Arginase2 mediates contrast-induced acute kidney injury via facilitating nitrosative stress in tubular cells.

Contrast-induced acute kidney injury(CI-AKI) is the third cause of AKI. Although tubular injury has been regarded as an important pathophysiology of CI-AKI, the underlying mechanism remains elusive. Here, we found arginase2(ARG2) accumulated in the tubules of CI-AKI mice, and was upregulated in iohexol treated kidney tubular cells and in blood samples of CI-AKI mice and patients, accompanied by increased nitrosative stress and apoptosis. However, all of the above were reversed in ARG2 knockout mice, as evidenced by the ameliorated kidney dysfunction and the tubular injury, and decreased nitrosative stress and apoptosis. Mechanistically, HO-1 upregulation could alleviate iohexol or ARG2 overexpression mediated nitrosative stress. Silencing and overexpressing ARG2 was able to upregulate and downregulate HO-1 expression, respectively, while HO-1 siRNA had no effect on ARG2 expression, indicating that ARG2 might inhibit HO-1 expression at the transcriptional level, which facilitated nitrosative stress during CI-AKI. Additionally, CREB1, a transcription factor, bound to the promoter region of ARG2 and stimulated its transcription. Similar findings were yielded in cisplatin- or vancomycin-induced AKI models. Taken together, ARG2 is a crucial target of CI-AKI, and activating CREB1/ARG2/HO-1 axis can mediate tubular injury by promoting nitrosative stress, highlighting potential therapeutic strategy for treating CI-AKI.

Clinical Efficacy Evaluation of Ultrasound-Guided C2 Dorsal Root Nerve Pulsed Radiofrequency Combined with Stellate Ganglion Block in the Treatment of Cervicogenic Headache: A Retrospective Cohort Study.

Purpose: To explore the therapeutic effect of C2 dorsal root ganglion pulsed radiofrequency (PRF) combined with stellate ganglion block (SGB) in patients with cervicogenic headache (CEH). Patients and Methods: We retrospectively reviewed 90 patients diagnosed with CEH who were admitted to our hospital between May 2019 and May 2022. All patients were divided into three groups (n = 30 each) according to the actual treatment method used: ultrasound-guided SGB, ultrasound-guided C2 dorsal root ganglion PRF treatment, and ultrasound-guided C2 dorsal root ganglion PRF combined with SGB treatment. Patients' pain intensity, sleep, and mood changes were assessed by statistically analyzing their pain visual analog scale (VAS), Pittsburgh Sleep Quality Inventory (PSQI), and short-form McGill Pain Questionnaire affective item scores before and after treatment. Results: The post-treatment VAS, PSQI, and McGill scores were significantly decreased in all patients (P < 0.05), and all three scores in ultrasound-guided C2 dorsal root ganglion PRF combined with SGB were lower than those in ultrasound-guided SGB alone and ultrasound-guided C2 dorsal root ganglion PRF alone (P < 0.05). Conclusion: The use of ultrasound-guided C2 dorsal root ganglion PRF combined with SGB in patients with CHE is effective in alleviating pain and improving sleep, and deserves to be replicated in the clinic.

Analysis of Risk Factors for Postherpetic Neuralgia in Patients With Postmalignancy Herpes Zoster.

BACKGROUND: The high risk of developing postherpetic neuralgia (PHN) is associated with severe immunosuppressive diseases. A malignancy itself, as well as surgery, radiotherapy, and other treatments, can lead to changes in the immune status of the body and predispose patients with a malignancy to PHN. OBJECTIVE: To investigate the risk factors of postherpetic neuralgia in herpes zoster (HZ) after a malignant tumor and to provide better preventive strategies for clinical practice. STUDY DESIGN: A retrospective cohort study. SETTING: The Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China. METHODS: Patients who developed HZ after being diagnosed with a malignant tumor in the Affiliated Hospital of Southwest Medical University from September 2018 through March 2022 were included in the research. A total of 70 patients were included, including 31 men and 39 women, aged 18- 82 years old (mean, SD: 59.77 ± 13.95). According to the occurrence of PHN, they were divided into a non-PHN (n = 46) and a PHN group (n = 24). General information about the patients was collected, including clinical data, treatment status, and prognosis. Univariate and multivariate analyses were conducted of influencing factors. RESULTS: A total of 19 factors, including gender, age, and white blood cell count, were included. A univariate analysis showed that there were differences in age, tumor stage, Numeric Rating Scale (NRS-11) score, and the use of antiviral drugs between the 2 groups; these differences were statistically significant, P <0.05. A multifactorial analysis revealed that the acute phase NRS-11 score (odds ratio [OR] = 4.21; 95% CI, 1.59-2.24, P = 0.004), antiviral drug use (OR = 0.28; 95% CI, 0.10-0.82, P = 0.020), and tumor stage (OR = 0.28, 95% CI, 0.08-0.98, P = 0.047) were statistically significant for the effect of PHN occurring in postmalignancy HZ. There was a statistically significant difference between the group with severe pain in the acute phase NRS-11 score and the group with mild and moderate pain, P < 0.05. There was a statistically significant difference between the group treated with 2 antivirals and the group not treated with antivirals, P < 0.05. LIMITATIONS: There are some limitations in our research. It was conducted at a single center, with a single race, and had a small sample size. A larger-scale study should be conducted to analyze the influencing factors of PHN in patients with herpes zoster after a malignant tumor. CONCLUSIONS: The NRS-11 score in the acute phase, whether the use of antiviral drugs in sufficient quantities, and tumor staging are the influencing factors of PHN after malignant tumors.

Role of Sensory Pathway Injury in Central Post-Stroke Pain: A Narrative Review of Its Pathogenetic Mechanism.

Central post-stroke pain (CPSP) is a severe chronic neuropathic pain syndrome that is a direct result of cerebrovascular lesions affecting the central somatosensory system. The pathogenesis of this condition remains unclear owing to its extensive clinical manifestations. Nevertheless, clinical and animal experiments have allowed a comprehensive understanding of the mechanisms underlying CPSP occurrence, based on which different theoretical hypotheses have been proposed. We reviewed and collected the literature and on the mechanisms of CPSP by searching the English literature in PubMed and EMBASE databases for the period 2002-2022. Recent studies have reported that CPSP occurrence is mainly due to post-stroke nerve injury and microglial activation, with an inflammatory response leading to central sensitization and de-inhibition. In addition to the primary injury at the stroke site, peripheral nerves, spinal cord, and brain regions outside the stroke site are involved in the occurrence and development of CPSP. In the present study, we reviewed the mechanism of action of CPSP from both clinical studies and basic research based on its sensory pathway. Through this review, we hope to increase the understanding of the mechanism of CPSP.

Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis.

BACKGROUND: Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality. AIM: To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit (ICU) patients. METHODS: PubMed, EMBASE, the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30, 2022. The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver. 12.1. Additionally, subgroup analyses and meta-regression were conducted to assess heterogeneity. RESULTS: A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis. The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%. The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B (PMB)-induced nephrotoxicity. The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval, nephrotoxicity criteria, age, publication year, study quality and sample size, which were confirmed in the univariable meta-regression analysis. Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses. Furthermore, older age, the presence of sepsis or septic shock, hypoalbuminemia, and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity, while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity. CONCLUSION: Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high. It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.

[Responses of radial growth of Juniperus przewalskii to different droughts over the northeastern Tibetan Plateau, China]. / 青藏高原东北部祁连圆柏径向生长对不同类型干旱的响应.

To study the responses of radial growth of Juniperus przewalskii to climate factors of the different periods (pre-growing season (February-April), growing season (May-July)), and the vulnerability (resistance, RT; recovery, RC) of J. przewalskii to different drought events (precipitation, temperature and the both caused), we used tree ring width data of J. przewalskii from 17 sampling sites across the northeastern Tibetan Plateau to analyze the correlation between radial growth and climate factors of different periods, and the vulnerability in different drought events. The results showed that radial growth of J. przewalskii had significant positive correlation with drought index and negative correlation with temperature in the growing season (P<0.1). The vulnerability of J. przewalskii to drought events of different periods had significant difference. In the pre-growing season drought events, the RT of J. przewalskii at low altitude was 2.3% higher than that at high altitude, the RC of J. przewalskii at low altitude was 25.1% lower than that at high altitude. For drought events in the growing season, the RT of J. przewalskii at low altitude was 23.7% lower than that at high altitude, the RC of J. przewalskii at low altitude was 107.1% higher than that at high altitude. The mean RC(1.68) of J. przewalskii in precipitation-caused drought events was strong, while the mean RT(1.43) of J. przewalskii in temperature-caused drought events was strong. The growth of J. przewalskii, especially for that at low altitude, would be largely limited by drought caused by global warming in the future.

Secondary damage and neuroinflammation in the spinal dorsal horn mediate post-thalamic hemorrhagic stroke pain hypersensitivity: SDF1-CXCR4 signaling mediation.

Central post-stroke pain (CPSP) is an intractable neuropathic pain, which can be caused by primary lesion of central somatosensory system. It is also a common sequelae of the thalamic hemorrhagic stroke (THS). So far, the underlying mechanisms of CPSP remain largely unknown. Our previous studies have demonstrated that SDF1-CXCR4 signaling in the hemorrhagic region contributes to the maintenance of the THS pain hypersensitivity via mediation of the thalamic neuroinflammation. But whether the spinal dorsal horn, an initial point of spinothalamic tract (STT), suffers from retrograde axonal degeneration from the THS region is still unknown. In this study, neuronal degeneration and loss in the spinal dorsal horn were detected 7 days after the THS caused by intra-thalamic collagenase (ITC) injection by immunohistochemistry, TUNEL staining, electron microscopy, and extracellular multi-electrode array (MEA) recordings, suggesting the occurrence of secondary apoptosis and death of the STT projecting neuronal cell bodies following primary THS via retrograde axonal degeneration. This retrograde degeneration was accompanied by secondary neuroinflammation characterized by an activation of microglial and astrocytic cells and upregulation of SDF1-CXCR4 signaling in the spinal dorsal horn. As a consequence, central sensitization was detected by extracellular MEA recordings of the spinal dorsal horn neurons, characterized by hyperexcitability of both wide dynamic range and nociceptive specific neurons to suprathreshold mechanical stimuli. Finally, it was shown that suppression of spinal neuroinflammation by intrathecal administration of inhibitors of microglia (minocycline) and astrocytes (fluorocitrate) and antagonist of CXCR4 (AMD3100) could block the increase in expression levels of Iba-1, GFAP, SDF1, and CXCR4 proteins in the dorsal spinal cord and ameliorate the THS-induced bilateral mechanical pain hypersensitivity, implicating that, besides the primary damage at the thalamus, spinal secondary damage and neuroinflammation also play the important roles in maintaining the central post-THS pain hypersensitivity. In conclusion, secondary neuronal death and neuroinflammation in the spinal dorsal horn can be induced by primary thalamic neural damage via retrograde axonal degeneration process. SDF1-CXCR4 signaling is involved in the mediation of secondary spinal neuroinflammation and THS pain hypersensitivity. This finding would provide a new therapeutic target for treatment of CPSP at the spinal level.

A bright, red-emitting water-soluble BODIPY fluorophore as an alternative to the commercial Mito Tracker Red for high-resolution mitochondrial imaging.

With the emergence and rapid development of super-resolution fluorescence microscopy, monitoring of mitochondrial morphological changes has aroused great interest for exploring the role of mitochondria in the process of cell metabolism. However, in the absence of water-soluble, photostable and low-toxicity fluorescent dyes, ultra-high-resolution mitochondrial imaging is still challenging. Herein, we designed two fluorescent BODIPY dyes, namely Mito-BDP 630 and Mito-BDP 760, for mitochondrial imaging. The results proved that Mito-BDP 760 underwent aggregation-caused quenching (ACQ) in the aqueous matrix owing to its hydrophobicity and was inaccessible to the cells, which restricted its applications in mitochondrial imaging. In stark contrast, water-soluble Mito-BDP 630 readily penetrated cellular and mitochondrial membranes for mitochondrial imaging with high dye densities under wash-free conditions as driven by membrane potential. As a comparison, Mito Tracker Red presented high photobleaching (the fluorescence intensity dropped by nearly 50%) and high phototoxicity after irradiation by a laser for 30 min. However, Mito-BDP 630 possessed excellent biocompatibility, photostability and chemical stability. Furthermore, clear and bright mitochondria distribution in living HeLa cells after incubation with Mito-BDP 630 could be observed by CLSM. Convincingly, the morphology and cristae of mitochondria could be visualized using an ultra-high-resolution microscope. In short, Mito-BDP 630 provided a powerful and convenient tool for monitoring mitochondrial morphologies in living cells. Given the facile synthesis, photobleaching resistance and low phototoxicity of Mito-BDP 630, it is an alternative to the commercial Mito Tracker Red.

A Novel Creatinine-Based Equation to Estimate Glomerular Filtration Rate in Chinese Population With Chronic Kidney Disease: Implications for DOACs Dosing in Atrial Fibrillation Patients.

Background: Over/under-estimating renal function may increase inappropriate dosing strategy associated adverse outcomes; however, previously reported equations to estimate renal function have limited accuracy in chronic kidney disease (CKD) patients. Consequently, we intended to develop a novel equation to precisely estimate renal function and subsequently guide clinical treatment for CKD patients. Methods: A novel approach, Xiangya-s equation, to estimate renal function for CKD patients was derived by linear regression analysis and validated in 1885 patients with measured glomerular filtration rate (mGFR) < 60 ml/min/1.73 m2 by renal dynamic imaging at three representative hospitals in China, with the performance evaluated by accuracy, bias and precision. In the meanwhile, 2,165 atrial fibrillation (AF) patients who initiated direct oral anticoagulants (DOACs) between December 2015 and December 2018 were identified and renal function was assessed by estimated creatinine clearance (eCrCl). Events per 100 patient-years was calculated. Cox proportional hazards regression was applied to compare the incidence of outcomes of each group. Results: Xiangya-s equation demonstrated higher accuracy, lower bias and improved precision when compared with 12 creatinine-based and 2 CysC-based reported equations to estimate GFR in multi-ethnic Chinese CKD patients. When we applied Xiangya-s equation to patients with AF and CKD prescribed DOACs, wide variability was discovered in eCrCl calculated by the Cockcroft-Gault (CG), Modification of Diet in Renal Disease Study (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Xiangya equation which we had developed for generally patients and Xiangya-s equations, which persisted after grouping by different renal function stages. Equation choice affected drug-dosing adjustments, with the formulas agreeing for only 1.19%, 5.52%, 33.22%, 26.32%, and 36.61% of potentially impacted patients for eCrCl cutoffs of <15, <30, 15-49, 30-49, ≥50 ml/min, respectively. Relative to CG equation, accordance in DOACs dosage was 81.08%, 88.54%, 62.25%, and 47.68% for MDRD, CKD-EPI, Xiangya and Xiangya-s equations for patients with CrCl < 50 ml/min (eCrCl cutoffs of <30, 30-49, ≥50 ml/min), respectively. Reclassification of renal function stages by Xiangya-s equation was significantly associated with stroke or systemic embolism, non-major clinically relevant bleeding and any bleeding events. Conclusion: Xiangya-s equation provides more accurate GFR estimates in Chinese CKD patients who need consecutive monitoring of renal function, which may assist clinicians in choosing appropriate drug dosages.

Vancomycin or Daptomycin Plus a ß-Lactam Versus Vancomycin or Daptomycin Alone for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections: A Systematic Review and Meta-Analysis.

Aims: Several in vitro and in vivo studies demonstrated that adding a ß-lactam to vancomycin (VAN) or daptomycin (DAP) can provide synergy against methicillin-resistant Staphylococcus aureus (MRSA). However, the results from clinical studies were controversial. The objective of this systematic review and meta-analysis was to compare the efficacy and safety of using VAN or DAP plus a ß-lactam (combination therapy) and using VAN or DAP alone (monotherapy) in MRSA bloodstream infections. Methods: We included randomized controlled trials and observational studies evaluating whether combination therapy can improve clinical and microbiological outcomes and safety compared to monotherapy with VAN or DAP in MRSA-related bacteremia. Results: Literature search identified 3 randomized clinical trials and 10 observational studies involving at least 1,796 patients. There were no significant associations between the combination therapy and risk of mortality within 30 days (risk ratios [RRs], 1.10, 95% confidence interval [CI], 0.82-1.46), in-hospital mortality (RR, 0.59, 95% CI, 0.31-1.13) and mortality within 60-90 days (RR, 0.91, 95% CI, 0.64-1.29). There was also no evidence that there was a difference in length of hospital stay between the combination therapy and monotherapy (mean difference, -0.41 days, 95% CI, -3.41 to 2.59). However, compared with monotherapy, combination therapy seemed to have a shorter duration of bacteremia(mean difference, -1.06 days, 95% CI, -1.53 to -0.60), a lower risk of persistent bacteremia (RR, 0.63, 95% CI, 0.51-0.79) and a lower risk of bacteremia recurrence within 60-90 days (RR, 0.61, 95% CI, 0.40-0.92). There were no statistically significant differences in the total number of adverse events, including acute kidney injury (AKI) (RR, 1.52, 95% CI, 0.84-2.73), thrombocytopenia (RR, 1.13, 95% CI, 0.74-1.73), and diarrhea (RR, 1.36, 95% CI, 0.70-2.65), between patients with combination therapy and monotherapy. In subgroup analysis, when the analysis was limited to the studies comparing using DAP plus ceftaroline with monotherapy, we found that the former had a lower risk of mortality within 30 days. In addition, a subgroup analysis limited to randomized clinical trials showed that the combination therapy was associated with a higher risk of AKI compared with using VAN or DAP alone. Conclusions: Although adding a ß-lactam to standard therapy seemed to experience a higher clearance compared with monotherapy in patients with MRSA bacteremia, the combination therapy did not increase survival benefits. Based on the available evidence, the combination therapy was not supported as the routine management of MRSA-related bacteremia, and both its harms and benefits should be taken into account.

Multifunction in One Molecule: Mitochondrial Imaging and Photothermal & Photodynamic Cytotoxicity of Fast-Response Near-Infrared Fluorescent Probes with Aggregation-Induced Emission Characteristics.

HJS and DHJS, two near-infrared emissive and mitochondria-targeted therapy probes, have been designed. They exhibited photothermal & photodynamic cytotoxicity and aggregation-induced emission (AIE) characteristics. Interestingly, we could receive fluorescence immediately after adding the probes without washing in 1 min. They could quickly enter cancer cells and selectively localized to the mitochondria firstly. When the concentration of probes was low (<5 µM), they could respond sensitively to the mitochondrial membrane potential and would selectively enter the mitochondria with red fluorescence. However, when the concentration was high (≥5 µM), they would preferentially enter the mitochondria and have the property of dual-channel fluorescence imaging (red and near-infrared) even after 24 h. What's more, they increased the intracellular reactive oxygen species (ROS) levels, decreased the mitochondrial membrane potentials, and then induced apoptosis, which were proved by confocal imaging and flow cytometry experiments. In addition, the results of photothermal experiment and cytotoxicity test showed that the probes had good photothermal and photodynamic toxicity to cancer cells. In vitro and in vivo experiments also proved the excellent near-infrared (NIR) imaging ability, good biocompatibility and certain inhibition of tumor growth ability of DHJS.

Spinophilin modulates pain through suppressing dendritic spine morphogenesis via negative control of Rac1-ERK signaling in rat spinal dorsal horn.

Both spinophilin (SPN, also known as neurabin 2) and Rac1 (a member of Rho GTPase family) are believed to play key roles in dendritic spine (DS) remodeling and spinal nociception. However, how SPN interacts with Rac1 in the above process is unknown. Here, we first demonstrated natural existence of SPN-protein phosphatase 1-Rac1 complex in the spinal dorsal horn (DH) neurons by both double immunofluorescent labeling and co-immunoprecipitation, then the effects of SPN over-expression and down-regulation on mechanical and thermal pain sensitivity, GTP-bound Rac1-ERK signaling activity, and spinal DS density were studied. Over-expression of SPN in spinal neurons by intra-DH pAAV-CMV-SPN-3FLAG could block both mechanical and thermal pain hypersensitivity induced by intraplantar bee venom injection, however it had no effect on the basal pain sensitivity. Over-expression of SPN also resulted in a significant decrease in GTP-Rac1-ERK activities, relative to naive and irrelevant control (pAAV-MCS). In sharp contrast, knockdown of SPN in spinal neurons by intra-DH pAAV-CAG-eGFP-U6-shRNA[SPN] produced both pain hypersensitivity and dramatic elevation of GTP-Rac1-ERK activities, relative to naive and irrelevant control (pAAV-shRNA [NC]). Moreover, knockdown of SPN resulted in increase in DS density while over-expression of it had no such effect. Collectively, SPN is likely to serve as a regulator of Rac1 signaling to suppress DS morphogenesis via negative control of GTP-bound Rac1-ERK activities at postsynaptic component in rat DH neurons wherein both mechanical and thermal pain sensitivity are controlled.

Mitochondria-Targeted BODIPY Nanoparticles for Enhanced Photothermal and Photoacoustic Imaging In Vivo.

Short-wavelength absorption and emission (<600 nm), hydrophobicity, and low selectivity have greatly restricted the biomedical applications of BODIPY. Herein, a series of mitochondria-targeted BODIPY nanoparticles with a cationic triphenylphosphine (TPP) group (Mito-BDP1-5 NPs) bearing different lengths of ethylene glycol (0-4 units), along with HO-BDP5 without a cationic TPP group for comparison, have been rationally designed and prepared to investigate the interplay between their structures and the related properties. Our studies found that Mito-BDP1-4 NPs showed a tendency of aggregation and precipitation while Mito-BDP5 NPs could be stable in aqueous solutions. Compared with HO-BDP5, tailor-made Mito-BDP5 possessed a high photothermal conversion efficiency (PCE) of 76.6 vs 9.0% and exhibited the highest photoinduced cytotoxicity. Upon NIR irradiation, the temperature induced by Mito-BDP5 NPs increased rapidly from room temperature to 76.0 °C in vitro and 50.0 °C at the tumor site in vivo within 5 min. Furthermore, effective mitochondrial imaging in vitro, photothermal imaging (PTI), and photoacoustic imaging (PAI) in vivo were achieved. In this paper, we developed tailor-made photothermal agents for targeting mitochondria and enhancing the PTI and PAI performances, which could be potentially applied in clinical precision theranostics.

Association Between Initiation, Intensity, and Cessation of Smoking and Mortality Risk in Patients With Cardiovascular Disease: A Cohort Study.

Objectives: To examine the effect of smoking status, smoking intensity, duration of smoking cessation and age of smoking initiation on the risk of all-cause and cause-specific mortality among cardiovascular disease (CVD) patients. Design: A population-based prospective cohort study. Setting: The National Health Interview Survey (NHIS) in the U.S. that were linked to the National Death Index (NDI). Participants: 66,190 CVD participants ≥ 18 years of age who were interviewed between 1997 and 2013 in the NHIS linked to the NDI through December 31, 2015. Outcome Measures: The primary outcome was all-cause mortality and the secondary outcome was cause-specific mortality including CVD mortality and cancer mortality. Results: During the mean follow-up of 8.1 years, we documented 22,518 deaths (including 6,473 CVD deaths and 4,050 cancer deaths). In the overall CVD population, former and current smokers had higher risk of all-cause (Former smokers: hazard ratios (HRs), 1.26; 95% confidence interval (CI), 1.21-1.31, P < 0.001; Current smokers: HRs, 1.96; 95%CI, 1.86-2.07, P < 0.001), CVD (Former smokers: HRs, 1.12; 95%CI, 1.05-1.21, P = 0.001; Current smokers: HRs, 1.80; 95%CI, 1.64-1.97, P < 0.001) and cancer mortality (Former smokers: HRs, 1.49; 95%CI, 1.35-1.64, P < 0.001; Current smokers: HRs, 2.78; 95%CI, 2.49-3.09, P < 0.001) than never smokers. Furthermore, similar results were observed when the study subjects were stratified according to the type of CVD. Among current smokers, the risk for cancer mortality increased as the daily number of cigarettes increased, regardless of the specific type of CVD. However, the association of the risk for all-cause and CVD mortality with smoking intensity did not present a dose-response relationship. In participants with angina pectoris or stroke, smoking intensity was inversely associated with deaths from CVD. In addition, the risk for all-cause, CVD and cancer mortality declined as years of smoking cessation increased. Finally, the relative risk of all-cause mortality was not significantly different in individuals with a younger age of smoking initiation. Conclusions: CVD patients who are smokers have an increased risk of all-cause, CVD and cancer mortality, and the risk decreases significantly after quitting smoking. These data further provide strong evidence that supports the recommendation to quit smoking for the prevention of premature deaths among individuals with CVD.

Ceftriaxone Relieves Trigeminal Neuropathic Pain Through Suppression of Spatiotemporal Synaptic Plasticity via Restoration of Glutamate Transporter 1 in the Medullary Dorsal Horn.

Using a rat model of trigeminal neuropathic pain (TNP) produced by chronic compression of the infraorbital nerve (CCI-ION), we investigated the analgesic effect and the underlying mechanisms of ceftriaxone (Cef), a ß-lactam antibiotic, that is thought to be a potent stimulator of glutamate transporter 1 (GLT-1). First, repeated intraperitoneal (i.p.) injections of Cef (200 mg/kg) for 5-days since Day 1 of CCI-ION could significantly relieve both mechanical and thermal pain hypersensitivity from day 10 after drug administration. Western blot and immunofluorescent results demonstrated that 5-days administration of Cef resulted in the restoration of GLT-1 expression to a level equivalent to the sham control which was dramatically lost under the TNP condition. Moreover, multi-electrode (8 × 8) array recordings of network field excitatory postsynaptic potentials (fEPSPs) were performed on the acutely dissociated medullary dorsal horn slice evoked by electrical stimulation of the trigeminal spinal tract. The results showed that the increased number of fEPSPs, induction rate, and maintenance of long-term potentiation caused by CCI-ION were significantly suppressed by 5-days administration of Cef. Taken together, the results indicate that Cef can relieve TNP through suppression of spatiotemporal synaptic plasticity via GLT-1 restoration in the medullary dorsal horn of the trigeminal nerve.

A Novel Laboratory-Based Model to Predict the Presence of Obstructive Coronary Artery Disease.

Commonly used tools to assess the probability of obstructive-coronary artery disease (CAD) were derived based on Caucasian cohorts, with their performance in China is still unknown. Furthermore, most were established based on non-laboratory variables, contributing to the limited predictive ability to some extent. Thus, we developed and internally validated a laboratory-based model with data from a Chinese cohort of 8963 inpatients, with suspected stable chest pain, referred to catheter-based coronary angiography (CAG) from September 2007 to April 2019, and then compared the present model's performance with the four most commonly used prediction tools, Coronary Artery Disease Consortium 1/2 Score (CAD1/2), Duke clinical score (DCS), and Diamond-Forrester score (DF). The final model was developed by random forest method, including 8 predictors derived from 70 variables. Five-fold cross-validation was performed to evaluate the model's prediction accuracy. In the external validation set, the present model showed a superior area under the receiver-operating curve (0.816), followed by DCS (0.66), CAD2 (0.61), CAD1 (0.59) and at last DF (0.58), respectively. Furthermore, the present model correctly classified 74.4% of obstructive-CAD patients as high-risk, and correctly classified more than one third of non-obstructive-CAD patients as low-risk. The present model's net reclassification improvement (NRI) showed a significant positive reclassification over CAD1 (NRI = 0.60, P < 0.001), DF (NRI = 0.59, P < 0.001), CAD2 (NRI = 0.57, P < 0.001), and DCS (NRI = 0.43, P < 0.001). Decision curve analysis demonstrated that the present model provided a larger net benefit compared with CAD1/2, DCS, and DF. In conclusion, the novel model, using 8 laboratory and non-laboratory variables, performed well in risk stratifying patients with suspected chest pain regarding the presence of obstructive-CAD in the present Chinese cohort.

Protective Effects of Amlodipine Pretreatment on Contrast-Induced Acute Kidney Injury And Overall Survival In Hypertensive Patients.

BACKGROUD: Contrast-induced acute kidney injury (CI-AKI) is the most common adverse reaction caused by contrast media, which has been reported to prolong hospitalization and increase mortality and morbidity. The hypertensive population has proved susceptible to CI-AKI. Unfortunately, no therapeutic has been shown to prevent and cure CI-AKI effectively. A few studies have shown the protection of amlodipine on renal function, but the relationship between amlodipine and CI-AKI in hypertensive group is unknown, we aimed to study the effects of amlodipine on CI-AKI and overall survival in a large Chinese hypertensive cohort. METHODS: A retrospective, matched, cohort study was conducted among adults hospitalized at the Third Xiangya Hospital of Central South University from October 2007 to May 2017. CI-AKI was the primary end point of the trial, time-related all-cause mortality (including in-hospital) and length of hospital stay were the secondary end points. Propensity Score Matching was used to reduce the effect of selection bias and potential confounding. RESULTS: 868 patients with and 1,798 ones without amlodipine before contrast administration were included. The incidence of CI-AKI was 10.50%. The unadjusted, adjusted, and propensity-score matched incidence of CI-AKI were lower in patients treated with amlodipine (OR, 0.650; P = 0 .003; OR, 0.577; P = 0.007; OR, 0.687; P = 0.015, respectively), and the same results were found in the subgroups of diabetes, chronic kidney disease (CKD), non-CKD, low-osmolar, and elderly. Moreover, amlodipine reduced hospital stay, whether matched or not (7.08 ± 7.28 vs 7.77 ± 7.82, P = 0.027, before matching; vs 7.81 ± 7.58, P = 0.040, after matching). 1,046 patients finished follow-up including 343 amlodipine users and 703 non-users. The overall mortality was significantly lower among amlodipine users (10.79%) than controls (16.07%), the significant difference was found in survival between them (P = 0.024, log-rank test), amlodipine was associated with longer overall survival [HR, 0.623; 95% CI (0.430-0.908), P = 0.014]. CONCLUSION: In conclusion, we first found amlodipine treatment before contrast exposure played a role in protecting hypertensive patients from CI-AKI and prolonging survival.

Oleanolic acid inhibits mouse spinal cord injury through suppressing inflammation and apoptosis via the blockage of p38 and JNK MAPKs.

Spinal cord injury (SCI) is reported as a devastating disease, leading to tissue loss and neurologic dysfunction. However, there is no effective therapeutic strategy for SCI treatment. Oleanolic acid (OA), as a triterpenoid, has anti-oxidant, anti-inflammatory, and anti-apoptotic activities. However, its regulatory effects on SCI have little to be elucidated, as well as the underlying molecular mechanisms. In this study, we attempted to explore the role of OA in SCI progression. Behavior tests suggested that OA treatments markedly alleviated motor function in SCI mice. Evans blue contents up-regulated in spinal cords of SCI mice were significantly reduced by OA in a dose-dependent manner, demonstrating the improved blood-spinal cord barrier. Moreover, we found that OA treatments significantly reduced the apoptotic cell death in spinal cord samples of SCI mice through decreasing the expression of cleaved Caspase-3. In addition, pro-inflammatory response in SCI mice was significantly attenuated by OA treatments. Furthermore, SCI mice exhibited higher activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways, but these effects were clearly blocked in SCI mice with OA treatments, as evidenced by the down-regulated phosphorylation of p38, c-Jun-NH 2 terminal kinase (JNK), IκB kinase α (IKKα), inhibitor of nuclear factor κB-α (IκBα) and NF-κB. The protective effects of OA against SCI were confirmed in lipopolysaccharide (LPS)-stimulated mouse neurons mainly through the suppression of apoptosis and inflammatory response, which were tightly associated with the blockage of p38 and JNK activation. Together, our data demonstrated that OA treatments could dose-dependently ameliorate spinal cord damage through impeding p38- and JNK-regulated apoptosis and inflammation, and therefore OA might be served as an effective therapeutic agent for SCI treatment.

Risk of non-melanoma skin cancer for rheumatoid arthritis patients receiving TNF antagonist: a systematic review and meta-analysis.

OBJECTIVE: Tumor necrosis factor inhibitors (anti-TNF) have become the standard treatment for rheumatoid arthritis (RA). However, evidence is inconsistent as to whether RA patients with anti-TNF are associated with an increased risk of non-melanoma skin cancer (NMSC) compared with those without anti-TNF. We performed a systematic review and meta-analysis to evaluate the risk of NMSC in patients with anti-TNF drugs compared with those without anti-TNF. METHODS: We did a systematic literature search with PubMed, EMBASE, and the Cochrane Library from inception to April 1, 2019. Prospective observational studies were eligible for inclusion if they included any of the approved anti-TNF drugs and reported the risk estimates and 95% confidence interval (95% CI) of NMSC associated with anti-TNF in RA patients. Pooled relative risks (RRs) and 95% CIs were calculated using a fixed-effects model. To assess the heterogeneity and risk of publication bias, we respectively conducted the subgroup and sensitivity analysis, funnel plot, Begg's and Egger's test. RESULTS: The present meta-analysis included six studies with 123,031 patients. Compared with RA patients without anti-TNF, patients with anti-TNF drugs were associated with an increased risk of NMSC (RR 1.28, 95% CI 1.19 to 1.38; I2 = 45.6%, P = 0.056), especially squamous cell skin cancer (SCC) (RR 1.30, 95% CI 1.09 to 1.54; I2 = 0%, P = 0.854), but not basal cell skin cancer (RR 1.13, 95% CI 0.97 to 1.31; I2 = 0%, P = 0.555). Sensitivity and subgroup analysis confirmed the robustness of the primacy results. There was no evidence of publication bias with Begg's and Egger's test or by inspection of the funnel plot. CONCLUSIONS: These results suggest that RA patients treated with anti-TNF are at an increased risk of NMSC, especially SCC. However, this association in RA urgently needs the more clinical studies and basic researches to further validate.Key Points• Rheumatoid arthritis patients treated with tumor necrosis factor inhibitors are associated with a higher risk of non-melanoma skin cancer compared to those patients treated without tumor necrosis factor inhibitors. Hence, tumor necrosis factor inhibitors may be avoided in rheumatoid arthritis patients who are at high risk of non-melanoma skin cancer.• Of note, rheumatoid arthritis patients who were treated for tumor necrosis factor inhibitors compared with patients who were not treated for tumor necrosis factor inhibitors were at significantly increased risk of squamous cell skin cancer, but were not at increased risk of basal cell skin cancer. Therefore, use of tumor necrosis factor inhibitors in rheumatoid arthritis patients should be paid attention to the occurrence of squamous cell skin cancer.