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Xingping Zhou,1,* Jinjin Luo,1,* Xi Liang,1,2 Peng Li,1 Keke Ren,1 Dongyan Shi,1,2 Jiaojiao Xin,1,2 Jing Jiang,1,2 Jiaxian Chen,1 Lulu He,1 Hui Yang,1 Shiwen Ma,1 Bingqi Li,1 Jun Li1,2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 2Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel/Fax +86-571-87236425, Email lijun2009@zju.edu.cnBackground and Aim: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with high short-term mortality. Effective biomarkers are required for its early diagnosis and prognosis. This study aimed to determine the diagnostic and prognostic value of thrombomodulin (TM) in patients with HBV-ACLF.Methods: The expression of TM during disease progression was evaluated through transcriptomics analysis. The plasma TM concentrations of 393 subjects with HBV-ACLF (n=213), acute-on-chronic hepatic dysfunction (ACHD, n=50), liver cirrhosis (LC, n=50) or chronic hepatitis B (CHB, n=50), and normal controls (NC, n=30) from a prospective multicenter cohort, were measured to verify the diagnostic and prognostic significance of plasma TM for HBV-ACLF patients by enzyme-linked immunosorbent assay (ELISA).Results: TM mRNA was highly expressed in the HBV-ACLF group compared with the ACHD group (AUROC=0.710). High expression of TM predicted poor prognosis for HBV-ACLF patients at 28/90 days (AUROCs=0.823/0.788). Functional analysis showed that TM was significantly associated with complement activation and the inflammatory signaling pathway. External validation confirmed its high diagnostic accuracy for HBV-ACLF patients (AUROC=0.796). Plasma TM concentrations were correlated with organ failure, including coagulation and kidney failure. Plasma TM concentrations showed a potential prognostic value for 28-day mortality rates (AUROC=0.702). Risk stratification specifically identified HBV-ACLF patients with a high risk of death as having a plasma TM concentration of ≥ 8.4 ng/mL.Conclusion: This study reveals that the plasma TM can be a candidate biomarker for early diagnosis and prognosis of HBV-ACLF, and might play a vital role in coagulation and inflammation.Keywords: thrombomodulin, HBV-ACLF, biomarker, organ failure

Abstract Few histological prognostic indicators for end-stage renal disease (ESRD) have been validated in diabetic patients. This biopsy-based study aimed to identify nephropathological risk factors for ESRD in Chinese patients with type 2 diabetes. Histological features of 322 Chinese type 2 diabetic patients with biopsy-confirmed diabetic nephropathy (DN) were retrospectively analysed. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) for ESRD. Single glomerular proteomics and immunohistochemistry were used to identify differentially expressed proteins and enriched pathways in glomeruli. During the median follow-up period of 24 months, 144 (45%) patients progressed to ESRD. In multivariable models, the Renal Pathology Society classification failed to predict ESRD, although the solidified glomerulosclerosis (score 1: HR 1.65, 95% confidence interval [CI] 1.04–2.60; score 2: HR 2.48, 95% CI 1.40–4.37) and extracapillary hypercellularity (HR 2.68, 95% CI 1.55–4.62) were identified as independent risk factors. Additionally, single glomerular proteomics, combined with immunohistochemistry, revealed that complement C9 and apolipoprotein E were highly expressed in solidified glomerulosclerosis. Therefore, solidified glomerulosclerosis and extracapillary hypercellularity predict diabetic ESRD in Chinese patients. Single glomerular proteomics identified solidified glomerulosclerosis as a unique pathological change that may be associated with complement overactivation and abnormal lipid metabolism.

Shuang-long Li, Yi Zhang, Qian-shi Cheng, Jun-zhe Xin, Ze-qin Dong, Xiang-jun Qiu School of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaTel +86 13698882699Fax +86 379-64830346Email lyxiangjun@126.comObjective: An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of selinexor was established to investigate the effects of isavuconazole, itraconazole and fluconazole on the pharmacokinetics of selinexor in rats, respectively.Methods: Twenty-four healthy male rats were randomly divided into four groups: group A, normal saline; group B, isavuconazole (20 mg/kg); group C, itraconazole (20 mg/kg); and group D, fluconazole (20 mg/kg). After 30 min of oral administration of normal saline, isavuconazole, itraconazole, and fluconazole, all the rats were given selinexor (8 mg/kg). The plasma concentration of selinexor was estimated by UPLC-MS/MS, and the pharmacokinetic parameters of selinexor were calculated by Drug and Statistics (DAS) 2.0 software.Results: Under these experimental conditions, the method showed good linearity and stability. Intraday and interday accuracy and sample recovery were acceptable. Compared with group A, the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group B increased by 59.05%, 31.69%, and 31.45%; the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group C increased by 56.14%, 25.34%, and 25.08%; the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group D increased by 43.44%, 29.16%, and 31.96%, respectively. The Tmax of the experimental groups were extended, and CLz/F was also significantly reduced.Conclusion: These results indicated that isavuconazole, itraconazole, and fluconazole have significant inhibitory effects on selinexor pharmacokinetics and increased selinexor plasma exposure in rats. Therefore, when these drugs were used in combination, clinicians should pay attention to the changes in treatment effects and the occurrence of adverse reactions caused by the drug-drug interactions.Keywords: isavuconazole, itraconazole, fluconazole, selinexor, UPLC-MS/MS, pharmacokinetics, drug-drug interactions

Background: Obesity is associated with a higher incidence of atrial fibrillation (AF). Weight reduction improves outcomes in patients known to have AF. Objective: The purpose of this study was to compare the incidence of heart failure (HF) or first-time AF hospitalization in obese patients undergoing bariatric surgery (BAS) vs other abdominal surgeries. Methods: A retrospective cohort study was conducted using linked hospital discharge records from 1994–2014. Obese patients without known AF or atrial flutter (AFL) who had undergone abdominal hernia or laparoscopic cholecystectomy surgery were identified for each case that underwent BAS (2:1). Clinical outcomes were HF, first-time hospitalization for AF, AFL, gastrointestinal bleeding (GIB), and ischemic or hemorrhagic stroke. Outcomes were analyzed using conditional proportional hazard modeling accounting for the competing risk of death, adjusting for demographics and comorbidities. Results: There were 1581 BAS cases and 3162 controls (48% age

Junling Yang,1 Zaijun Hao,1 Wei Li,1 Caiping Duan,1 Xiujuan Fan,1 Jing Xin,1 Chunguang Ren2 1Department of Anesthesiology, Ordos Central Hospital, Ordos, People’s Republic of China; 2Department of Anesthesiology, Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of ChinaCorrespondence: Chunguang Ren Email weiyichunguang@163.comBackground: Although video-assisted thoracoscopic surgery (VATS) is increasingly used, the optimal analgesia strategy is still unknown. We explore the efficacy and safety of preemptive ultrasound-guided paravertebral block (PVB) combined with parecoxib during VATS.Methods: Seventy-four patients were divided into two groups. PVBs were performed before anesthesia induction under real-time ultrasound guidance. Visual analog scale (VAS) score with coughing at 48 h after surgery, postoperative sufentanil consumption and level of sedation (LOS) at 1, 4, 8, 12, 24, and 48 h postoperatively, intraoperative hemodynamics, satisfaction scores of patients and surgeons, remedial measures, time to chest tube removed and mobilization, adverse effects and hospital stay length were recorded. We also recorded inflammatory markers, respiratory function and the prevalence of chronic pain after surgery.Results: VAS scores at rest and with coughing during the first 24 h after surgery were significantly lower in the P group (P< 0.05). Consumption of sevoflurane, remifentanil, and dexmedetomidine was all significantly reduced in the P group (P< 0.05). The consumption of sufentanil within 48 h after surgery, time to first dose and total dose of rescue ketorolac was significantly lower in the P group (P< 0.05). The FEV1/FVC ratio was significantly higher in the P group at 1 and 3 d after surgery (P< 0.05). Times to chest tube removal and mobilization were significantly shorter in the P group (P< 0.05). Compared with the C group, the level of both ACTH and cortisol was significantly reduced in the P group at 1 and 3 d after surgery (P< 0.05).Conclusion: PVB combined with parecoxib was associated with better pain relief, decreased sufentanil and ketorolac consumption, less hemodynamic instability, and a lower surgery-related stress response. However, the incidences of chronic pain 3 and 6 months after surgery and the risk of complication except urinary retention were not significantly different between groups.Keywords: paravertebral block, parecoxib, video-assisted thoracic surgery, preemptive analgesia

Aimei Li,1 Feng Yang,2 Jiaying Xin,1 Xuebo Bai1 1Department of Anesthesiology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China; 2Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China Purpose: Local anesthetics are used clinically for the control of pain following operation (including gastrointestinal surgery) or for the management of other acute and chronic pain. This study aimed to develop a kind of lipid-polymer hybrid nanoparticles (LPNs), which were constructed using poly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE) as the hydrophilic lipid shell and poly-ε-caprolactone (PCL) as the hydrophobic polymeric core.Methods: Ropivacaine (RPV) was entrapped in the LPNs (RPV-LPNs) and the physicochemical and biochemical properties such as size, zeta potential, drug release, and cytotoxicity were studied. The long-lasting effects and safety aspects of the LPNs were evaluated in vitro and in vivo.Results: The particle size and zeta potential of RPV-LPNs were 112.3±2.6 nm and -33.2±3.2 mV, with an entrapment efficiency (EE) of 90.2%±3.7%. Ex vivo permeation efficiency of LPNs was better than the drug solution. The RPV-LPNs exhibited a long-lasting in vivo anesthesia effect in both rats and mice.Conclusion: Considering the low cytotoxicity, the LPNs prepared here could be used as an efficient local anesthetic for the control of pain. Keywords: postoperative pain, gastrointestinal surgery, poly(ethylene glycol), poly-ε-caprolactone, ropivacaine

Background and Purpose: This study aims to quantify the reperfusion status within severely damaged brain tissue and to evaluate its relationship with high grade of hemorrhagic transformation (HT).Methods: Pseudo-continuous ASL was performed along with DWI in 102 patients within 24 h post-treatments. The infarction core was identified using ADC values

Abstract Background The use of lengthy, detailed, and complex informed consent forms (ICFs) is of paramount concern in biomedical research as it may not truly promote the rights and interests of research participants. The extent of information in ICFs has been the subject of debates for decades; however, no clear guidance is given. Thus, the objective of this study was to determine the perspectives of research participants about the type and extent of information they need when they are invited to participate in biomedical research. Methods This multi-center, cross-sectional, descriptive survey was conducted at 54 study sites in seven Asia-Pacific countries. A modified Likert-scale questionnaire was used to determine the importance of each element in the ICF among research participants of a biomedical study, with an anchored rating scale from 1 (not important) to 5 (very important). Results Of the 2484 questionnaires distributed, 2113 (85.1%) were returned. The majority of respondents considered most elements required in the ICF to be ‘moderately important’ to ‘very important’ for their decision making (mean score, ranging from 3.58 to 4.47). Major foreseeable risk, direct benefit, and common adverse effects of the intervention were considered to be of most concerned elements in the ICF (mean score = 4.47, 4.47, and 4.45, respectively). Conclusions Research participants would like to be informed of the ICF elements required by ethical guidelines and regulations; however, the importance of each element varied, e.g., risk and benefit associated with research participants were considered to be more important than the general nature or technical details of research. Using a participant-oriented approach by providing more details of the participant-interested elements while avoiding unnecessarily lengthy details of other less important elements would enhance the quality of the ICF.

Jing Xin,1,* Sijia Wang,1,* Bing Wang,1 Jiazhuang Wang,1 Jing Wang,1 Luwei Zhang,1 Bo Xin,2 Lijian Shen,1 Zhenxi Zhang,1 Cuiping Yao1 1Key Laboratory of Biomedical Information Engineering of Education Ministry, Institute of Biomedical Analytical Technology and Instrumentation, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; 2School of Innovation and Entrepreneurship, Xi’an Fan Yi University, Xi’an, Shaanxi, China *These authors contributed equally to this work Purpose: As a promising photodynamic therapy (PDT) agent, Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) provides deep penetration into tissue, high quantum yields, good photostability, and low photobleaching. However, its low delivery efficiency and high binding affinity to serum albumin cause its low penetration into cancer cells, further limiting its PDT effect on gastric cancer. In order to improve AlPcS4/PDT effect, the AlPcS4 delivery sys­tems with different drug carriers were synthesized and investigated. Materials and methods: Gold nanorods, cationic liposomes, and Pluronic® F127 nanomicellars were used to formulate the AlPcS4 delivery systems. The anticancer effect was evaluated by CCK-8 assay and colony formation assay. The delivery efficiency of AlPcS4 and the binding affinity to serum proteins were determined by fluorescence intensity assay. The apoptosis and necrosis ability, reactive oxygen species and singlet oxygen generation, mitochondrial transmembrane potential and ([Ca2+]i) concentration were further measured to evaluate the mechanism of cell death. Results: The series of synthesized AlPcS4 delivery sys­tems with different drug carriers improve the limited PDT effect in varying degrees. In contrast, AlPcS4 complex with gold nanorods has significant anticancer effects because gold nanorods are not only suitable for AlPcS4 delivery, but also exhibit enhanced singlet oxygen generation effect and photothermal effect to induce cell death directly. Moreover, AlPcS4 complex with cationic liposomes shows the potent inhibition effect because of its optimal AlPcS4 delivery efficiency and ability to block serum albumin. In addition, AlPcS4 complex with Pluronic F127 exhibits infe­rior PDT effect but presents lower cytotoxicity, slower dissociation rate, and longer retention time of incorporated drugs; thus, F127–AlPcS4 is used for prolonged gastric cancer therapy. Conclusion: The described AlPcS4 drug delivery systems provide promising agents for gastric cancer therapy. Keywords: drug delivery carriers, AlPcS4, gastric cancer therapy, gold nanoparticles, cationic liposome, nanomicelle

Sijia Wang, Jing Xin, Luwei Zhang, Yicheng Zhou, Cuiping Yao, Bing Wang, Jing Wang, Zhenxi Zhang Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Institute of Biomedical Analytical Technology and Instrumentation, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China Purpose: Plasmonic nanostructure-mediated photothermal therapy (PTT) is a promising alternative therapy for the treatment of skin cancer and other diseases. However, the insufficient efficiency of PTT at irradiation levels tolerable to tissues and the limited biodegradability of nanomaterials are still crucial challenges. In this study, a novel nanosystem for PTT based on liposome–nanoparticle assemblies (LNAs) was established.Materials and methods: Thermal-sensitive liposomes (TSLs) encapsulating cantharidin (CTD) were coated with gold nanoparticles (GNPs) and used in near-infrared (NIR) illumination-triggered PTT and thermally induced disruption on A431 cells.Results: The coated GNPs disintegrated into small particles of 5–6 nm after disruption of TSLs, allowing their clearance by the liver and kidneys. CTD encapsulated in the TSLs was released into cytoplasm after PTT. The released CTD increased the apoptosis of PTT-treated tumor cells by blocking the heat shock response (HSR) and inhibiting the expression of HSP70 and BAG3 inhibiting the expression of HSP70 and BAG3 with the synergistic enhancement of CTD, the new nanosystem CTD-encapsulated TSLs coated with GNPs (CTD-TSL@GNPs) had an efficient PTT effect using clinically acceptable irradiation power (200 mW/cm2) on A431 cells.Conclusion: The developed CTD-TSL@GNPs may be a promising PTT agent for clinical skin cancer therapy. Keywords: gold nanoparticles, liposome, cantharidin, photothermal therapy, heat shock response

The 129sv mouse strain is particularly sensitive to experimental immune-mediated nephritis. Previous studies have indicated that transforming growth factor-β (TGF-β) plays a critical role in both immune modulation and tissue fibrogenesis in various diseases and that its biological activities are exerted via the SMAD family. In this study, we aimed to determine whether TGF-β/SMAD signaling is essential for the development of immune-mediated nephritis in 129sv mice. Relative to C57BL/6J control mice with anti-glomeruli basement membrane (GBM) nephritis, 129sv mice with anti-GBM nephritis exhibited increased renal collagen deposition. Additionally, higher mRNA levels of pro-collagen and collagen IV, higher serum levels of active and total TGF-β1, and increased TGF-β1, TGF-βIIR, and phosphorylated SMAD expression were detected in these mice. Deletion of Smad3 in 129sv mice ameliorated anti-GBM induced nephritis, including crescentic glomerulonephritis. Collectively, these findings indicate that the heightened experimental nephritis and fibrotic disease in the 129sv strain of mice are regulated by SMAD3, which could be a potential therapeutic target for immune-mediated nephritis.

Fang Li,1,2,* Chunli Zheng,1,* Junbo Xin,2 Fangcheng Chen,1 Hua Ling,3 Linlin Sun,4 Thomas J Webster,4,5 Xin Ming,6 Jianping Liu1 1School of Pharmacy, China Pharmaceutical University, Nanjing, 2School of Pharmacy, Yancheng Vocational Institute of Health Sciences, Yancheng, People’s Republic of China; 3School of Pharmacy, Hampton University, Hampton, VA, 4Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 5Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia; 6Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA *These authors contributed equally to this work Abstract: A novel method was developed here to prepare albumin-based nanoparticles (NPs) for improving the therapeutic and safety profiles of chemotherapeutic agents. This approach involved crosslinking bovine serum albumin (BSA) using a Schiff base-containing vanillin, into NPs and loading doxorubicin (DOX) into the NPs by incubation. The resultant NPs (DOX-BSA-V-NPs) displayed a particle size of 100.5±1.3 nm with a zeta potential of –23.05±1.45 mV and also showed high drug-loading efficiency and excellent stability with respect to storage and temperature. The encapsulation of DOX into the BSA-V-NPs was confirmed by dynamic scanning calorimetry and Raman spectroscopy. DOX-BSA-V-NPs exhibited a significantly faster DOX release at pH 6.5 than pH 7.4, as well as in a solution with a higher glutathione concentration. In vitro studies showed that the cellular uptake of DOX-BSA-V-NPs was time-dependent, concentration-dependent, and faster than free DOX, while the cytotoxicity of DOX-BSA-V-NPs (IC50 value of 3.693 µg/mL) was superior to free DOX (IC50 value of 4.007 µg/mL). More importantly, DOX-BSA-V-NPs showed a longer mean survival time of 24.83 days, a higher tumor inhibition rate of 56.66%, and a decreased distribution in the heart than other DOX formulations in animal studies using a tumor xenograft model. Thus, the vanillin-based albumin NPs were shown here to be a promising carrier for tumor-targeted delivery of chemotherapeutic agents and, thus, should be further studied. Keywords: doxorubicin, albumin nanoparticles, Schiff base, tumor delivery, anticancer response

The Bi-M (M = Ti, Cr, V) systems have been critically reviewed and modeled by means of the CALPHAD technique. All the intermetallics (BiTi3, BiTi2, Bi9Ti8, Bi3Ti2 and Bi2Ti) were treated as stoichiometric compounds. The enthalpy of formation at 0 K for BiTi2 was computed via first-principles calculations to assist the thermodynamic modeling. The gas phases for the Bi-Cr and Bi-V systems were treated as ideal gas. A set of self-consistent thermodynamic parameters has been finally obtained for each of these binary systems. Comparisons between the calculated and measured phase diagrams as well as first-principles calculations show that most of experimental data can be satisfactorily reproduced by the present thermodynamic descriptions.

Ding-Wei Kuang,1,2,* Chiu-Leong Li,1,* Un-I Kuok,1 Kin Cheung,1 Weng-In Lio,1 Jing Xin1,21Department of Nephrology, Centro Hospitalar Conde de São Januário, Macao, China; 2Department of Nephrology, Huashan Hospital, Shanghai, China*These authors contributed equally to this workBackground: Rapid growth of the elderly peritoneal dialysis (PD) population is posing a special challenge for renal teams. Peripheral artery disease (PAD) has been reported to be an independent predictor of cardiovascular and all-cause mortality in hemodialysis patients. However, the prevalence and associated risk factors for PAD in elderly PD patients have not yet been fully investigated.Methods: A total of 69 elderly PD patients were included in the present study. PAD was defined as either an ankle-brachial index < 0.9 or a history of intermittent claudication, lower-limb amputation, foot ulcers, or gangrene. On enrollment, clinical and biochemical characteristics were collected.Results: The overall prevalence of PAD was 31.9%. Compared with non-PAD patients, PAD patients were significantly older and more likely to be female and have longer PD duration and lower diastolic blood pressure (P < 0.001, = 0.002, 0.018, and 0.007, respectively). Serum albumin level (P < 0.001) and residual renal Kt/V value (P < 0.001) were significantly lower, but the serum C-reactive protein level (P = 0.005) was significantly higher, in PAD patients compared with non-PAD patients. Logistic regression analysis showed that serum albumin level (odds ratio = 1.485, P = 0.040) and residual renal Kt/V value (odds ratio = 1.725, P = 0.016) were independently associated with PAD.Conclusion: A high prevalence of PAD appeared among elderly PD patients in Macao. Serum albumin level and residual renal Kt/V value were independently related to PAD.Keywords: ankle-brachial index, atherosclerosis, elderly, peripheral artery disease, peritoneal dialysis

BackgroundPulmonary injury is the main cause of death in acute paraquat (PQ) poisoning. However, whether quantitative lung computed tomography (CT) can be useful in predicting the outcome of PQ poisoning remains unknown. We aimed to identify early findings of quantitative lung CT as predictors of outcome in acute PQ poisoning.MethodsLung CT scanning (64-slide) and quantitative CT lesions were prospectively measured for patients after PQ intoxication within 5 days. The study outcome was mortality during 90 days follow-up. Survival curves were derived by the Kaplan-Meier method, and mortality risk factors were analyzed by the forward stepwise Cox regression analysis.ResultsOf 97 patients, 41 (42.3%) died. Among the eight different types of lung CT findings which appeared in the first 5-day of PQ intoxication, four ones discriminated between survivors and non-survivors including ground glass opacity (GGO), consolidation, pneumomediastinum and "no obvious lesion". With a cutoff value of 10.8%, sensitivity of 85.4% and specificity of 89.3%, GGO volume ratio is better than adopted outcome indicators in predicting mortality, such as estimated amount of PQ ingestion, plasma or urine PQ concentration, acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores. GGO volume ratios above 10.8% were associated with increased mortality (hazard ratio, 5.82; 95% confidence interval, 4.77-7.09; P < 0.001).ConclusionsThe volume ratio of GGO exceeding 10.8% is a novel, reliable and independent predictors of outcome in acute PQ poisoning.

Crescentic glomerulonephritis (GN) is the most severe form of GN and is associated with significant morbidity and mortality despite aggressive immunotherapy with steroids, cytotoxic drugs, and plasmapheresis. We examined the therapeutic efficacy of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG, 50 mg/kg BW/day x3 weeks), a potent anti-inflammatory and anti-oxidant agent, on experimental crescentic GN induced in 129/svJ mice by administration of rabbit anti-mouse glomerular basement membrane sera. Routine histology and key molecules involved in inflammatory and redox signaling were studied. EGCG treatment significantly reduced mortality, decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. The improvements in renal function and histology were accompanied by the restoration of Nrf2 signaling (which was impaired in vehicle-treated mice) as shown by increased nuclear translocation of Nrf2 and cytoplasmic glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione peroxidase. EGCG-treated mice also showed reduction in p-Akt, p-JNK, p-ERK1/2 and p-P38 as well as restoration of PPARγ and SIRT1 levels. Lower dose of EGCG (25 mg/kg BW/day x2 weeks) treatment also significantly decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. Thus, our data illustrate the efficacy of EGCG in reversing the progression of crescentic GN in mice by targeting multiple signaling and inflammatory pathways as well as countering oxidative stress.

Previously we have shown that kallikreins (klks) play a renoprotective role in nephrotoxic serum induced nephritis. In this study, we have used mesenchymal stem cells (MSCs) as vehicles to deliver klks into the injured kidneys and have measured their therapeutic effect on experimental antibody induced nephritis and lupus nephritis. Human KLK-1 (hKLK1) gene was transduced into murine MSCs using a retroviral vector to generate a stable cell line, hKLK1-MSC, expressing high levels of hKLK1. 129/svj mice subjected to anti-GBM induced nephritis were transplanted with 10(6) hKLK1-MSCs and hKLK1 expression was confirmed in the kidneys. Compared with vector-MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria, blood urea nitrogen (BUN) and ameliorated renal pathology. Using the same strategy, we treated lupus-prone B6.Sle1.Sle3 bicongenic mice with hKLK1-MSCs and demonstrated that hKLK1-MSCs delivery also attenuated lupus nephritis. Mechanistically, hKLK1-MSCs reduced macrophage and T-lymphocyte infiltration into the kidney by suppressing the expression of inflammation cytokines. Moreover, hKLK1 transduced MSCs were more resistant to oxidative stress-induced apoptosis. These findings advance genetically modified MSCs as potential gene delivery tools for targeting therapeutic agents to the kidneys in order to modulate inflammation and oxidative stress in lupus nephritis.

Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG.

Mouse models of experimental anti-glomerular basement membrane (anti-GBM) nephritis provide an analytical tool for studying spontaneous lupus nephritis. The potential of Positron Emission Tomography (PET) was evaluated using 2-deoxy-2-[(18)F]fluoro-d-glucose (FDG) as a probe to monitor the progression of anti-GBM induced nephritis in a mouse model. The imaging results were compared to conventional measures of renal function and pathological changes. Serum and urinary vascular cell adhesion molecule-1 (VCAM-1) levels were used as measures of endothelial cell activation and inflammation. Following a challenge with anti-glomerular antibodies, mice exhibited peak changes in serum creatinine, proteinuria, and glomerulonephritis score at 14 days post-challenge (p.c.). In contrast, VCAM levels peaked at day 7 p.c. On dynamic PET images (0-60 min) of day 7, kidneys of the anti-GBM nephritis mice demonstrated a unique pattern of FDG uptake. Compared to the time activity curve (TAC) prior to challenge, a rightward shift was observed after the challenge. By day 10 p.c., kidney FDG uptake was lower than baseline and remained so until the study ended at 21 days p.c. During this time frame measures of renal dysfunction remained high but VCAM-1 levels declined. These changes were accompanied by an increase in kidney volume as measured by Computed Tomography (CT) and intra-abdominal fluid collection. Our results suggest that FDG-PET-CT can be used as a non-invasive imaging tool to longitudinally monitor the progression of renal disease activity in antibody mediated nephritis and the magnitude of renal FDG retention correlates better with early markers of renal inflammation than renal dysfunction.

Non-invasive monitoring of disease progression in kidney disease is still a major challenge in clinical practice. In vivo near-infrared (NIR) imaging provides a new tool for studying disease mechanisms and non-invasive monitoring of disease development, even in deep organs. The LI-COR IRDye® 800CW RGD optical probe (RGD probe) is a NIR fluorophore, that can target integrin alpha v beta 3 (α(v)β(3)) in tissues.This study aims to monitor renal disease progression in an anti-glomerular basement membrane (GBM) nephritis mouse model.Anti-GBM nephritis was induced in 129x1/svJ mice by anti-GBM serum challenge. The expression of integrin α(v)β(3) in the diseased kidney was examined by immunohistochemistry and quantitative polymerase chain reaction. The RGD probe and control fluorophores, the 800CW dye, and the BSA-conjugated 800CW dye, were administered into anti-GBM nephritic mice. LI-COR Pearl® Impulse imaging system was used for in vivo imaging; while ex vivo organ imaging was acquired using the Maestro(TM) imaging system.Kidney tissue from anti-GBM nephritic mice showed higher levels of integrin α(v)β(3) expression at both the protein and the mRNA level compared to normal mice. The RGD probe allowed in vivo renal imaging and the fluorescent signal could be specifically captured in the diseased kidneys up to 14 days, reflecting longitudinal changes in renal function.The infrared RGD molecular probe that tracks integrin expression can be successfully used to monitor renal disease progression following immune-mediated nephritis.

Dysregulation of phosphate homeostasis as occurs in chronic kidney disease is associated with cardiovascular complications. It has been suggested that both hyperphosphatemia and hypophosphatemia can cause cardiovascular disease. The molecular mechanisms by which high or low serum phosphate levels adversely affect cardiovascular function are poorly understood. The purpose of this study was to explore the mechanisms of endothelial dysfunction in the presence of non-physiologic phosphate levels.We studied the effects of simulated hyper- and hypophosphatemia in human umbilical vein endothelial cells in vitro. We found both simulated hyperphosphatemia and hypophosphatemia decrease eNOS expression and NO production. This was associated with reduced intracellular calcium, increased protein kinase C β2 (PKCβ2), reduced cell viability, and increased apoptosis. While simulated hyperphosphatemia was associated with decreased Akt/p-Akt, Bcl-xl/Bax ratios, NFkB-p65 and p-Erk abundance, simulated hypophosphatemia was associated with increased Akt/p-Akt and Bcl-xl/Bax ratios and p-Mek, p38, and p-p38 abundance.This is the first demonstration of endothelial dysfunction with hypophosphatemia. Our data suggests that both hyperphosphatemia and hypophosphatemia decrease eNOS activity via reduced intracellular calcium and increased PKCβ2. Hyperphosphatemia also appears to reduce eNOS transcription via reduced signaling through PI3K/Akt/NF-kB and MAPK/NF-kB pathways. On the other hand, hypophosphatemia appears to activate these pathways. Our data provides the basis for further studies to elucidate the relationship between altered phosphate homeostasis and cardiovascular disease. As a corollary, our data suggests that the level of phosphate in the culture media, if not in the physiologic range, may inadvertently affect experimental results.

Intense emission peaks of Eu(DBM)3Phen (DBM and Phen are dibenzoylmethane and 1,10-phenanthroline, respectively) in the microcapsules containing molecules of quaternary ammonium chitosan (QACS) and sodium alginate are observed. The microcapsules are assembled by using CaCO3 particles as template cores by the layer-by-layer (LbL) technique. Observation of microcapsules by the fluorescence mode and the transmission mode in the confocal laser scanning microscopy shows that the microcapsules are intact after core decomposition. Fluorescence under ultraviolet irradiation comes directly from the Eu(DBM)3Phen. Homogeneous assembly of Eu(DBM)3Phen can be deduced due to the homogeneous fluorescence of the microcapsules in the fluorescence micrographs. The microcapsules show adherence to solid substrates due to large quantities of hydroxyl groups of QACS. AFM measurements of dried hollow microcapsules with only 4 bilayers of (CS/SA) fabricated with Eu(DBM)3Phen show the intact shell with a thickness of 3.0 nm. Regarding the biocompatible natural polysaccharides and the intense fluorescence emission, the microcapsules in this work might be of great importance in potential application in drug delivery and bioassay.

BackgroundObesity is associated with a higher incidence of atrial fibrillation (AF). Weight reduction improves outcomes in patients known to have AF.ObjectiveThe purpose of this study was to compare the incidence of heart failure (HF) or first-time AF hospitalization in obese patients undergoing bariatric surgery (BAS) vs other abdominal surgeries.MethodsA retrospective cohort study was conducted using linked hospital discharge records from 1994-2014. Obese patients without known AF or atrial flutter (AFL) who had undergone abdominal hernia or laparoscopic cholecystectomy surgery were identified for each case that underwent BAS (2:1). Clinical outcomes were HF, first-time hospitalization for AF, AFL, gastrointestinal bleeding (GIB), and ischemic or hemorrhagic stroke. Outcomes were analyzed using conditional proportional hazard modeling accounting for the competing risk of death, adjusting for demographics and comorbidities.ResultsThere were 1581 BAS cases and 3162 controls (48% age

Background and Purpose- Selection of patients with acute ischemic stroke for endovascular treatment generally relies on dynamic susceptibility contrast magnetic resonance imaging or computed tomography perfusion. Dynamic susceptibility contrast magnetic resonance imaging requires injection of contrast, whereas computed tomography perfusion requires high doses of ionizing radiation. The purpose of this work was to develop and evaluate a deep learning (DL)-based algorithm for assisting the selection of suitable patients with acute ischemic stroke for endovascular treatment based on 3-dimensional pseudo-continuous arterial spin labeling (pCASL). Methods- A total of 167 image sets of 3-dimensional pCASL data from 137 patients with acute ischemic stroke scanned on 1.5T and 3.0T Siemens MR systems were included for neural network training. The concurrently acquired dynamic susceptibility contrast magnetic resonance imaging was used to produce labels of hypoperfused brain regions, analyzed using commercial software. The DL and 6 machine learning (ML) algorithms were trained with 10-fold cross-validation. The eligibility for endovascular treatment was determined retrospectively based on the criteria of perfusion/diffusion mismatch in the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke). The trained DL algorithm was further applied on twelve 3-dimensional pCASL data sets acquired on 1.5T and 3T General Electric MR systems, without fine-tuning of parameters. Results- The DL algorithm can predict the dynamic susceptibility contrast-defined hypoperfusion region in pCASL with a voxel-wise area under the curve of 0.958, while the 6 ML algorithms ranged from 0.897 to 0.933. For retrospective determination for subject-level endovascular treatment eligibility, the DL algorithm achieved an accuracy of 92%, with a sensitivity of 0.89 and specificity of 0.95. When applied to the GE pCASL data, the DL algorithm achieved a voxel-wise area under the curve of 0.94 and a subject-level accuracy of 92% for endovascular treatment eligibility. Conclusions- pCASL perfusion magnetic resonance imaging in conjunction with the DL algorithm provides a promising approach for assisting decision-making for endovascular treatment in patients with acute ischemic stroke.

The purpose of this study was to develop and evaluate a scoring system for assessing reperfusion status based on arterial spin labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) patients receiving thrombolysis and/or endovascular treatment. Pseudo-continuous ASL with background suppressed 3D GRASE was acquired along with DWI in 90 patients within 24 h post-treatment. An automatic reperfusion scoring system (auto-RPS) was devised based on the Alberta Stroke Program Early CT Score (ASPECTS) template, and compared with manual RPS and DWI-ASPECTS. TICI (thrombolysis in cerebral infarction) scores were graded in 48 patients who received endovascular treatment. Favorable outcomes were defined by a modified Rankin Scale score of 0-2 at three months. Auto-RPS was positively correlated with DWI-ASPECTS (ρ = 0.6, P

PurposeDifferentiating WHO grade I-III of meningioma by non-invasive imaging is challenging. This study investigated the potential of MR arterial spin labeling (ASL) to establish tumor grade in meningioma patients.Material and methodsPseudo-continuous ASL with 3D background suppressed gradient and spin echo (GRASE) was acquired on 54 patients with newly diagnosed or recurrent intracranial meningioma. Perfusion patterns characterized in CBF color maps were independently evaluated by three neuroradiologists blinded to patient history, and correlated with tumor grade from histo-pathological review.ResultsThree perfusion patterns could be discerned by visual evaluation of CBF maps. Pattern 1 consisted of homogeneous hyper-perfusion of the entire tumor; pattern 2 demonstrated heterogeneous hyper-perfusion; pattern 3 showed no substantial hyper-perfusion. Evaluation of the perfusion patterns was highly concordant among the three readers (Kendall W=0.9458, P

A computational method, based on ℓ1-minimization, is proposed for the problem of link flow correction, when the available traffic flow data on many links in a road network are inconsistent with respect to the flow conservation law. Without extra information, the problem is generally ill-posed when a large portion of the link sensors are unhealthy. It is possible, however, to correct the corrupted link flows accurately with the proposed method under a recoverability condition if there are only a few bad sensors which are located at certain links. We analytically identify the links that are robust to miscounts and relate them to the geometric structure of the traffic network by introducing the recoverability concept and an algorithm for computing it. The recoverability condition for corrupted links is simply the associated recoverability being greater than 1. In a more realistic setting, besides the unhealthy link sensors, small measurement noises may be present at the other sensors. Under the same recoverability condition, our method guarantees to give an estimated traffic flow fairly close to the ground-truth data and leads to a bound for the correction error. Both synthetic and real-world examples are provided to demonstrate the effectiveness of the proposed method.

As a common industrial valve solution in slurry pipeline systems, Y-type slurry valves must be designed with properly shaped valve seat sealing rings to alleviate particle erosion and keep the valve operating in optimal condition. In this study, we investigate four different valve seat shapes with varying inner angles to understand the effect of the seat structure on particle erosion in Y-type slurry valves. We conducted computation fluid dynamics discrete element method simulations to analyze the impact of different valve seat shapes on the characteristics of particle-liquid two-phase flows and erosion. We also performed a detailed analysis of velocity and pressure distributions for liquid phase and particle velocity distributions as well as surface erosion on key valve components. We observed the primary erosion areas to be the back surface of the valve body, the inner surface of the valve seat, and the front surface of the valve disc, and as a result, we investigated the erosion distribution in these areas with different valve seat structures. Our simulation results indicate that the variation in particle diameter and the inner angle of the valve seat sealing ring have significant impacts on erosion in the studied areas. [ABSTRACT FROM AUTHOR]

Given a set of mixtures, blind source separation attempts to retrieve the source signals without or with very little information of the mixing process. We present a geometric approach for blind separation of nonnegative linear mixtures termed facet component analysis. The approach is based on facet identification of the underlying cone structure of the data. Earlier works focus on recovering the cone by locating its vertices (vertex component analysis) based on a mutual sparsity condition which requires each source signal to possess a stand-alone peak in its spectrum. We formulate alternative conditions so that enough data points fall on the facets of a cone instead of accumulating around the vertices. To find a regime of unique solvability, we make use of both geometric and density properties of the data points and develop an efficient facet identification method by combining data classification and linear regression. For noisy data, total variation technique may be employed. We show computational results on nuclear magnetic resonance spectroscopic data to substantiate our method.

The purpose of this study was to investigate the relationship between hyperperfusion and hemorrhagic transformation (HT) in acute ischemic stroke (AIS). Pseudo-continuous arterial spin labeling (ASL) with background suppressed 3D GRASE was performed during routine clinical magnetic resonance imaging (MRI) on AIS patients at various time points. Arterial spin labeling cerebral blood flow (CBF) maps were visually inspected for the presence of hyperperfusion. Hemorrhagic transformation was followed during hospitalization and was graded on gradient recalled echo (GRE) scans into hemorrhagic infarction (HI) and parenchymal hematoma (PH). A total of 361 ASL scans were collected from 221 consecutive patients with middle cerebral artery stroke from May 2010 to September 2013. Hyperperfusion was more frequently detected posttreatment (odds ratio (OR) = 4.8, 95% confidence interval (CI) 2.5 to 8.9, P < 0.001) and with high National Institutes of Health Stroke Scale (NIHSS) scores at admission (P

Crescentic glomerulonephritis (GN) is the most severe form of GN and is associated with significant morbidity and mortality despite aggressive immunotherapy with steroids, cytotoxic drugs, and plasmapheresis. We examined the therapeutic efficacy of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG, 50 mg/kg BW/day x3 weeks), a potent anti-inflammatory and anti-oxidant agent, on experimental crescentic GN induced in 129/svJ mice by administration of rabbit anti-mouse glomerular basement membrane sera. Routine histology and key molecules involved in inflammatory and redox signaling were studied. EGCG treatment significantly reduced mortality, decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. The improvements in renal function and histology were accompanied by the restoration of Nrf2 signaling (which was impaired in vehicle-treated mice) as shown by increased nuclear translocation of Nrf2 and cytoplasmic glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione peroxidase. EGCG-treated mice also showed reduction in p-Akt, p-JNK, p-ERK1/2 and p-P38 as well as restoration of PPARγ and SIRT1 levels. Lower dose of EGCG (25 mg/kg BW/day x2 weeks) treatment also significantly decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. Thus, our data illustrate the efficacy of EGCG in reversing the progression of crescentic GN in mice by targeting multiple signaling and inflammatory pathways as well as countering oxidative stress.

Crescentic glomerulonephritis (GN) is the most severe form of GN and is associated with significant morbidity and mortality despite aggressive immunotherapy with steroids, cytotoxic drugs, and plasmapheresis. We examined the therapeutic efficacy of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG, 50 mg/kg BW/day x3 weeks), a potent anti-inflammatory and anti-oxidant agent, on experimental crescentic GN induced in 129/svJ mice by administration of rabbit anti-mouse glomerular basement membrane sera. Routine histology and key molecules involved in inflammatory and redox signaling were studied. EGCG treatment significantly reduced mortality, decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. The improvements in renal function and histology were accompanied by the restoration of Nrf2 signaling (which was impaired in vehicle-treated mice) as shown by increased nuclear translocation of Nrf2 and cytoplasmic glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione peroxidase. EGCG-treated mice also showed reduction in p-Akt, p-JNK, p-ERK1/2 and p-P38 as well as restoration of PPARγ and SIRT1 levels. Lower dose of EGCG (25 mg/kg BW/day x2 weeks) treatment also significantly decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. Thus, our data illustrate the efficacy of EGCG in reversing the progression of crescentic GN in mice by targeting multiple signaling and inflammatory pathways as well as countering oxidative stress.