Outcomes of double-valve surgery for infective endocarditis are improving in the modern era.

BACKGROUND: The incidence of infective endocarditis (IE) is rapidly increasing. Contemporary outcomes following high-risk double valve surgery (DVS) for IE are not well described. METHODS: Between 2001 and 2021, 211 patients with IE underwent combined aortic and mitral valve surgery at a tertiary care referral center. Data from the Society of Thoracic Surgeons registry, including demographics, operative details, and outcomes, were collected. Risk factors for 30-day and 1-year-mortality were analyzed. Survival was analyzed using Kaplan-Meier and Cox proportional hazards modeling. RESULTS: The study cohort had a male preponderance (73%), with a median age of 56 years (interquartile range [IQR], 44 to 63 years). Forty-five patients (21%) had a history of intravenous (IV) drug abuse, 50 (24%) were on preoperative dialysis, and 50 (24%) had prosthetic valve endocarditis. Thirty-day and 1-year mortality were 14% (n = 30) and 30% (n = 61), respectively. On multivariable Cox regression adjusting for age, prosthetic valve endocarditis, postoperative intra-aortic balloon pump (IABP), history of dialysis (adjusted hazard ratio [aHR], 1.9; 95% confidence interval [CI], 1.3 to 2.9; P = .002) and IV drug abuse (aHR, 2.0; 95% CI, 1.1-3.5; P = .02) were predictive of decreased survival. Undergoing surgery after 2010 was predictive of improved survival (aHR, 0.5; 95% CI, 0.3 to 0.8; P = .006). These patients were more likely to undergo urgent/emergent surgery (83% vs 29%; P < .001) and less likely to have an aortic root abscess (40% vs 58%; P = .03) or to require the commando procedure (13% vs 33%; P = .002). CONCLUSIONS: In this large series evaluating outcomes of DVS for IE in the modern era, although the mortality risk remained elevated, improving outcomes may be associated with earlier surgical intervention before significant disease progression. Multidisciplinary evaluation for complex IE may be considered to better understand the optimal timing and repair strategy.

Combining sensitivity and robustness: EIT-like characteristic in a 2D topological photonic crystal.

The study of topological photonics has gained significant attention due to its potential application for robust and efficient light manipulation. In this work, we theoretically investigate a two-dimensional photonics crystal that exhibits a topological edge state (TES) and a topological corner state (TCS). Furthermore, we also achieve a coupling between a topological corner state and a trivial cavity (TC), resulting in a phenomenon similar to the electromagnetically induced transparency (EIT) effect. To verify the stability of the EIT-like effect, disorders around TES and TCS are introduced, and the theoretical results show that this structure is immune to the disorders. The achievement of the coupling between topological states can have potential applications in the areas of waveguiding, sensing, and logic gates. It is hoped that this work will contribute to the ongoing efforts in the exploration and utilization of topological photonics.

Identification of the blasting vibration characteristics of groundwater-sealed tunnel.

Blasting is widely used in mining, subway, demolition and groundwater-sealed tunnel, among them, the last one is widely concerned because of its many adjacent tunnels, high anti-seepage requirements, strict blasting control, etc. The identification of blasting characteristics is of great significance to the blasting construction and the safety evaluation of the groundwater-sealed tunnel. In view of the problem that conventional feature identification methods are less explored in groundwater-sealed tunnel, a complementary ensemble empirical mode decomposition with adaptive noise and multiscale permutation entropy and Hilbert-Huang transform (HHT) method was proposed. Then, the proposed method was verified by the numerical simulation and the Huangdao groundwater-sealed tunnel engineering. The results show that the proposed method can suppress modal aliasing and signal noise and identify the blasting characteristics of groundwater-sealed tunnel effectively. In addition, the blasting vibration energy which accounts for 94.7% in the frequency range of 0-200 Hz, 72.5% of 0-50 Hz was summarized. Furthermore, the safety status of each monitoring point was evaluated through HHT and the feasibility of millisecond blasting was identified. The method proposed can identify the vibration characteristics and safety status of groundwater-sealed tunnel from the perspective of time-frequency and energy effectively.

Crystal Structures and Microwave Dielectric Properties of Novel MgCu2Nb2O8 Ceramics Prepared by Two-Step Sintering Technique.

In this work, novel MgCu2Nb2O8 (MCN) ceramics were synthesized by the two-step sintering (TSS) technique, and the phase composition, crystal structures, and microwave dielectric properties were comprehensively studied. X-ray diffraction (XRD) and Raman analysis demonstrated that MCN ceramics are multi-phase ceramics consisting of MgNb2O6 and CuO phases. X-ray photoelectron spectroscopy (XPS) was utilized to investigate the chemical composition and element valence of MgCu2Nb2O8 ceramics. Scanning electron microscopy (SEM) analysis demonstrated dense microstructures in the MCN ceramics prepared at a sintering temperature of 925 °C. The microwave dielectric properties were largely affected by the lattice vibrational modes and densification level of the ceramics. The outstanding microwave dielectric properties of εr = 17.15, Q × f = 34.355 GHz, and τf = -22.5 ppm/°C were obtained for the MCN ceramics sintered at 925 °C, which are results that hold promise for low temperature co-fired ceramic (LTCC) applications.

CircPVT1 promotes the tumorigenesis and metastasis of osteosarcoma via mediation of miR-26b-5p/CCNB1 axis.

INTRODUCTION: Osteosarcoma (OS) is the most aggressive malignancy among the bone tumors in the world. Circular RNAs (circRNAs) have been reported to be participated in multiple cancers, including OS. Meanwhile, circPVT1 has been proved to be upregulated in OS. However, the mechanism by which circPVT1 mediates the tumorigenesis of OS remains to be further explored. MATERIALS AND METHODS: Protein and gene expressions in OS cells were measured by western blot and RT-qPCR, respectively. Cell growth was assessed by flow cytometry and colony formation, respectively. In addition, cell migration was assessed by wound healing, and invasion was evaluated by Transwell assay. Meanwhile, the correlation among circPVT1, miR-26b-5p and CCNB1 was explored by RNA pull-down and dual luciferase assay. Finally, in vivo model was established to explore the role of circPVT1 in OS in vivo. RESULTS: CircPVT1 and CCNB1 were significantly upregulated in OS cells, while miR-26b-5p was downregulated. Knockdown of circPVT1 notably inhibited proliferation and induced apoptosis of OS cells. CircPVT1 shRNA significantly suppressed the OS cell invasion and migration. Meanwhile, circPVT1 sponged miR-26b-5p and CCNB1 was found to be the direct target of miR-26b-5p. Furthermore, silencing of circPVT1 inhibited the growth and metastasis of OS in vivo. CONCLUSION: Silencing of circPVT1 notably suppressed the tumorigenesis and metastasis of OS via miR-26b-5p/CCNB1 axis. Therefore, circPVT1 might be used as a target for OS treatment.

Enhancement of Electrochromic Properties of Polyaniline Induced by Copper Ions.

Driven by the urgent need for adaptive infrared (IR) electrochromic devices, the improvement in electrochromic performance based on polyaniline (PANI) conducting polymers has become an outstanding challenge. In recent years, the acid doping strategy has been proven to increase the IR modulation ability of PANI, in particular for the Bronsted acid doping. Herein, the effects of copper ions, a Lewis acid, on the structure and electrochromic properties of polyaniline were investigated. Compared to pure polyaniline, the Cu-doped PANI porous films show better IR modulation ability. With the increasing concentration of copper ions, the Cu-doped PANI porous films exhibit a trend in volcanic patterns for the emittance variation (∆ε), depending on the number of polarons and bipolarons. The optimal IR emissivity (ε) modulation obtained on Cu-doped PANI films shows the ∆ε modulation of 0.35 and 0.3 in the wavelength range of 8-14 µm and 2.5-25 µm, superior to previously reported pure sulfuric acid-doped PANI. Furthermore, a flexible IR electrochromic device was fabricated with the present Cu-doped PANI porous films. The modulation of the emittance variation varied between 0.513 and 0.834 (∆ε = 0.32 in ranges of wavelength 8-12 µm), suggesting the great potential for applications in military camouflage and intelligent IR thermal management. We believe that the results in this work will provide a novel perspective and avenue for improving the IR modulation ability of electrochromic devices based on polyaniline conducting polymers.

The Practice of Pediatric Cardiac Anesthesiology in the United States.

BACKGROUND: With advances in surgical and catheter-based interventions and technologies in patients with congenital heart disease (CHD), the practice of pediatric cardiac anesthesiology has evolved in parallel with pediatric cardiac surgery and pediatric cardiology as a distinct subspecialty over the past 80 years. To date, there has not been an analysis of the distribution of pediatric cardiac anesthesiologists relative to cardiac and noncardiac procedures in the pediatric population. The primary aim is to report the results of a survey and its subsequent analysis to describe the distribution of pediatric cardiac anesthesiologists relative to pediatric cardiac procedures that include surgical interventions, cardiac catheterization procedures, imaging studies (echocardiography, magnetic resonance, computed tomography, positron emission tomography), and noncardiac procedures. METHODS: A survey developed in Research Electronic Data Capture (REDcap) was sent to the identifiable division chiefs/cardiac directors of 113 pediatric cardiac anesthesia programs in the United States. Data regarding cardiac surgical patients and procedures were collected from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHD). RESULTS: This analysis reveals that only 38% (117 of 307) of pediatric cardiac anesthesiologists caring for patients with CHD pursued additional training in pediatric cardiac anesthesiology, while 44% (136 of 307) have gained experience during their clinical practice. Other providers have pursued different training pathways such as adult cardiac anesthesiology or pediatric critical care. Based on this survey, pediatric cardiac anesthesiologists devote 35% (interquartile range [IQR], 20%-50%) of clinical time to the care of patients in the cardiac operating room, 25% (20%-35%) of time to the care of patients in the cardiac catheterization laboratory, 10% (5%-10%) to patient care in imaging locations, and 15% covering general pediatric, adult, or cardiac patients undergoing noncardiac procedures. Attempts to actively recruit pediatric cardiac anesthesiologists were reported by 49.2% (29 of 59) of the institutions surveyed. Impending retirement of staff was anticipated in 17% (10 of 59) of the institutions, while loss of staff to relocation was anticipated in 3.4% (2 of 59) of institutions. Thirty-seven percent of institutions reported that they anticipated no immediate changes in current staffing levels. CONCLUSIONS: The majority of currently practicing pediatric cardiac anesthesiologists have not completed a fellowship training in the subspecialty. There is, and will continue to be, a need for subspecialty training to meet increasing demand for services especially with increase survival of this patient population and to replace retiring members of the workforce.

Difficult tracheal intubation and perioperative outcomes in patients with congenital heart disease: A retrospective study.

BACKGROUND AND OBJECTIVE: Management of difficult tracheal intubation during induction of anesthesia in children with congenital heart disease is challenging. The aim of this study is to evaluate the incidence of difficult tracheal intubation in patients with congenital heart disease and compare the incidence of perioperative complications and outcomes in patients with and without difficult tracheal intubation. DESIGN: Retrospective cohort study. SETTING: Tertiary Children's Hospital. PARTICIPANTS: 6858 patient-encounters including cardiac diagnostic, interventional or surgical procedures from 2012 to 2018 were reviewed. EXCLUSION CRITERIA: age > 18 years, endotracheal tube or tracheostomy in-situ. METHODS/INTERVENTIONS: Patients' demographics, number and methods of intubation, peri-intubation hemodynamics, intensive care unit and postoperative hospital length of stay were recorded. Multivariable mixed-effects median, logistic, ordinal, and multinomial regression modeling were implemented to analyze outcomes in the matched sets. RESULTS: Of the 6014 encounters examined in the study, the incidence of DTI was 0.96% and all 58 difficult tracheal intubations (DTI) were matched using 1:2 propensity score matching to 116 non-DTI encounters. Number of intubation attempts was significantly higher among patients with difficult tracheal intubation (ordinal logistic regression odds ratio = 2; 95% CI; 1.3, 2.7; P < 0.001). No significant differences in peri-intubation hemodynamic stability were noted. Patients with difficult tracheal intubation had longer postoperative hospital length of stay (median = 12.1 vs 7.9 days, coef. = 4; 95% CI: 1.3, 6.8; P = 0.004) than patients without. CONCLUSION: Despite a higher number of intubation attempts, our study shows no major differences in the peri-intubation hemodynamics in patients with and without difficult tracheal intubation. This risk can be mitigated by a good understanding of cardiac physiology, management of hemodynamics, and early use of an indirect intubation technique to maximize first attempt success.

N,N-Dimethyl Formamide Regulating Fluorescence of MXene Quantum Dots for the Sensitive Determination of Fe3.

Due to the wide use of iron in all kinds of areas, the design and construction of direct, fast, and highly sensitive sensor for Fe3+ are highly desirable and important. In the present work, a kind of fluorescent MXene quantum dots (MQDs) was synthesized via an intermittent ultrasound process using N,N-dimethyl formamide as solvent. The prepared MQDs were characterized via a combination of UV-Vis absorption, fluorescence spectra, X-ray photoelectron energy spectra, and Fourier-transform infrared spectroscopy. Based on the electrostatic-induced aggregation quenching mechanism, the fluorescent MQDs probes exhibited excellent sensing performance for the detection of Fe3+, with a sensitivity of 0.6377 mM-1 and the detection limit of 1.4 µM, superior to those reported in studies. The present MQDs-based probes demonstrate the potential promising applications as the sensing device of Fe3+.

Porous Carbon Substrate Improving the Sensing Performance of Copper Nanoparticles Toward Glucose.

An accurate sensor to rapidly determine the glucose concentration is of significant importance for the human body health, as diabetes has become a very high incidence around the world. In this work, copper nanoparticles accommodated in porous carbon substrates (Cu NP@PC), synthesized by calcinating the filter papers impregnated with copper ions at high temperature, were designed as the electrode active materials for electrochemical sensing of glucose. During the formation of porous carbon, the copper nanoparticles spontaneously accommodated into the formed voids and constituted the half-covered composites. For the electrochemical glucose oxidation, the prepared Cu NP@PC composites exhibit much superior catalytic activity with the current density of 0.31 mA/cm2 at the potential of 0.55 V in the presence of 0.2 mM glucose. Based on the high electrochemical oxidation activity, the present Cu NP@PC composites also exhibit a superior glucose sensing performance. The sensitivity is determined to be 84.5 µA /(mmol.L) with a linear range of 0.01 ~ 1.1 mM and a low detection limit (LOD) of 2.1 µmol/L. Compared to that of non-porous carbon supported copper nanoparticles (Cu NP/C), this can be reasonable by the improved mass transfer and strengthened synergistic effect between copper nanoparticles and porous carbon substrates.

A mV-level real-time peak-voltage detection circuit based on differential structure.

A peak-voltage detection circuit based on a differential comparison structure is proposed to synchronize the control and the input signal. The detection circuit is hence free of reset signals for the sampling capacitors. Furthermore, a two-channel parallel sample and hold structure (i.e., S/H circuit) is used, and a correlated double sampling technique is used, in combination with the ping-pong technique, to sample the signal value and offset voltage within one sample cycle. Consequently, the parallel connected S/H structure can not only extract the offset voltage of the op-amp but also effectively reduce the detection error, which is caused by circuit noise and leakage current. Measurements of the implemented peak detector show that in the case that the detection signal frequency is 20 kHz and the amplitude is 10 mV, the detection error is decreased to 30 µV with the equivalent output noise of 71 nV/Hz.

An Integrated Positioning and Attitude Determination System for Immersed Tunnel Elements: A Simulation Study.

Immersed tunnel elements need to be exactly controlled during their immersion process. Position and attitude of the element should be determined quickly and accurately to navigate the element from the holding area to the final location in the tunnel trench. In this paper, a newly-developed positioning and attitude determination system, integrating a 3-antenna Global Navigation Satellite System (GNSS) system, an inclinometer and a range-measurement system, is presented. The system is designed to provide the absolute position of both ends of the element with sufficient accuracy in real time. Special attention in the accuracy analysis is paid to the influence of GNSS multipath error and sound speed profile. Simulations are conducted to illustrate the performance of the system in different scenarios. If both elements are very close, the accuracies of the system are higher than 0.02 m in the directions perpendicular to and along the tunnel axis.

microRNA-148a-3p in extracellular vesicles derived from bone marrow mesenchymal stem cells suppresses SMURF1 to prevent osteonecrosis of femoral head.

Extracellular vesicle (EV)-associated microRNAs (miRNAs) have been found as the important biomarkers participating in the development of osteonecrosis of the femoral head (ONFH). Consequently, this study sought to examine the underlying mechanism of bone marrow mesenchymal stem cell (BMSC)-derived EVs containing miR-148a-3p in ONFH. The ONFH rat models were established. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were applied to detect miR-148a-3p, Smad ubiquitination regulatory factor 1 (SMURF1), SMAD7 and B-cell CLL/lymphoma 2 (BCL2) expression, followed by determination of relationship between miR-148a-3p and SMURF1. BMSCs were isolated from normal rats and ONFH rats, and EVs were extracted from BMSCs of normal rats. BMSCs from ONFH rats were treated with mimic, inhibitor, small interfering RNA or EVs from miR-148a-3p mimic-treated BMSCs from normal rats (BMSC-EV-miR-148a-3p mimic). Cell Counting Kit-8 and alizarin red staining were utilized to detect cell viability and osteogenic differentiation of BMSCs. ONFH rats were injected with BMSC-EV-miR-148a-3p mimic to explore the function of BMSC-EV-delivered miR-148a-3p in vivo. miR-148a-3p was down-regulated in BMSCs and EVs from ONFH rats following decreased BMSCs viability and osteogenic differentiation. SMURF1 was a target gene of miR-148a-3p, and resulted in ubiquitination and degradation of SMAD7 to decreased BCL2 expression. The proliferation and differentiation of BMSCs were promoted by BMSC-EV-miR-148a-3p mimic or SMURF1 silencing. Additionally, BMSC-EV-miR-148a-3p mimic increased cell proliferation and osteogenic response, diminished SMURF1 expression, and elevated SMAD7 and BCL2 expression in ONFH rats. Collectively, miR-148a-3p overexpressed in BMSC-EVs promoted SMAD7 and BCL2 expression by inhibiting SMURF1, thus alleviating ONFH.

Multipurpose chemical liquid sensing applications by microwave approach.

In this work, a novel sensor based on printed circuit board (PCB) microstrip rectangular patch antenna is proposed to detect different ratios of ethanol alcohol in wines and isopropyl alcohol in disinfectants. The proposed sensor was designed by finite integration technique (FIT) based high-frequency electromagnetic solver (CST) and was fabricated by Proto Mat E33 machine. To implement the numerical investigations, dielectric properties of the samples were first measured by a dielectric probe kit then uploaded into the simulation program. Results showed a linear shifting in the resonant frequency of the sensor when the dielectric constant of the samples were changed due to different concentrations of ethanol alcohol and isopropyl alcohol. A good agreement was observed between the calculated and measured results, emphasizing the usability of dielectric behavior as an input sensing agent. It was concluded that the proposed sensor is viable for multipurpose chemical sensing applications.

A sensitivity-enhanced capacitance readout circuit with symmetric cross-coupling structure.

This paper presents a proposed capacitance readout circuit that enables a quadrupled (x4) output strength. A symmetric cross-coupling structure is proposed to amplify the voltage difference between two adjacent channels; hence, the detected signal can be integrated twice every clock cycle. Compared with conventional schematics, the proposed readout circuit shows an increased output strength for integration times within dozens of µs. In addition, the measurements show that the integrator resistors should be less than 1 kΩ to suppress the resistance-capacitance delay effects. Although the proposed capacitance readout circuit is implemented using discrete transistors, it has a good signal integrity at an operating clock cycle of 100 µs. Therefore, the proposed readout circuit is a promising way to detect small capacitance variations with short integration times.

Bibliometric Analysis of the 100 Most Cited Articles on Intervertebral Disk Research: From 1900 to 2017 Year.

STUDY DESIGN: A bibliometric review of the literature. OBJECT: To analyze and quantify the most frequently cited papers in intervertebral disk research. SUMMARY OF BACKGROUND DATA: The number of citations that a paper has received reflects its impact in related research area. In the field of disk research, however, it remains unknown which papers are most cited. By searching related literature databases, we identified the most cited 100 articles that advanced the understanding of the intervertebral disk to provide a historic view of scientific research of the disk. MATERIALS AND METHODS: Intervertebral disk original research-related publications from January 1, 1900 to December 31, 2017 were retrieved from the Web of Science database. Each retrieved article was analyzed using the Cited Reference Search tool to identify the most cited articles. The number of citations, year of publication, publishing journal, authorship, country of publication, and the knowledge maps of keywords were gathered and generated. RESULTS: The number of citations of the 100 selected articles ranges from 209 to 1269, and they were published from 1953 to 2009. Basic research is the most common type of study (n=60), followed by epidemiological study (n=40). Spine published 57 of the most cited 100 papers. The greatest contribution came from the United States of America (n=41), followed by the United Kingdom (n=18) and Japan (n=9). Frequently appearing keywords classified into 3 clusters: "biological study," "clinical study," and "imageological study." The keyword "degeneration" was mentioned the most, 51 items, and the word "development" was the latest hot spot in the most cited articles. CONCLUSIONS: In the field of disk research, some papers were heavily cited more than 100 times, suggesting these studies have substantially contributed to the body of knowledge of the intervertebral disk and findings were widely accepted by related clinicians and scientists.

Ground Control Point-Free Unmanned Aerial Vehicle-Based Photogrammetry for Volume Estimation of Stockpiles Carried on Barges.

In this study, an approach using ground control point-free unmanned aerial vehicle (UAV)-based photogrammetry is proposed to estimate the volume of stockpiles carried on barges in a dynamic environment. Compared with similar studies regarding UAVs, an indirect absolute orientation based on the geometry of the vessel is used to establish a custom-built framework that can provide a unified reference instead of prerequisite ground control points (GCPs). To ensure sufficient overlap and reduce manual intervention, the stereo images are extracted from a UAV video for aerial triangulation. The region of interest is defined to exclude the area of water in all UAV images using a simple linear iterative clustering algorithm, which segments the UAV images into superpixels and helps to improve the accuracy of image matching. Structure-from-motion is used to recover three-dimensional geometry from the overlapping images without assistance of exterior parameters obtained from the airborne global positioning system and inertial measurement unit. Then, the semi-global matching algorithm is used to generate stockpile-covered and stockpile-free surface models. These models are oriented into a custom-built framework established by the known distance, such as the length and width of the vessel, and they do not require GCPs for coordinate transformation. Lastly, the volume of a stockpile is estimated by multiplying the height difference between the stockpile-covered and stockpile-free surface models by the size of the grid that is defined using the resolution of these models. Results show that a relatively small deviation of approximately ±2% between the volume estimated by UAV photogrammetry and the volume calculated by traditional manual measurement was obtained. Therefore, the proposed approach can be considered the better solution for the volume measurement of stockpiles carried on barges in a dynamic environment because UAV-based photogrammetry not only attains superior density and spatial object accuracy but also remarkably reduces data collection time.

Bupivacaine at clinically relevant concentrations induces toxicity in human intervertebral disc cells via the induction of autophagy in vitro.

It has been reported that bupivacaine, the most widely used local anesthetic to relieve discogenic back pain in clinical settings, is cytotoxic to intervertebral disc (IVD) cells in vitro; however, the precise mechanisms of cytotoxicity induced by bupivacaine remain unclear. Autophagy is an intracellular lysosomal degradation process that is important for cellular survival. The present study investigated the role of autophagy in the survival of IVD cells subjected to bupivacaine treatment. Human nucleus pulposus (NP) cells isolated from IVD cells were exposed to various concentrations of bupivacaine for 2, 6 and 12 h, and analyzed for cellular viability using MTT assay and western blotting. Additionally, autophagosome formation and autophagy­associated biomarkers were evaluated by electron microscopy and western blotting to determine the autophagic activity and signaling alterations in NP cells under bupivacaine treatment. Furthermore, autophagic activity was inhibited in vitro using 3­methyladenine to further analyze the association between autophagy and apoptosis in bupivacaine­treated NP cells. Bupivacaine exhibited time­ and dose­dependent cytotoxic effects on human IVD cells at clinically relevant concentrations. Bupivacaine increased autophagic activity by promoting autophagosome formation, and LC3­II and Beclin­1 production. Additionally, bupivacaine inhibited protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/S6 kinase (S6K) signaling, which is a negative regulator of autophagic activity. Of note, pharmacological inhibition of autophagy alleviated bupivacaine­induced cytotoxicity of IVD cells. The findings indicated that application of clinically relevant concentrations of bupivacaine upregulated autophagic activity via inhibition of Akt/mTOR/S6K signaling. In addition, the inhibition of autophagic activation served as a protective mechanism against bupivacaine­induced cytotoxicity. Collectively, these findings may provide novel insight into the mechanisms underlying cytotoxicity induced by bupivacaine when controlling spine­associated pain.

Myeloid-derived macrophages and secreted HSP90α induce pancreatic ductal adenocarcinoma development.

We detected a significant elevation of serum HSP90α levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90α levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90α levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90α levels were detected before PDAC formation and an extracellular HSP90α (eHSP90α) inhibitor effectively prevented PDAC development. Both serum HSP90α level and pancreatic lesion were suppressed when the mice were administered a CD11b-antagonizing antibody, suggesting that CD11b+-myeloid cells were associated with eHSP90α levels and pancreatic carcinogenesis. Consistently, in CD11b-DTR-EGFP transgenic mouse model with CD11b+-myeloid cells depletion, serum HSP90α levels were suppressed and Panc-02 cell grafts failed to develop tumors. Macrophages and granulocytes are two common tissue-infiltrating CD11b+-myeloid cells. Duplex in situ hybridization assays suggested that macrophages were predominant HSP90α-expressing CD11b+-myeloid cells during PDAC development. Immunohistochemical and immunohistofluorescent staining results revealed that HSP90α-expressing cells included not only macrophages but also pancreatic ductal epithelial (PDE) cells. Cell culture studies also indicated that eHSP90α could be produced by macrophages and macrophage-stimulated PDE cells. Macrophages not only secreted significant amount of HSP90α, but also secreted interleukin-6 and interleukin-8 to induce a JAK2-STAT3 signaling axis in PDE cells, stimulating them to express and secrete HSP90α. eHSP90α further promoted cellular epithelial-mesenchymal transition, migration, and invasion in PDE cells. Besides myeloid cells, eHSP90α can be potentially taken as a target to suppress PDAC pathogenesis.

TRPC3 Is Dispensable for ß-Alanine Triggered Acute Itch.

The detection of pruritic (itchy) stimuli is mediated by a variety of receptors and channels expressed by primary sensory neurons. The G protein-coupled receptor (GPCR) MRGPRD is selectively expressed by a subset of mouse non-peptidergic nociceptors and functions as the molecular receptor for the itch-inducing chemical ß-alanine. However, the channels responsible for generating electrical signals downstream of MRGPRD remain unclear. Here, we found that a member of the canonical TRP channel family, TRPC3, is highly expressed in MRGPRD+ non-peptidergic nociceptors, raising the possibility of whether TRPC3 functions as a downstream channel in the MRGPRD signaling pathway. We tested TrpC3 null mice for ß-alanine induced itch, and found that these mice exhibit normal responses to ß-alanine. At the cellular level, calcium influx triggered by ß-alanine is also unchanged in cultured DRG neurons from TrpC3 null mice compared to wild type. Together, our results demonstrate that mouse TrpC3 is dispensable for ß-alanine-induced acute itch.