Study on the fire extinguishing effect of compressed nitrogen foam on 280 Ah lithium iron phosphate battery.

This study conducted experimental analyses on a 280 Ah single lithium iron phosphate battery using an independently constructed experimental platform to assess the efficacy of compressed nitrogen foam in extinguishing lithium-ion battery fires. Based on theoretical analysis, the fire-extinguishing effects of compressed nitrogen foam at different outlet pressures from foam mixture tanks were analyzed, examining factors such as battery surface temperature, flame temperature, and thermal weight loss. The results indicate that the compressed nitrogen foam can extinguish the open flame of the battery in 14 s at 0.7 MPa, with the battery's surface temperature dropping by approximately 11 % before and after the application of the extinguishing agent. Compared with other commonly used extinguishing agents, the compressed nitrogen foam demonstrates superior extinguishing efficiency, but its cooling efficiency is somewhat lower. At pressures ranging from 0.4 to 0.6 MPa, the foam displays prolonged drainage time and sustained cooling effects, rendering it more suitable for lithium-ion battery fire scenarios. To address the issue of reduced cooling performance during later stages of fire suppression by compressed nitrogen foam, an intermittent injection approach has been proposed to effectively preserve its cooling efficacy.

Quercetin on the properties of rice bran oil body: Focused surface charge, oxidative stability and digestive properties.

To further enhance the stability of rice bran oil body (RBOB) emulsions, this study examined the impact of various concentrations of quercetin (QU) on the microstructure, rheological properties, oxidative stability, and digestive properties of RBOB emulsions. The results indicated that by incorporating QU concentration, the particle size of RBOB emulsions could be significantly reduced to 300 nm; QU could improve the surface hydrophobicity, the emulsifying activity index and emulsification stability index of RBOB emulsions of 550, 0.078 m2/g and 50.78 min, respectively; the storage stability of RBOB emulsions was further improved; the higher concentration of QU could delay the oxidation of RBOB emulsions, among which, the 500 µmol/L concentration inhibited the strongest effect of oil oxidation. It also improved the thermal stability of RBOB emulsions. After gastrointestinal digestion, the free fatty acids release rate of RBOB emulsions with QU addition decreased to 14.68%, and RBOB emulsions were slowly hydrolyzed. Therefore, adding QU to RBOB helps to improve its stability and delay digestion.

Well-defined alginate oligosaccharides ameliorate joint pain and inflammation in a mouse model of gouty arthritis.

Background: Gouty arthritis causes severe pain and inflammation. Alginate oligosaccharides (AOSs) are natural products derived from alginate and have anti-inflammatory properties. We explored the potential effects of AOSs with different degrees of polymerization (Dp) on gouty arthritis and associated mechanisms. Methods: We established a mouse model of gouty arthritis by injecting monosodium urate (MSU) into ankle joint. Nocifensive behavior, gait and ankle swelling were used to study AOS's effects. Biochemical assays, in vivo imaging, live cell Ca2+ imaging, electrophysiology, RNA-sequencing, etc. were used for mechanism exploration. Results: AOS2 (Dp=2), AOS3 (Dp=3) and AOS4 (Dp=4) all inhibited ankle swelling, whereas AOS2&3 produced the most obvious analgesia on model mice. AOS3, which was picked for further evaluation, produced dose-dependent ameliorative effects on model mice. AOS3 reversed gait impairments but did not alter locomotor activity. AOS3 inhibited NLRP3 inflammasome activation and inflammatory cytokine up-regulation in ankle joint. AOS3 ameliorated MSU-induced oxidative stress and reactive oxygen species (ROS) production both in vivo and in vitro and reversed the impaired mitochondrial bioenergetics. AOS3 activated the Nrf2 pathway and promoted Nrf2 disassociation from Keap1-bound complex and Nrf2 nuclear translocation, thus facilitating antioxidant gene expression via Nrf2-dependent mechanism. Nrf2 gene deficiency abolished AOS3's ameliorative effects on pain, inflammation and oxidative stress in ankle joints of model mice. AOS3 reduced TRPV1 functional enhancement in DRG neurons and constrained neuroactive peptide release. Conclusions: AOS3 ameliorates gouty arthritis via activating Nrf2-dependent antioxidant signaling, resulting in suppression of ROS-mediated NLRP3 inflammasome activation and TRPV1 enhancement. AOS3 may be novel therapeutics for gouty arthritis.

Transcranial volumetric imaging using a conformal ultrasound patch.

Accurate and continuous monitoring of cerebral blood flow is valuable for clinical neurocritical care and fundamental neurovascular research. Transcranial Doppler (TCD) ultrasonography is a widely used non-invasive method for evaluating cerebral blood flow1, but the conventional rigid design severely limits the measurement accuracy of the complex three-dimensional (3D) vascular networks and the practicality for prolonged recording2. Here we report a conformal ultrasound patch for hands-free volumetric imaging and continuous monitoring of cerebral blood flow. The 2 MHz ultrasound waves reduce the attenuation and phase aberration caused by the skull, and the copper mesh shielding layer provides conformal contact to the skin while improving the signal-to-noise ratio by 5 dB. Ultrafast ultrasound imaging based on diverging waves can accurately render the circle of Willis in 3D and minimize human errors during examinations. Focused ultrasound waves allow the recording of blood flow spectra at selected locations continuously. The high accuracy of the conformal ultrasound patch was confirmed in comparison with a conventional TCD probe on 36 participants, showing a mean difference and standard deviation of difference as -1.51 ± 4.34 cm s-1, -0.84 ± 3.06 cm s-1 and -0.50 ± 2.55 cm s-1 for peak systolic velocity, mean flow velocity, and end diastolic velocity, respectively. The measurement success rate was 70.6%, compared with 75.3% for a conventional TCD probe. Furthermore, we demonstrate continuous blood flow spectra during different interventions and identify cascades of intracranial B waves during drowsiness within 4 h of recording.

CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis.

Gouty arthritis evokes joint pain and inflammation. Mechanisms driving gout pain and inflammation remain incompletely understood. Here we show that CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to drive gout pain and inflammation. CXCL5 expression was increased in ankle joints of gout arthritis model mice, whereas CXCR2 showed expression in joint-innervating sensory neurons. CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to trigger TRPA1 activation, resulting in hyperexcitability and pain. Neuronal CXCR2 coordinates with neutrophilic CXCR2 to contribute to CXCL5-induced neutrophil chemotaxis via triggering CGRP- and substance P-mediated vasodilation and plasma extravasation. Neuronal Cxcr2 deletion ameliorates joint pain, neutrophil infiltration and gait impairment in model mice. We confirmed CXCR2 expression in human dorsal root ganglion neurons and CXCL5 level upregulation in serum from male patients with gouty arthritis. Our study demonstrates CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and inflammation that expands our knowledge of immunomodulation capability of nociceptive sensory neurons.

Neutrophil-derived oxidative stress contributes to skin inflammation and scratching in a mouse model of allergic contact dermatitis via triggering pro-inflammatory cytokine and pruritogen production in skin.

Allergic contact dermatitis (ACD) is a common skin disease featured with skin inflammation and a mixed itch/pain sensation. The itch/pain causes the desire to scratch, affecting both physical and psychological aspects of patients. Nevertheless, the mechanisms underlying itch/pain sensation of ACD still remain elusive. Here, we found that oxidative stress and oxidation-related injury were remarkably increased in the inflamed skin of a mouse model of ACD. Reducing oxidative stress significantly attenuated itch/pain-related scratching, allokonesis and skin inflammation. RNA-Sequencing reveals oxidative stress contributes to a series of skin biological processes, including inflammation and immune response. Attenuating oxidative stress reduces overproduction of IL-1ß and IL-33, two critical cytokines involved in inflammation and pain/itch, in the inflamed skin of model mice. Exogenously injecting H2O2 into the neck skin of naïve mice triggered IL-33 overproduction in skin keratinocytes and induced scratching, which was reduced in mice deficient in IL-33 receptor ST2. ACD model mice showed remarkable neutrophil infiltration in the inflamed skin. Blocking neutrophil infiltration reduced oxidative stress and attenuated scratching and skin inflammation. Therefore, our study reveals a critical contribution of neutrophil-derived oxidative stress to skin inflammation and itch/pain-related scratching of ACD model mice via mechanisms involving the triggering of IL-33 overproduction in skin keratinocytes. Targeting skin oxidative stress may represent an effective therapy for ameliorating ACD.

Research on gesture recognition algorithm based on MME-P3D.

A Multiscale-Motion Embedding Pseudo-3D (MME-P3D) gesture recognition algorithm has been proposed to tackle the issues of excessive parameters and high computational complexity encountered by existing gesture recognition algorithms deployed in mobile and embedded devices. The algorithm initially takes into account the characteristics of gesture motion information, integrating the channel attention (CE) mechanism into the pseudo-3D (P3D) module, thereby constructing a P3D-C feature extraction network that can efficiently extract spatio-temporal feature information while reducing the complexity of the algorithmic model. To further enhance the understanding and learning of the global gesture movement's dynamic information, a Multiscale Motion Embedding (MME) mechanism is subsequently designed. The experimental findings reveal that the MME-P3D model achieves recognition accuracies reaching up to 91.12% and 83.06% on the self-constructed conference gesture dataset and the publicly available Chalearn 2013 dataset, respectively. In comparison with the conventional 3D convolutional neural network, the MME-P3D model demonstrates a significant advantage in terms of parameter count and computational requirements, which are reduced by as much as 82% and 83%, respectively. This effectively addresses the limitations of the original algorithms, making them more suitable for deployment on embedded and mobile devices and providing a more effective means for the practical application of hand gesture recognition technology.

Oil-in-water and oleogel-in-water emulsion encapsulate with hemp seed oil containing Δ9-tetrahydrocannabinol and cannabinol: Stability, degradation and in vitro simulation characteristics.

The present study focused on investigating the stability and in vitro simulation characteristics of oil-in-water (O/W) and oleogel-in-water (Og/W) emulsions. Compared with O/W emulsion, the Og/W emulsion exhibited superior stability, with a more evenly spread droplet distribution, and the Og/W emulsion containing 3 % hemp seed protein (HSP) showed better stability against environmental factors, including heat treatment, ionic strength, and changes in pH. Additionally, the stability of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabinol (CBN) and the in vitro digestion of hemp seed oil (HSO) were evaluated. The half-life of CBN in the Og/W emulsion was found to be 131.82 days, with a degradation rate of 0.00527. The in vitro simulation results indicated that the Og/W emulsion effectively delayed the intestinal digestion of HSO, and the bioaccessibility of Δ9-THC and CBN reached 56.0 % and 58.0 %, respectively. The study findings demonstrated that the Og/W emulsion constructed with oleogel and HSP, exhibited excellent stability.

Investigating Escherichia coli habitat transition from sediments to water in tropical urban lakes.

Background: Escherichia coli is a commonly used faecal indicator bacterium to assess the level of faecal contamination in aquatic habitats. However, extensive studies have reported that sediment acts as a natural reservoir of E. coli in the extraintestinal environment. E. coli can be released from the sediment, and this may lead to overestimating the level of faecal contamination during water quality surveillance. Thus, we aimed to investigate the effects of E. coli habitat transition from sediment to water on its abundance in the water column. Methods: This study enumerated the abundance of E. coli in the water and sediment at five urban lakes in the Kuala Lumpur-Petaling Jaya area, state of Selangor, Malaysia. We developed a novel method for measuring habitat transition rate of sediment E. coli to the water column, and evaluated the effects of habitat transition on E. coli abundance in the water column after accounting for its decay in the water column. Results: The abundance of E. coli in the sediment ranged from below detection to 12,000 cfu g-1, and was about one order higher than in the water column (1 to 2,300 cfu mL-1). The habitat transition rates ranged from 0.03 to 0.41 h-1. In contrast, the E. coli decay rates ranged from 0.02 to 0.16 h-1. In most cases (>80%), the habitat transition rates were higher than the decay rates in our study. Discussion: Our study provided a possible explanation for the persistence of E. coli in tropical lakes. To the best of our knowledge, this is the first quantitative study on habitat transition of E. coli from sediments to water column.

Combined impact of hypoalbuminemia and pharmacogenomic variants on voriconazole trough concentration: data from a real-life clinical setting in the Chinese population.

Voriconazole (VRC) displays highly variable pharmacokinetics impacting treatment efficacy and safety. To provide evidence for optimizing VRC therapy regimens, the authors set out to determine the factors impacting VRC steady-state trough concentration (Cmin) in patients with various albumin (Alb) level. A total of 275 blood samples of 120 patients and their clinical characteristics and genotypes of CYP2C19, CYP3A4, CYP3A5, CYP2C9, FMO3, ABCB1, POR, NR1I2 and NR1I3 were included in this study. Results of multivariate linear regression analysis demonstrated that C-reactive protein (CRP) and total bilirubin (T-Bil) were predictors of the VRC Cmin adjusted for dose in patients with hypoalbuminemia (Alb < 35 g/L) (R2 = 0.16, P < 0.001). Additionally, in patients with normal albumin level (Alb ≥ 35 g/L), it resulted in a significant model containing factors of the poor metabolizer (PM) CYP2C19 genotype and CRP level (R2 = 0.26, P < 0.001). Therefore, CRP and T-Bil levels ought to receive greater consideration than genetic factors in patients with hypoalbuminemia.

Activation of Nrf2 antioxidant signaling alleviates gout arthritis pain and inflammation.

Excessive deposition of monosodium urate (MSU) crystal in the joint results in gout arthritis, which triggers severe pain and affects life quality. Oxidative stress is a pivotal mechanism that contributes to etiology of gout pain and inflammation. Here we investigated whether activating Nrf2, which plays important roles in regulating endogenous antioxidant response, would attenuate gout arthritis via promoting antioxidant signaling in joint tissues. Gout arthritis model was established by intra-articular injection of MSU (500 µg/ankle) into the right ankle joint of mouse. Pharmacologically activating Nrf2 by activator oltipraz (50, 100 or 150 mg/kg, intraperitoneal) at 1 h before and 5, 23, 47 h after model establishment dose-dependently inhibited joint inflammation, mechanical and heat hypersensitivities in model mice. Oltipraz (100 mg/kg) reversed gait impairments without altering locomotor activity and reduced neutrophil infiltrations in ankle joints. In vitro studies revealed oltipraz (25 µM) inhibited MSU-induced ROS production in mouse macrophages and improved mitochondrial bioenergetics impairments caused by MSU. In vivo ROS imaging combined with biochemical assays confirmed the antioxidant effects of oltipraz on model mice. Nrf2 activation inhibited pro-inflammatory cytokine overproduction in ankle joint and attenuated the overexpression and enhancement in TRPV1 channel in DRG neurons innervating hind limb. Therapeutic effects of oltipraz were abolished by inhibiting Nrf2 or in Nrf2 knockout mice. These results suggest pharmacologically activating Nrf2 alleviates gout pain, gait impairments, inflammation and peripheral sensitization via Nrf2-dependent antioxidant mechanism. Targeting Nrf2 may represent a novel treatment option for gout arthritis.

Assessment of Total Ropivacaine Concentration in Blood after Bilateral Pecto-Intercostal Fascial Block Combined with Rectus Sheath Block in Cardiac Surgery Patients.

OBJECTIVES: Pecto-intercostal fascial block (PIFB) and rectus sheath block (RSB) have been combined to offer better analgesia for cardiac surgery patients, but safety of the analgesic protocol with a large volume of ropivacaine is uncertain. METHODS: This is a prospective observational study at Peking University People's Hospital to investigate the pharmacokinetic profile of ropivacaine after combined regional blocks. Patients undergoing elective cardiac surgery by a median sternotomy were enrolled to receive bilateral PIFB and RSB with 70 mL 0.3% ropivacaine (total dose 210 mg). Blood was sampled at 5, 10, 15, 30, 60, 90 and 120 mins after blocks. Total blood concentration of ropivacaine for patients were measured. RESULTS: Ten patients were enrolled and analyzed. The peak total ropivacaine concentration varied from 0.67 to 2.42 µg/mL. Time to reach the peak values mainly located between 10 and 30 mins after the performance. No patients had ropivacaine concentration values above toxic threshold (4.3 µg/mL), and there were no systemic toxicity symptoms during the perioperative period. CONCLUSIONS: PIFB combined with RSB in a general injection of 70 mL 0.3% ropivacaine does not give rise to toxic levels, and it is an effective and safe analgesic protocol for cardiac surgery patients.

Outcomes of Castor Single-Branched Stent Graft for Reconstruction of Multiple Supra-Aortic Branches in Aortic Arch Disease.

PURPOSE: To report the outcomes of a combination of Castor single-branched stent grafts with other techniques for the reconstruction of multiple supra-aortic branches in aortic arch disease. MATERIALS AND METHODS: Between December 2019 and December 2021, 20 patients with aortic arch disease underwent thoracic endovascular aortic repair (TEVAR) at our institution using a Castor single-branched stent graft combined with the fenestration, chimney, or bypass techniques. Thoracic endovascular aortic repair is indicated for complicated or acute type B aortic dissection (TBAD), nonruptured aneurysms with a maximum aneurysm diameter >5.5 cm or showing rapidly expanded, ruptured, or threatened aneurysms, and penetrating aortic ulcers (PAUs) with a maximal aortic diameter >5.5 cm or with PAUs >10 mm deep or >20 mm in diameter. Preoperative, intraoperative, and postoperative clinical data were recorded. RESULTS: The median age of the patients was 56 (range=52-69 years) years, and 19 patients were men. Seven patients underwent the Castor single-branched stent graft and left common carotid artery (LCCA) chimney technique, 8 patients underwent the Castor single-branched stent graft and fenestration technique, and 5 patients underwent the Castor single-branched stent graft and bypass technique. The technical success rate was 100%. Major adverse events included 2 endoleaks, 1 spinal cord ischemia, and 1 early-stage retrograde type A aortic dissection. No cerebral stroke-related complications were observed. The mortality rate was 10% (2/20 patients). One patient with thoracic aortic aneurysm (TAA) died because of a sudden decrease in oxygen saturation and blood pressure after surgery. Relatives declined autopsy, and the cause of death was not determined. Another patient died of a retrograde type A dissection after surgery. The median follow-up period was 6 months (range=3.5-12 months). During follow-up, 1 patient with type I endoleak underwent thoracotomy again after a year. The remaining patients recovered well. CONCLUSIONS: The combination of a Castor single-branched stent graft with fenestration, chimney, or bypass techniques may be an effective treatment for preserving multiple supra-aortic branches in aortic arch disease. CLINICAL IMPACT: This study introduced three methods of reconstruction of multiple supra-aortic branches using a Castor single-branched stent graft (Castor single-branched stent graft combined with fenestration, chimney, or bypass technique) and analysed their advantages and shortcomings to provide experience for the future treatment of aortic arch diseases.

Electroacupuncture may alleviate diabetic neuropathic pain by inhibiting the microglia P2X4R and neuroinflammation.

Diabetic neuropathic pain (DNP) is a common and destructive complication of diabetes mellitus. The discovery of effective therapeutic methods for DNP is vitally imperative because of the lack of effective treatments. Although 2 Hz electroacupuncture (EA) was a successful approach for relieving DNP, the mechanism underlying the effect of EA on DNP is still poorly understood. Here, we established a rat model of DNP that was induced by streptozotocin (STZ) injection. P2X4R was upregulated in the spinal cord after STZ-injection. The upregulation of P2X4R was mainly expressed on activated microglia. Intrathecal injection of a P2X4R antagonist or microglia inhibitor attenuated STZ-induced nociceptive thermal hyperalgesia and reduced the overexpression of brain-derived neurotrophic factor (BDNF), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the spinal cord. We also assessed the effects of EA treatment on the pain hypersensitivities of DNP rats, and further investigated the possible mechanism underlying the analgesic effect of EA. EA relieved the hyperalgesia of DNP. In terms of mechanism, EA reduced the upregulation of P2X4R on activated microglia and decreased BDNF, IL-1ß and TNF-α in the spinal cord. Mechanistic research of EA's analgesic impact would be beneficial in ensuring its prospective therapeutic effect on DNP as well as in extending EA's applicability.

Population Pharmacokinetics and Pharmacogenetics Analyses of Dasatinib in Chinese Patients with Chronic Myeloid Leukemia.

AIMS: Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration. METHODS: PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. RESULTS: The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients. CONCLUSIONS: This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.

Tartary buckwheat root polysaccharides ameliorate non-alcoholic fatty liver disease via the IL6-SOCS3-SREBP1c pathway.

Our previous study demonstrated that Tartary buckwheat root polysaccharides (TBRP) could reduce insulin resistance in diabetes mellitus by inhibiting SOCS3-stimulated IRS1 protein degradation. However, whether TBRP has the efficiency to treat non-alcoholic fatty liver disease (NAFLD) is still undetermined. This investigation aimed to examine the effects of TBRP on a high-fat diet (HFD)-triggered NAFLD, and elucidate the underlying molecular mechanisms. Briefly, TBRP toxicity in hepatoma (BEL7404) and pancreatic cancer (BxPC3) cells and zebrafish embryos developmental models, were evaluated in-vitro and in-vivo, respectively. TBRP inhibited cellular lipid accumulation by suppressing fat synthesis, furthermore, it improved body weight gain, liver weight, liver-to-body weight ratio, serum lipids triglyceride, total cholesterol, ALT, LDL-C, HDL-C, and AST levels in the NAFLD mice model. Additionally, TBRP treatment also lowered the nitric oxide content. The qPCR assay revealed that mRNA expression of TNF, IL1ß, and IL6 was also markedly reduced in TBRP-treated NAFLD mice. The expression of SOCS3, SREBP1c, and STAT3 was elucidated by western blot analysis, which indicated that TBRP markedly decreased the gene expression for de novo fat synthesis by the SOCS3-SREBP1c pathway. These findings reveal that TBRP ameliorates NAFLD via the IL6-SOCS3-SREBP1c signaling pathway and therefore, may represent a promising approach for NAFLD treatment.

Realistic Spin Model for Multiferroic NiI_{2}.

A realistic first-principle-based spin Hamiltonian is constructed for the type-II multiferroic NiI_{2}, using a symmetry-adapted cluster expansion method. Besides single ion anisotropy and isotropic Heisenberg terms, this model further includes the Kitaev interaction and a biquadratic term, and can well reproduce striking features of the experimental helical ground state, that are, e.g., a proper screw state, canting of rotation plane, propagation direction, and period. Using this model to build a phase diagram, it is demonstrated that, (i) the in-plane propagation direction of ⟨11[over ¯]0⟩ is determined by the Kitaev interaction, instead of the long-believed exchange frustrations and (ii) the canting of rotation plane is also dominantly determined by Kitaev interaction, rather than interlayer couplings. Furthermore, additional Monte Carlo simulations reveal three equivalent domains and different topological defects. Since the ferroelectricity is induced by spins in type-II multiferroics, our work also implies that Kitaev interaction is closely related to the multiferroicity of NiI_{2}.

Population pharmacokinetics and pharmacogenetics analyses of imatinib in Chinese patients with chronic myeloid leukemia in a real-world situation.

BACKGROUND: Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support individualized medicine. This work aims to characterize population pharmacokinetics in Chinese patients with chronic myeloid leukemia, investigate the effects of several covariates on imatinib exposure, and provide support for personalized medicine and dose reduction. METHODS: A total of 230 patients with chronic myeloid leukemia were enrolled, and 424 steady-state concentration measurements were taken to perform the population pharmacokinetic analysis and Monte Carlo simulations with Phoenix NLME software. The effects of the demographic, biological, and pharmacogenetic (ten SNP corresponding to CYP3A4, CYP3A5, ABCB1, ABCG2, SCL22A1 and POR) covariates on clearance were evaluated. RESULTS: A one-compartmental model best-described imatinib pharmacokinetics. The hemoglobin and the estimated glomerular filtration rate (< 85 mL⋅min-1⋅1.73 m2) were associated with imatinib clearance. The genetic polymorphisms related to pharmacokinetics were not found to have a significant effect on the clearance of imatinib. The final model estimates of parameters are: ka (h-1) = 0.329; Vd/F (L) = 270; CL/F (L⋅h-1) = 7.60. CONCLUSIONS: Key covariates in the study population accounting for variability in imatinib exposure are hemoglobin and the estimated glomerular filtration rate. There is some need for caution when treating patients with moderate-to-severe renal impairment and significant hemoglobin changes.

Electroacupuncture Inhibits Pain Memory and Related Anxiety-Like Behaviors by Blockading the GABAB Receptor Function in the Midcingulate Cortex.

Pain memory is commonly considered an underlying cause of chronic pain and is also responsible for a range of anxiety. Electroacupuncture (EA) has been shown to ameliorate pain memories and exert anti-anxiety effects. Previous research has indicated that GABAergic neurons and/or GABA receptors (GABARs) in the midcingulate cortex (MCC) have potential associations with chronic pain and anxiety. However, there is no known empirical research that has specifically studied the effects of EA on the GABAergic system in the MCC. Here, we used cross-injection of carrageenan to establish the pain memory rats model. Immunofluorescence were used to detect the excitability of GABAergic neurons within MCC. Von Frey filament, elevated zero maze, and open field tests were used to measure mechanical allodynia and anxiety-like behaviors, combined with chemogenetic and pharmacologic technologies. Finally, this study provides evidence that pain memories contribute to generalized negative emotions and that downregulating the activity of GABAergic neurons within MCC could block pain memories and reverse anxiety emotion. Specifically, GABABR is involved in pain memory and related anxiety-like behaviors. Activation of GABAergic neurons in the MCC did not reverse the effects of EA on pain memories and related anxiety-like behaviors, whereas these effects could be reversed by a GABABR agonist. These findings highlight the functional significance of GABABR in the EA-mediated attenuation of pain memories and related anxiety-like behaviors in rats.

Electroacupuncture improves gout arthritis pain via attenuating ROS-mediated NLRP3 inflammasome overactivation.

BACKGROUND: Gout results from disturbed uric acid metabolism, which causes urate crystal deposition in joints and surrounding tissues. Gout pain management is largely limited to colchicine and nonsteroidal anti-inflammatory drugs. Constant usage of these medications leads to severe side effects. We previously showed electroacupuncture (EA) is effective for relieving pain in animal model of gout arthritis. Here we continued to study the mechanisms underlying how EA alleviates gout pain. METHODS: Monosodium urate was injected into ankle joint to establish gout arthritis model in mice. EA or sham EA was applied at ST36 and BL60 acupoints of model animals. Biochemical assays, immunostaining, live cell Ca2+ imaging and behavioral assays were applied. RESULTS: Model mice displayed obvious mechanical allodynia, accompanied with gait impairments. EA attenuated mechanical hypersensitivities and improved gait impairments. EA reduced the overexpression of NLRP3 inflammasome signaling molecules in ankle joints of model animals. EA-induced anti-allodynia, as well as inhibition on NLRP3 inflammasome, were mimicked by antagonizing but abolished by activating NLRP3 inflammasome via pharmacological methods. EA attenuated oxidative stress, an upstream signaling of NLRP3 inflammasome in ankle joints of model mice. Exogenously increasing oxidative stress abolished EA's inhibitory effect on NLRP3 inflammasome and further reversed EA's anti-allodynic effect. EA reduced neutrophil infiltrations in ankle joint synovium, a major mechanism contributing to oxidative stress in gout. Pharmacological blocking NLRP3 inflammasome or EA reduced TRPV1 channel overexpression in dorsal root ganglion (DRG) neurons. Ca2+ imaging confirmed that EA could reduce functional enhancement in TRPV1 channel in DRG neurons during gout. CONCLUSIONS: Our results demonstrate that EA reduces gout pain possibly through suppressing ROS-mediated NLRP3 inflammasome activation in inflamed ankle joints and TRPV1 upregulation in sensory neurons, supporting EA as a treatment option for gout pain.