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Dengming Lai,1,* Kun Zhu,2,* Sisi Li,3,* Yi Xiao,1 Qi Xu,4 Yisheng Sun,5 Pingping Yao,5 Daqing Ma,6,7 Qiang Shu7 1Department of Neonatal Surgery, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 2Department of Pathology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 3School of Medicine, Hangzhou City University, Hangzhou, People’s Republic of China; 4School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, People’s Republic of China; 5Key Laboratory of Vaccine, Prevention and Control of Infectious Disease of Zhejiang Province, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, People’s Republic of China; 6Division of Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK; 7Department of Thoracic and Cardiovascular Surgery, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiang Shu, Department of Thoracic and Cardiovascular Surgery, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310052, People’s Republic of China, Tel +86-13906500193, Email shuqiang@zju.edu.cn Dengming Lai, Department of Neonatal Surgery, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310052, People’s Republic of China, Tel +86-13567164728, Email dengming_lai@zju.edu.cnBackground: SARS-CoV-2-induced acute lung injury but its nucleocapsid (N) and/or Spike (S) protein involvements in the disease pathology remain elusive.Methods: In vitro, the cultured THP-1 macrophages were stimulated with alive SARS-CoV-2 virus at different loading dose, N protein or S protein with/without TICAM2-siRNA, TIRAP-siRNA or MyD88-siRNA. The TICAM2, TIRAP and MyD88 expression in the THP-1 cells after N protein stimulation were determined. In vivo, naïve mice or mice with depletion macrophages were injected with N protein or dead SARS-CoV-2. The macrophages in the lung were analyzed with flow cytometry, and lung sections were stained with H&E or immunohistochemistry. Culture supernatants and serum were harvested for cytokines measurements with cytometric bead array.Results: Alive SARS-CoV-2 virus or N protein but not S protein induced high cytokine releases from macrophages in a time or virus loading dependent manner. MyD88 and TIRAP but not TICAM2 were highly involved in macrophage activation triggered by N protein whilst both inhibited with siRNA decreased inflammatory responses. Moreover, N protein and dead SARS-CoV-2 caused systemic inflammation, macrophage accumulation and acute lung injury in mice. Macrophage depletion in mice decreased cytokines in response to N protein.Conclusion: SARS-CoV-2 and its N protein but not S protein induced acute lung injury and systemic inflammation, which was closely related to macrophage activation, infiltration and release cytokines.Keywords: SARS-CoV-2, S protein, N protein, macrophage, cytokine, acute lung injury

Platinum-containing stents are commonly used in humans with hypercholesterolemia, whereas preclinical stent evaluation has commonly been performed in healthy animal models, providing inadequate information about stent performance under hypercholesterolemic conditions. In this investigation, we used an ApoE−/− mouse model to test the impact of hypercholesterolemia on neointima formation on platinum-containing implants. We implanted 125 μm diameter platinum wires into the abdominal aortas of ApoE−/− and ApoE+/+ mice for 6 months, followed by histological and immunofluorescence examination of neointimal size and composition. It was found that ApoE−/− mice developed neointimas with four times larger area and ten times greater thickness than ApoE+/+ counterparts. Neointimas developed in the ApoE−/− mice also contained higher amounts of lipids quantified as having 370 times more coverage compared to ApoE+/+, a 3-fold increase in SMCs, and a 22-fold increase in macrophages. A confluent endothelium had regenerated in both mouse strains. The ApoE−/− mice experienced luminal reductions more closely resembling clinically relevant restenosis in humans. Overall, the response to platinum arterial implants was highly dependent upon the atherogenic environment.

Abstract The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia–reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3−/− mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3.

Qing Shu,1,* Qingqing Fan,1,* Bingzhu Hua,2 Hang Liu,1 Shiying Wang,2 Yunxing Liu,1 Yao Yao,1 Han Xie,1 Weihong Ge1 1Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China; 2Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihong GeDepartment of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of ChinaEmail 6221230@sina.comIntroduction: Mycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.Methods: This study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 − 118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 − 106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.Results: SLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 − 106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).Conclusion: For Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 − 106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.Keywords: mycophenolic acid, gene polymorphisms, adverse drug reactions, infections, anemia, autoimmune diseases

Elastic laminae, an elastin-based, layered extracellular matrix structure in the media of arteries, can inhibit leukocyte adhesion and vascular smooth muscle cell proliferation and migration, exhibiting anti-inflammatory and anti-thrombogenic properties. These properties prevent inflammatory and thrombogenic activities in the arterial media, constituting a mechanism for the maintenance of the structural integrity of the arterial wall in vascular disorders. The biological basis for these properties is the elastin-induced activation of inhibitory signaling pathways, involving the inhibitory cell receptor signal regulatory protein α (SIRPα) and Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1). The activation of these molecules causes deactivation of cell adhesion- and proliferation-regulatory signaling mechanisms. Given such anti-inflammatory and anti-thrombogenic properties, elastic laminae and elastin-based materials have potential for use in vascular reconstruction.

Liumei Shou,1,2,* Tianyu Shao,2,* Fangmin Zhao,2 Shuyi Chen,1 Qunwei Chen,1 Qijin Shu1 1Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2The First Clinical Medicine College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qijin ShuDepartment of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, People’s Republic of ChinaTel +86-13605706566Fax +86-571-6707-2196Email shuqjhz@163.comBackground: Multi-kinase inhibitors (MKIs) treatment plays an important role in cancer therapy, but still suffers from a high incidence of hand–foot skin reaction (HFSR), leading to MKIs dose modification or termination. Thus, there is a high need for therapeutic strategy for HFSR.Patients and Methods: This prospective analysis included twenty patients, who were continuously administered with MKIs treatment and presented with a grade 3 HFSR during January 2018 to December 2019. All the patients were treated with the Shouzu Ning Decoction (SND) twice a day, in addition to the MKIs treatment. Grading of HFSR was assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Pain intensity was evaluated using the numerical rating scale (NRS). Quality of life was assessed using the Hand–Foot Quality of Life Scale (HF-QoLS).Results: The median time from MKIs initiation to onset of grade 3 HFSR was 26.2 days. Following the SND treatment, seventeen (17/20) patients displayed grade 2 HFSR with a median time of 5.1 days. Among whom, seven (7/17) finally transformed to grade 1 with a median time of 9.9 days. While all of the grade 1 patients (7/7) had local recurrence, and retreatment of the SND was effective. In addition, after the SND treatment, the score of NRS and HF-QoLS decreased to 1.60 ± 1.14 (P < 0.01) and 26.75 ± 11.76 (P < 0.01), respectively.Conclusion: The SND treatment could alleviate symptoms, relieve pain and improve quality of life in HFSR patients. The SND treatment was proved to be an effective and well-tolerated treatment for MKIs-associated grade 3 HFSR patients for the first time. Indeed, further randomized controlled trails with large-scale, multi-center are require to fully determine the clinical application of the SND in MKIs-associated HFSR.Keywords: hand-foot skin reaction, multi-kinase inhibitors, Shouzu Ning Decoction, efficacy, safety

Keping Cheng,1 Miao He,2 Qin Shu,3 Ming Wu,3 Cuifang Chen,2 Yulei Xue4 1Department of Infection Management, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People’s Republic of China; 2Department of Public Health, Huangshi Central Hospital, Huangshi 435000, People’s Republic of China; 3Department of Infection Prevention and Control, Huangshi Traditional Chinese Medicine Hospital, Huangshi 435004, Republic of China; 4Department of Infectious Diseases, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, People’s Republic of ChinaCorrespondence: Keping ChengZhongda Hospital Affiliated to Southeast University, No. 87 Dingjiaqiao, Nanjing, People’s Republic of ChinaEmail chengkeping@sina.comBackground: Infection surveillance and risk factor analysis are among the most important prerequisites for the prevention and treatment of nosocomial bacteria infections, which are the demands for both infected and non-infected patients.Purpose: To explore the risk factors for nosocomial bacterial infection of patients with COVID-19, and further to provide a theoretical basis for scientific prevention and control of nosocomial bacterial infection.Methods: Between 10 January 2020 and 9 March 2020, we collected data of 212 patients with COVID-19 and then explored the influence of age, gender, length of stay, use of ventilator, urinary catheterization, central venous catheterization, white blood cell (WBC) count and procalcitonin on the nosocomial bacterial infection of patients with COVID-19 by a retrospective study.Results: There were 212 confirmed cases of COVID-19, of which 31 cases had nosocomial bacterial infections, with an incidence of 14.62%. The most common types of nosocomial bacterial infections were lower respiratory tract (12 cases, 38.71%), which was the most frequent site, followed by urinary tract (10 cases, 32.26%), blood stream (7 cases, 22.58%), upper respiratory tract (1 case, 3.23%) and gastrointestinal tract infection (1 case, 3.23%). The incidence of nosocomial bacterial infection was significantly correlated with age, arteriovenous catheterization, urinary catheterization, WBC count and procalcitonin. Moreover, multivariate analysis confirmed that WBC (OR 8.38, 95% CI 1.07 to 65.55), procalcitonin (OR 4.92, 95% CI 1.39 to 17.33) and urinary catheterization (OR 25.38, 95% CI 5.09 to 126.53) were independent risk factors for the nosocomial bacterial infection of patients with COVID-19.Conclusion: Understanding the risk factors for nosocomial bacterial infection of patients with COVID-19 and strengthening the monitoring of various susceptible factors are helpful to control the occurrence of nosocomial bacterial infection in the COVID-19 isolation wards.Keywords: COVID-19, nosocomial bacterial infection, risk factor

Hua Fan,1,* Damiao Li,1,* Xinlei Guan,2,* Yanhui Yang,1 Junqiang Yan,1 Jian Shi,1 Ranran Ma,3 Qing Shu3 1The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471000, People’s Republic of China; 2Department of Pharmacy, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 3Department of Pharmacy, Ninth Hospital of Xi’an, Affiliated to Medical College of Xi’an Jiaotong University, Xi’an 710054, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua FanThe First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24, Jinghua Road, Jianxi District, Luoyang 471000, Henan Province, People’s Republic of ChinaTel +86-18538825892Email fanhua19851229@126.comQing ShuDepartment of Pharmacy, Ninth Hospital of Xi’an, Affiliated to Medical College of Xi’an Jiaotong University, No. 151, Eastern Section of South 2nd Ring Road, Xi’an 710054, Shaanxi Province, People’s Republic of ChinaTel +86-18627121873Email shuqinglwz@163.comIntroduction: Demyelination causes neurological deficits involving visual, motor, sensory symptoms. Deregulation of several enzymes has been identified in demyelination, which holds potential for the development of treatment strategies for demyelination. However, the specific effect of methionine sulfoxide reductase A (MsrA) on demyelination remains unclear. Hence, this study aims to explore the effect of MsrA on oxidative stress and inflammatory response of microglia in demyelination.Methods: Initially, we established a mouse model with demyelination induced by cuprizone and a cell model provoked by lipopolysaccharide (LPS). The expression of MsrA in wild-type (WT) and MsrA-knockout (MsrA-/-) mice were determined by RT-qPCR and Western blot analysis. In order to further explore the function of MsrA on inflammatory response, and oxidative stress in demyelination, we detected the expression of microglia marker Iba1, inflammatory factors TNF-α and IL-1β and intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, as well as expression of the NOX2-MAPKs/NF-κB signaling pathway-related genes in MsrA-/- mice and LPS-induced microglia following different treatments.Results: MsrA expression was downregulated in MsrA-/- mice. MsrA silencing was shown to produce severely injured motor coordination, increased expressions of Iba1, TNF-α, IL-1β, ROS and NOX2, and extent of ERK, p38, IκBα, and p65 phosphorylation, but reduced SOD activity. Conjointly, our study suggests that Tat-MsrA fusion protein can prevent the cellular inflammatory response and subsequent demyelination through negative regulation of the NOX2-MAPKs/NF-κB signaling pathway.Conclusion: Our data provide a profound insight on the role of endogenous antioxidative defense systems such as MsrA in controlling microglial function.Keywords: demyelination, MsrA, NOX2-MAPKs/NF-κB signaling pathway, microglia, oxidative stress, inflammatory activation

To explore the effects of TiO2 and/or B2O3 on crystallization of the glassy fluoride-free slag film near the copper mould, the crystallization characteristics of glassy fluoride-free mold fluxes with fluoride being substituted by TiO2 and/or B2O3 were investigated using X- ray diffraction (XRD), scanning electron microscope (SEM) and differential thermal analysis (DTA) techniques. The glass forming ability index (Kgl) of the glassy fluoride-free mold fluxes was studied using Hruby’s method. The XRD and SEM analysis show that Ca2Al2SiO7, CaTiO3 and CaSiO3 are the dominant crystals of this fluoride-free mold fluxes system. With the content of TiO2 increasing from 0 to 7%, the crystallization of Ca2Al2SiO7 and CaSiO3 are inhibited and the formation of CaTiO3 is also weak, so crystallization tendency of the glassy fluoride-free mold fluxes weakens. But as TiO2 content reaches 10%, the crystallization tendency strengthens because of the strong crystallization of CaTiO3. An increase of B2O3 inhibits the crystallization of calcium silicate, so it weakens the crystallization tendency of the glassy fluoride-free mold fluxes. The crystallization processes of the studied fluoride-free mold fluxes correspond to the surface crystallization mechanism. This research provides important reference for further investigation on the heat transfer behavior of the TiO2 and B2O3-bearing slag between copper mould and slab to evaluate the feasibility of B2O3 and TiO2- bearing fluoride-free mold fluxes.

Motivated by the recent development of advanced experimental techniques in molecular biology, this paper focuses on the study of the dynamical properties of a two-gene regulatory network. A mathematical model for a two-gene regulatory network is derived and several of their properties are analyzed. Due to the presence of mixed continuous/discrete dynamics and hysteresis, we employ hybrid systems models to capture the dynamics of the system. The proposed model incorporates binary hysteresis with different thresholds capturing the interaction between the genes. We analyze properties of the solutions and asymptotic stability of equilibria in the system as a function of their parameters. As a difference to previous efforts employing piecewise-linear models, the analysis of our hybrid system model reveals the presence of limit cycles for a certain range of parameters, a behavior that is associated with the presence of hysteresis. The set of points defining the limit cycle is characterized and its asymptotic stability properties are studied. Furthermore, we determine conditions under which the stability properties of the limit cycle are robust to changes of parameters. Numerical simulations are presented to illustrate the findings. © 2014 Elsevier Inc.

Kankan Yang,1,* Bing Jiang,1,* Yecai Lu,1,* Qingbing Shu,1 Pan Zhai,1 Qiaoming Zhi,2 Qixin Li1 1Department of Gastrointestinal Surgery, Chaohu Hospital of Anhui Medical University, Hefei 238000, Anhui, China; 2Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China *These authors contributed equally to this work Purpose: Our previous study proved that FOXM1 regulates colorectal cancer (CRC) cell metastasis through epithelial–mesenchymal transition program. The aim of this study is to further explore the underlying mechanism of FOXM1 in CRC.Materials and methods: In this study, we detected the mRNA and protein expressions of FOXM1 and β-catenin in CRC tissues and their corresponding normal-appearing tissues (NATs) by quantitative reverse transcription-PCR and western blot analysis, respectively. Then the potential link between FOXM1 and β-catenin in CRC tissues was analyzed. Furthermore, we systematically analyzed the biological functions of FOXM1 in CRC cells after reconstitution of FOXM1 expression in vitro. Moreover, the mechanism of FOXM1-promoted CRC progression by improving β-catenin nuclear translocation was also discussed.Results: Our data demonstrated that FOXM1 and β-catenin were upregulated in CRC tissues compared with the corresponding NATs (P

Qian Zhang, Qiuhong Shu, Liyong Wu, Ran Zhang, Yong Meng Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, People’s Republic of China Objective: The objective of the study was to evaluate the dose-related influence of metoprolol on cardiac performance, motor function, quality of life (QoL), and mental status in Chinese patients with chronic heart failure (CHF).Patients and methods: This was a prospectively designed single-center study which enrolled CHF patients with resting heart rate (HR) >80 bpm belonging to the New York Heart Association (NYHA) III/IV functional classification. Patients were initiated with 12.5 mg of metoprolol, and every second week, the dose was escalated until the target HR level (60–70 bpm) was achieved during the follow-up at 1st, 3rd, 6th, and 12th months. Patients were divided into two groups depending on the doses administered: 47.5 mg (n=37) and 118.75 mg (n=74), respectively, for comparison in terms of change in cardiac function, motor function, QoL, and mental status.Results: Among the 111 patients with CHF, no significant difference was shown between the two doses administered. Irrespective of the dose, the cardiac performance, motor function, QoL, and anxiety improved and there was an increase in depression, whereas the effect on burnout, calculated as Copenhagen Burnout Inventory (CBI), equally was insignificant throughout the 1-year follow-up period in both the CHF patient groups.Conclusion: Lower dose of metoprolol (47.5 mg) is as effective as higher dose (118.75 mg) in Chinese population with CHF to improve the cardiac function, motor function, QoL, and mental status. Keywords: metoprolol, heart rate, motor function, quality of life, mental status, ejection fraction

While abnormal muscle tone has been observed in people with stroke, how these changes in muscle tension affect sarcomere morphology remains unclear. The purpose of this study was to examine time-course changes in passive muscle fiber tension and sarcomeric adaptation to these changes post-ischemic stroke in a mouse model by using a novel in-vivo force microscope. Twenty-one mice were evenly divided into three groups based on the time point of testing: 3 days (D3), 10 days (D10), and 20 days (D20) following right middle cerebral artery ligation. At each testing time, the muscle length, width, and estimated volume of the isolated soleus muscle were recorded, subsequently followed by in-vivo muscle tension and sarcomere length measurement. The mass of the soleus muscle was measured at the end of testing to calculate muscle density. Two-way ANOVA with repeated measures was used to examine the differences in each of the dependent variable among the three time-point groups and between the two legs. The passive muscle stress of the impaired limbs in the D3 group (27.65 ± 8.37 kPa) was significantly lower than the less involved limbs (42.03 ± 18.61 kPa; p = 0.05) and the impaired limbs of the D10 (48.92 ± 14.73; p = 0.03) and D20 (53.28 ± 20.54 kPa; p = 0.01) groups. The soleus muscle density of the impaired limbs in the D3 group (0.69 ± 0.12 g/cm3) was significantly lower than the less involved limbs (0.80 ± 0.09 g/cm3; p = 0.04) and the impaired limbs of the D10 (0.87 ± 0.12 g/cm3; p = 0.02) and D20 (1.00 ± 0.14 g/cm3; p < 0.01) groups. The D3 group had a shorter sarcomere length (2.55 ± 0.26 μm) than the D10 (2.83 ± 0.20 μm; p = 0.03) and D20 group (2.81 ± 0.15 μm; p = 0.04). These results suggest that, while ischemic stroke may cause considerable changes in muscle tension and stress, sarcomere additions under increased mechanical loadings may be absent or disrupted post-stroke, which may contribute to muscle spasticity and/or joint contracture commonly observed in patients following stroke.

Myopia in human and animals is caused by the axial elongation of the eye and is closely linked to the thinning of the sclera which supports the eye tissue. This thinning has been correlated with the overproduction of matrix metalloproteinase (MMP-2), an enzyme that degrades the collagen structure of the sclera. In this short paper, we propose a descriptive model of a regulatory network with hysteresis, which seems necessary for creating oscillatory behavior in the hybrid model between MMP-2, MT1-MMP and TIMP-2. Numerical results provide insight on the type of equilibria present in the system.

A mathematical model for a two-gene regulatory network is derived and several of its properties are analyzed. Due to the presence of continuous dynamics and binary hysteresis, we propose a hybrid system model. Binary hysteresis with different thresholds captures the interaction between the genes. We analyze properties of the solutions and asymptotic stability of equilibria in the system as a function of its parameters. Our analysis reveals the presence of limit cycles for a certain range of parameters, a behavior that is associated with the presence of binary hysteresis. The set of points defining the limit cycle is characterized and its asymptotic stability properties are studied. Numerical simulations are presented to illustrate some of the results. ©2013 IEEE.

Selinexor is a selective inhibitor of nuclear export with anti-cancer properties. We performed a phase I study to determine the safety and maximum tolerated dose of selinexor when combined with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (DICE) in relapsed/refractory T-cell lymphoma (TCL) and natural-killer/T-cell lymphoma (NKTL). Patients with relapsed/refractory TCL and NKTL were treated with standard dose ICE, dexamethasone 20 mg on days 3 to 7, and escalating doses of oral selinexor on days 3, 5 and 7 in a 3+3 design. Dose levels (DL) 1, 2 and 3 were 40, 60 and 80 mg, respectively. Eleven patients with a median age of 60 years were enrolled; six at DL1 and five at DL2. Patients had received a median of two (range, 1-4) prior lines of treatment and seven had primary refractory disease at entry into the study. Patients received a median of three cycles (range, 1-6) of selinexor-DICE. The most common grade 1 or 2 toxicities included nausea (64%), fatigue (55%), and anorexia (45%) and the most common grade 3 or 4 toxicities included thrombocytopenia (82%), anemia (82%), neutropenia (73%), and hyponatremia (73%). Two patients developed dose-limiting toxicities at DL2 and one at DL1. Five patients discontinued treatment for reasons other than disease progression or lack of response. Of the ten evaluable patients, the overall and complete response rates were 91% and 82%, respectively. The maximum tolerated dose of selinexor was 40 mg when combined with DICE. The combination showed promising complete response rates in patients with relapsed/refractory TCL and NKTL but was poorly tolerated. (clinicaltrials. gov identifier: NCT03212937).

Abstract Background Frequent use (FU) of hospital services impacts on patients and health service expenditure. Studies examining FU in emergency departments and inpatient settings have found heterogeneity and the need to differentiate between potentially preventable FU and that associated with ongoing management of complex conditions. Psychosocial factors have often been reported as underpinning or exacerbating the phenomena. Most FU studies have been limited by time, to a single study site, or restricted to specific diagnoses or patient groups. This study provides a comprehensive description of adult patient characteristics, conditions and risk factors associated with FU, based on admissions to the five public hospitals in the Northern Territory (NT) of Australia over a nine year period. The study population is distinctive comprising both Aboriginal and non-Aboriginal patients. Methods Data on all inpatient episodes in NT public hospitals between 2005 and 2013 was analysed to identify patients with any FU (four or more episodes within any 12-month period) and measure FU duration (number of FU years) and intensity (mean number of episodes per FU year). Pregnancy, alcohol-related and mental health condition flags were assigned to patients with any episode with relevant diagnoses during the study period. Multivariate analysis was used to assess factors associated with any FU, FU duration and FU intensity, separately for Aboriginal and non-Aboriginal patients. Results Of people with any inpatient episodes during the study period, 13.6% were frequent users (Aboriginal 22%, non-Aboriginal 10%) accounting for 46.6% of all episodes. 73% of frequent users had only one FU year. Any FU and increased FU duration were more common among individuals who were: Aboriginal; older; female; and those with a pregnancy, alcohol or mental health flag. Having two or more alcohol-related episodes in the nine-year period was strongly associated with any FU for both Aboriginal (odds ratio 8.9, 95% CI. 8.20–9.66) and non-Aboriginal patients (11.5, 9.92–13.26). Conclusion For many people, frequent inpatient treatment is necessary and unavoidable. This study suggests that damage arising from excessive alcohol consumption (either personal or by others) is the single most avoidable factor associated with FU, particularly for Aboriginal people.