a Ca2+ antagonist, has a certain neuroprotective role to avoid these adverse effects. Our data suggest that Nim could be used to attenuate the learning and memory impairment in DBP-exposed mice, to down-regulate intracellular Ca2+ levels, subordinate the ERK1/2 pathway and attenuate apoptosis in hippocampal tissue.

Branched-chain amino acid aminotransferase-1 regulates self-renewal and pluripotency of mouse embryonic stem cells through Ras signaling.

The developmental plasticity of embryonic stem cells (ESCs) is mainly controlled by well-characterized transcription factors, but additional factors, especially those related to metabolism that modulate this intrinsic program remain elusive. Here, using whole transcriptome analysis, we identified branched-chain amino acid aminotransferase-1(Bcat1) as highly-expressed in mouse ESCs and dramatically down-regulated upon differentiation. Bcat1 deletion impaired pluripotency and self-renewal in mouse ESCs, while Bcat1 overexpression resulted in robust ESC self-renewal and inhibition of differentiation. Whole genome bisulfite sequencing (WGBS) analysis showed that Bcat1 deletion altered whole genome methylation levels and hence gene expression in multiple pathways. Specifically, Bcat1 deletion increased expression of RAS protein activator like 1(Rasal1), leading to inactivation of Ras-Erk/MAPK signaling, while Rasal1 inhibition rescued defects seen in Bcat1 deleted cells. In summary, we demonstrate that Bcat1 is essential for mouse ESC self-renewal and pluripotency and that this effect is mediated by DNA methylation and the Ras signaling pathway.