bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatially selective myosin regulatory light chain regulation is absent in dedifferentiated vascular smooth muscle cells but is partially induced by fibronectin and Klf4
Authors: Matsui Tsubasa S. , Deguchi Shinji
Published: January 2019

The phosphorylation state of myosin regulatory light chain (MRLC) is central to the regulation of contractility that impacts cellular homeostasis and fate decisions. Rho-kinase (ROCK) and myosin light chain kinase (MLCK) are major kinases for MRLC documented to selectively regulate MRLC in a subcellular position-specific manner; specifically, MLCK in some nonmuscle cell types works in the cell periphery to promote migration, while ROCK does so at the central region to sustain contractility. However, it remains unclear whether or not the spatially selective regulation of the MRLC kinases is universally present in other cell types, including dedifferentiated vascular smooth muscle cells (SMCs). Here, we demonstrate the absence of the spatial regulation in dedifferentiated SMCs using both cell lines and primary cells. Thus, our work is distinct from previous reports on cells with migratory potential. We also observed that the spatial regulation is partly induced upon fibronectin stimulation and Krüppel-like factor 4 overexpression. To find clues to the mechanism, we reveal how the phosphorylation state of MRLC is determined within dedifferentiated A7r5 SMCs under the enzymatic competition among three major regulators ROCK, MLCK, and MRLC phosphatase (MLCP). We show that ROCK, but not MLCK, predominantly regulates the MRLC phosphorylation in a manner distinct from previous in vitro-based and in silico-based reports. In this ROCK-dominating cellular system, the contractility at physiological conditions was regulated at the level of MRLC diphosphorylation, because its monophosphorylation is already saturated. Thus, the present study provides insights into the molecular basis underlying the absence of spatial MRLC regulation in dedifferentiated SMCs.
Lipoprotein lipase in mouse kidney: effects of nutritional status and high-fat diet
Authors: Nyrén Rakel , Makoveichuk Elena , Malla Sandhya , Kersten Sander , Nilsson Stefan K. , Ericsson Madelene , Olivecrona Gunilla
Published: January 2019

Activity of lipoprotein lipase (LPL) is high in mouse kidney, but the reason is poorly understood. The aim was to characterize localization, regulation, and function of LPL in kidney of C57BL/6J mice. We found LPL mainly in proximal tubules, localized inside the tubular epithelial cells, under all conditions studied. In fed mice, some LPL colocalized with the endothelial markers CD31 and GPIHBP1 and could be removed by perfusion with heparin, indicating a vascular location. The role of angiopoietin-like protein 4 (ANGPTL4) for nutritional modulation of LPL activity was studied in wild-type and Angptl4−/−mice. In Angptl4−/−mice, kidney LPL activity remained high in fasted animals, indicating that ANGPTL4 is involved in suppression of LPL activity on fasting, like in adipose tissue. The amount of ANGPTL4 protein in kidney was low, and the protein appeared smaller in size, compared with ANGPTL4 in heart and adipose tissue. To study the influence of obesity, mice were challenged with high-fat diet for 22 wk, and LPL was studied after an overnight fast compared with fasted mice given food for 3 h. High-fat diet caused blunting of the normal adaptation of LPL activity to feeding/fasting in adipose tissue, but in kidneys this adaptation was lost only in male mice. LPL activity increases to high levels in mouse kidney after feeding, but as no difference in uptake of chylomicron triglycerides in kidneys is found between fasted and fed states, our data confirm that LPL appears to have a minor role for lipid uptake in this organ.
Estrogen-related receptor-α mediates puromycin aminonucleoside-induced mesangial cell apoptosis and inflammatory injury
Authors: Gong Wei , Song Jiayu , Chen Xi , Li Shuzhen , Yu Jing , Xia Weiwei , Ding Guixia , Zhang Yue , Jia Zhanjun , Zhang Aihua , Huang Songming
Published: January 2019

Glomerular diseases are the leading cause of chronic kidney disease, and mesangial cells (MCs) have been demonstrated to be involved in the pathogenesis. Puromycin aminonucleoside (PAN) is a nephrotoxic drug that induces glomerular injury with elusive mechanisms. The present study was undertaken to investigate the role of PAN in MC apoptosis, as well as the underlying mechanism. Here we found that PAN induced MC apoptosis accompanied by declined cell viability and enhanced inflammatory response. The apoptosis was further evidenced by increments of apoptosis regulator BAX (BAX) and caspase-3 expression. In line with the apoptotic response in MCs following PAN treatment, we also found a remarkable induction of estrogen-related receptor-α (ERRα), an orphan nuclear receptor, at both mRNA and protein levels. Interestingly, ERRα silencing by an siRNA approach resulted in an attenuation of the apoptosis and inflammatory response caused by PAN. More importantly, overexpression of ERRα in MCs significantly triggered MC apoptosis in line with increased BAX and caspase-3 expression. In PAN-treated MCs, ERRα overexpression further aggravated PAN-induced apoptosis. In agreement with the in vitro study, we also observed increased ERRα expression in line with enhanced apoptotic response in renal cortex from PAN-treated rats. These data suggest a detrimental effect of ERRα on PAN-induced MC apoptosis and inflammatory response, which could help us to better understand the pathogenic mechanism of MC injury in PAN nephropathy.
Improved Chicken Swarm Algorithms Based on Chaos Theory and Its Application in Wind Power Interval Prediction
Authors: Wang Bing , Li Wei , Chen Xianhui , Chen Haohao
Published: January 2019

Probabilistic interval prediction can be used to quantitatively analyse the uncertainty of wind energy. In this paper, a wind power interval prediction model based on chaotic chicken swarm optimization and extreme learning machine (CCSO‐ELM) is proposed. Traditional optimization has limitations of low population diversity and a tendency to easily fall into local minima. To address these limitations, chaos theory is adopted in the chicken swarm optimization (CSO), which improves its performance and efficiency. In addition, the traditional cost function does not reflect the deviation degree of off‐interval points; hence, an evaluation index considering the relative deviation of off‐interval points is proposed in this paper. Finally, the new cost function is taken as the fitness function, the output layer weight of ELM is optimized using CCSO, and the lower upper bound estimation (LUBE) is adopted to output the prediction interval directly. The simulation result shows that the proposed method can effectively reduce the average bandwidth, improve the quality of interval prediction, and guarantee the interval coverage.
Estimating the Force of Infection with Helicobacter pylori in Japan
Authors: Kayano Taishi , Lee Ki-Deok , Nishiura Hiroshi
Published: January 2019

Background. Although the seroprevalence against Helicobacter pylori (H. pylori) in Japan has declined over the birth year, Japanese people have yet exhibited a relatively high risk of gastric cancer. The present study employed mathematical models to estimate the time- and age-dependent force of infection with H. pylori in Japan, predicting the future seroprevalence by time and age. Methods. We investigated the published seroprevalence data against H. pylori in Japan from 1980–2018. Solving the McKendrick partial differential equation model, the seroprevalence was modeled as a function of survey year and age. Maximum likelihood estimation was conducted to estimate parameters governing the time- and age-dependent force of infection. Results. Among all fitted models, the time-dependent and age-independent model with an exponentially decaying force of infection over years was most favored. Fitted models indicated that the force of infection started to decrease during and/or shortly after the World War II. Using the parameterized model, the predicted fraction seropositive at the age of 40 years in 2018 was 0.22, but it is expected to decrease to 0.13 in 2030 and 0.05 in 2050, respectively. Conclusion. The time dependence was consistent with the decline in the force of infection as a function of the birth year. The force of infection has continuously and greatly declined over time, implying the diminished transmission of H. pylori through the time course and small chance of persistence. These findings are critical to anticipate the future decline in gastric cancer incidence.
Domestic Horse Bite: An Unusual Etiology of Crush Injury of the Fourth Finger—How to Manage?
Authors: Elghoul Naoufal , Jalal Youssef , Bouya Ayoub , Zine Ali , Jaafar Abdeloihab
Published: January 2019

Almost 2% of all emergency admissions involve an animal bite. While horses bite humans very rarely, their bites are mostly associated with fatalities. Herein, we report the case of a 23-year old bitten by a domestic horse causing a crush injury to his fourth finger with fracture dislocation of the proximal interphalangeal joint. The patient benefited upon arrival at the emergency department from copious irrigation with saline serum, tetanus toxoid, postexposure rabies vaccination, and prophylactic antibiotic therapy. In the operating room, surgical exploration found the ulnar digital pedicle sectioned, the flexor and extensor tendons sectioned and shredded, and the skin shredded. An excisional debridement of devitalized tissue with copious irrigation was performed, and the finger regularized at the level of traumatic amputation with tendon striping followed by coverage of the bone by the radial digital flap with careful clinical and biological monitoring after the surgery. At the last follow-up, the patient revealed no sign of infection, and he returned to his usual activities and has been discharged from care. This wound management, based on a careful examination, a meticulous debridement, and an efficient cleaning with early and targeted antibiotic therapy, might promote good results and avoid dangerous complications.
Image Segmentation Based on Modified Fractional Allen–Cahn Equation
Authors: Lee Dongsun , Lee Seunggyu
Published: January 2019

We present the image segmentation model using the modified Allen–Cahn equation with a fractional Laplacian. The motion of the interface for the classical Allen–Cahn equation is known as the mean curvature flows, whereas its dynamics is changed to the macroscopic limit of Lévy process by replacing the Laplacian operator with the fractional one. To numerical implementation, we prove the unconditionally unique solvability and energy stability of the numerical scheme for the proposed model. The effect of a fractional Laplacian operator in our own and in the Allen–Cahn equation is checked by numerical simulations. Finally, we give some image segmentation results with different fractional order, including the standard Laplacian operator.
Magnetohydrodynamic (MHD) Boundary Layer Flow Past a Wedge with Heat Transfer and Viscous Effects of Nanofluid Embedded in Porous Media
Authors: Ibrahim Wubshet , Tulu Ayele
Published: January 2019

The problem of two‐dimensional steady laminar MHD boundary layer flow past a wedge with heat and mass transfer of nanofluid embedded in porous media with viscous dissipation, Brownian motion, and thermophoresis effect is considered. Using suitable similarity transformations, the governing partial differential equations have been transformed to nonlinear higher‐order ordinary differential equations. The transmuted model is shown to be controlled by a number of thermophysical parameters, viz. the pressure gradient, magnetic, permeability, Prandtl number, Lewis number, Brownian motion, thermophoresis, and Eckert number. The problem is then solved numerically using spectral quasilinearization method (SQLM). The accuracy of the method is checked against the previously published results and an excellent agreement has been obtained. The velocity boundary layer thickness reduces with an increase in pressure gradient, permeability, and magnetic parameters, whereas thermal boundary layer thickness increases with an increase in Eckert number, Brownian motion, and thermophoresis parameters. Greater values of Prandtl number, Lewis number, Brownian motion, and magnetic parameter reduce the nanoparticles concentration boundary layer.
Richardson Extrapolation‐Based Verification Method of Scientific Calculation Program without the Oracles: A Case Study
Authors: Yan Shiyu , Yang Xiaohua , Cheng Guodong , Liu Hua
Published: January 2019

For the verification test of some scientific calculation programs, different comparison methods are commonly applied to ensure the correctness of the computations. However, it is difficult to verify whether the testing output is correct, because the oracles which include the expected output are not always available or too hard to get. For this reason, the authors focus on using the Richardson Extrapolation to estimate the convergences of the numerical solution on different levels of mesh refinement. These numerical convergence properties can be applied to verification test, without the need for giving the oracles. In the present study, the authors take the program test of the multigroup neutron diffusion equations as a study case and propose the Richardson Extrapolation‐based verification method. Three verification criterions are obtained based on our approach. In addition, a test experiment is conducted demonstrating the validity of our theoretical results.
Modelling a Cracked Beam Structure Using the Finite Element Displacement Method
Authors: Long Hui , Liu Yilun , Huang Changzheng , Wu Weihui , Li Zhaojun
Published: January 2019

A new model is presented for studying the effects of crack parameters on the dynamics of a cracked beam structure. The model is established by the finite element displacement method. In particular, the stiffness matrix of the cracked beam element is firstly derived by the displacement method, which does not need the flexibility matrix inversion calculation compared with the previous local flexibility approaches based on the force method. Starting with a finite element model of cracked beam element, the equation of strain energy of a cracked beam element is formed by the displacement method combined with the linear fracture mechanics. Then, based on the finite element method, the dynamic model of the cracked beam structure is obtained. The results show that the dynamic model discovers the internal relation between the dynamic characteristics of cracked beam structure and structural parameters, material parameters, and crack parameters. Finally, an example is presented to validate the proposed dynamic model.
Astrocyte-Conditioned Medium Protects Prefrontal Cortical Neurons from Glutamate-Induced Cell Death by Inhibiting TNF-α Expression
Authors: Song Cai , Wu Yih-Shyuan , Yang Zhi-You , Kalueff Allan V. , Tsao Yin-Yin , Dong Yilong , Su Kuan-Pin
Published: January 2019

Objective: Both excitotoxicity and neurotrophin deficiency may contribute to the etiology of depression and neurodegeneration. Astrocytes not only regulate glutamate metabolism and clearance, they also produce neurotrophins in the brain. However, the direct interaction between neurons and astrocytes remains unknown. Methods: This study evaluated the cellular mechanisms by which astrocyte-conditioned medium (ACM) protects prefrontal cortical neurons from glutamate-induced death by measuring cell viability and morphology as well as mRNA and protein expression of brain-derived neurotrophic factor (BDNF), BDNF receptors, glial cell line-derived neurotrophic factor (GDNF), and the proinflammatory cytokine, tumor necrosis factor (TNF)-α. Neurons and astrocytes were purified from the brains of neonatal 1-day-old Sprague-Dawley rats. ACM was harvested after exposing astrocytes to culture medium containing 100 μM glutamate for 48 h. Results: Glutamate insult (100 μM for 6 h) significantly reduced neuronal cell viability and increased the mRNA expression of BDNF. Glutamate (24 h) decreased neuronal viability and the expression of BDNF, but increased mRNA expression of GFAP, p75 neurotrophin receptor (p75NTR), and TNF-α. ACM pretreatment (2 h) reversed glutamate-decreased cell viability and increased BDNF, but reduced the expression of GDNF, P75NTR, and TNF-α at the mRNA level. Western blotting generally confirmed the mRNA expression following 24 glutamate insults. Furthermore, the glutamate-induced decrease in the protein expression of BDNF and full-length TrkB receptor and increase in pro-BDNF, truncated TrkB isoform 1 receptor, p75NTR, GDNF, and TNF-α were significantly attenuated by ACM pretreatment. Conclusions: The study demonstrates that ACM exerts neuroprotective effects on cell viability, and this effect is most likely mediated through the modulation of neurotrophin and TNF-α expression.
Fatty Liver and Autoimmune Hepatitis: Two Forms of Liver Involvement in Lipodystrophies
Authors: Ribeiro Andreia , Brandão José Ricardo , Cleto Esmeralda , Santos Manuela , Borges Teresa , Santos Silva Ermelinda
Published: January 2019

Introduction: Lipodystrophies are a heterogeneous group of rare diseases (genetic or acquired) characterized by a partial or generalized deficit of adipose tissue, resulting in less energy storage capacity. They are associated with severe endocrine-metabolic complications with significant morbidity and mortality. In the pathogenesis of the acquired forms, immunological disorders may be involved. Case 1: A 13-year-old female was diagnosed with acquired generalized lipodystrophy and observed for suspicion of portal hypertension. She presented with generalized absence of adipose tissue, cervical and axillary acanthosis nigricans, and massive hepatosplenomegaly. Laboratory tests revealed AST 116 IU/L, ALT 238 IU/L, GGT 114 IU/L, HOMA-IR 28.2, triglycerides 491 mg/L, and leptin < 0.05 ng/mL. Upper gastrointestinal endoscopy saw no signs of portal hypertension. Hepatic histology showed macrovesicular fatty infiltration (60% of hepatocytes) and advanced fibrosis/cirrhosis. Her clinical condition worsened progressively to diabetes requiring treatment with subcutaneous insulin and hepatopulmonary syndrome. Case 2: A 15-year-old female, diagnosed with acquired partial lipodystrophy, Parkinson syndrome, autoimmune thyroiditis, and autoimmune thrombocytopenia was observed for hypertransaminasemia since the age of 8 years. She had absence of subcutaneous adipose tissue in the upper and lower limbs and ataxia. Laboratory tests showed AST 461 IU/L, ALT 921 IU/L, GGT 145 IU/L, HOMA-IR 32.6, triglycerides 298 mg/dL, normal leptin levels, platelets 84,000/μL, IgG 1,894 mg/dL, positive anti-LKM and anti-LC-1. Hepatic histology was suggestive of autoimmune hepatitis, without steatosis. She progressed favorably under metformin and immunosuppressive treatment. Conclusion: Early recognition and adequate characterization of liver disease in lipodystrophies is essential for a correct treatment approach. In acquired generalized lipodystrophy, the severe endocrine-metabolic disorder, which leads to steatohepatitis with cirrhotic progression, may benefit from recombinant leptin treatment.
Cuff-Based Oscillometric Measurements of Central Hemodynamics: Factors Influencing Central Augmentation Pressure in Normotensive Japanese Individuals
Authors: Obayashi Masakazu , Kobayashi Shigeki , Kohno Michiaki , Nakashima Tomoko , Yano Masafumi
Published: January 2019

Background: Recently, new devices using oscillometric cuff have been developed to derive central blood pressure (BP) waveform from brachial BP waveform. Late systolic pressure augmentation of central BP waveform is a marker of central hemodynamics. Mobil-O-Graph, a cuff-based oscillometric device, can assess central augmentation pressure (AP) together with central BP. Central AP measurement using the Mobil-O-Graph in the European population was reported to be associated with age and sex. However, factors influencing central AP in the Asian population have not been shown. Objectives and Methods: We enrolled 110 normotensive volunteers (50 men; age range, 21‒76 years). Central BP and AP were measured using the Mobil-O-Graph on the left arm with the subjects in the seated position after resting for at least 5 min. We compared central hemodynamics between the sexes. We investigated factors influencing central AP in uni- and multivariate linear regression analyses and age-related change in central AP using the Mobil-O-Graph in healthy Japanese individuals. Results: Central AP were lower in men than in women (5.5 ± 2.8 vs. 11.0 ± 4.7 mm Hg, p < 0.001). The central AP in the total cohort was positively correlated with age (r = 0.325, p < 0.001) and inversely correlated with height (r = −0.601, p < 0.001) in the Pearson correlations. In multivariate regression analysis, the parameters influencing central AP (R2 = 0.467) were age (β = 0.097, p < 0.001), sex (β = −2.890, p = 0.010), and height (β = −0.153, p = 0.031). The central AP (10.0 ± 4.8 mm Hg) in the ≥50-year-old group significantly increased compared with those in the 20- to 39-year-old group (6.7 ± 4.2 mm Hg, p < 0.05). Conclusions: Age, sex, and height influenced central AP, as assessed using the Mobil-O-Graph. Age-related increase in central AP was observed in normotensive Japanese individuals. Brachial cuff-based waveform recordings using the Mobil-O-Graph are feasible for the estimation of central AP in the Asian population.
Meta-Analysis of the Association between Fibroblast Growth Factor 23 and Mortality and Cardiovascular Events in Hemodialysis Patients
Authors: Gao Shaohui , Xu Jinsheng , Zhang Shenglei , Jin Jingjing
Published: January 2019

Introduction: This study was conducted to ensure the correlation between fibroblast growth factor 23 (FGF23) and death and cardiovascular events in hemodialysis patients. Methods: We conducted a literature search of PubMed database to April 2018 for relevant articles that reported the association between FGF23 and risk of all-cause mortality and cardiovascular disease (CVD) events. The meta-analysis was performed using the Revman 5.3 software. Results: A total of 7 articles were included, and all reported mortality in hemodialysis patients, and 3 reported cardiovascular events in hemodialysis patients. Since the current reagent can detect C-terminal FGF23 (cFGF23) and intact-FGF23 (iFGF23), we discuss the association between cFGF23 and iFGF23 and death and cardiovascular events in hemodialysis patients. The correlation between serum iFGF23 levels and death in hemodialysis patients: high levels of iFGF23 vs. low levels of iFGF23: RR 1.14, 95% CI (1.01–1.30), p = 0.04 (I2 = 0%, p = 0.38). The correlation between serum C-terminal levels and death in hemodialysis patients: high levels of cFGF23 versus low levels of cFGF23: RR 1.39, 95% CI (1.21–1.59), p < 0.001 (I2 = 2%, p = 0.38). The correlation of serum iFGF23 levels with cardiovascular events: high levels of iFGF23 versus low levels of iFGF23: RR 1.21, 95% CI (1.13–1.30), p < 0.001 (I2 = 0%, p = 0.49). A paper has reported the association between cFGF23 and CVD events, so we did not conduct meta-analysis. Conclusions: Elevated serum FGF23 levels are positively associated with all-cause mortality and cardiovascular events in hemodialysis patients, with a 14 or 39% increase in all-cause mortality and a 21% increased risk of cardiovascular events.
Mini-Sling Ophira at 8 Years Follow-Up: Does It Sustain Results?
Authors: Mira Gon Lucas , Zanettini Riccetto Cassio Luis  , Citatini de Campos Caio Cesar  , Iamashita Voris Brunno Raphael  , Reis Leonardo O. , Rodrigues Palma Paulo Cesar 
Published: January 2019

Purpose: To evaluate mini-sling long-term results and correlate them to failure predictors. Many studies show comparable results among different single-incision slings developed as an attempt to reduce complications while keeping good results, but there is a lack of evidence about mini-slings outcomes in the long term. Methods: This prospective, single-center study evaluated 40 patients for long-term outcomes after mini-sling placement. Objective cure was defined as leakage of less than 1 g in 1-hour pad-test and no leakage at Valsalva maneuver. An objective improvement was defined as leakage of a maximum 50% of the preoperative test. Subjective continence was considered as a zero score at International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). Patients were also evaluated for comorbidities and previous surgeries. Results: The mean age was 56 (±9.3) years, the mean ICIQ-SF score was 16 (±2.98) before surgery and 3.5 (± 5) at last follow-up, showing sustained improvement in the long term, mean 100 (84–109) months follow-up. The objective results show 67.5% of success, 17.5% of improvement, and 15% of failure. Age and parity were not related to outcomes (p = 0.33), but previous surgeries increase failure rate with 5.66 OR (p = 0.04). Success, improvement, and failure rates were 85, 10, and 5% for treatment-naive patients versus 50, 25, and 25% for patients with previous surgeries, respectively. Conclusion: Mini-sling Ophira shows good long-term results with low complications rates in patients without previous anti-incontinence surgery. Randomized trials are necessary to compare mini-slings results to other mid-urethral slings in recurred stress urinary incontinence.
Postoperative Acute Kidney Injury: Focus on Renal Recovery Definitions, Kidney Disease Progression and Survival
Authors: Long Thorir E. , Helgadottir Solveig , Helgason Dadi , Sigurdsson Gisli H. , Gudbjartsson Tomas , Palsson Runolfur , Indridason Olafur S. , Sigurdsson Martin I.
Published: January 2019

Background: The aim of this study was to examine different definitions of renal recovery following postoperative acute kidney injury (AKI) and how these definitions associate with survival and the development and progression of chronic kidney disease (CKD). Methods: This was a retrospective study of all patients who underwent abdominal, cardiothoracic, vascular, or orthopedic surgery at a single university hospital between 1998 and 2015. Recovery of renal function following postoperative AKI was assessed comparing 4 different definitions: serum creatinine (SCr) (i) < 1.1 × baseline, (ii) 1.1–1.25 × baseline, (iii) 1.25–1.5 × baseline, and (iv) > 1.5 × baseline. One-year survival and the development or progression of CKD within 5 years was compared with a propensity score-matched control groups. Results: In total, 2,520 AKI patients were evaluated for renal recovery. Risk of incident and progressive CKD within 5 years was significantly increased if patients did not achieve a reduction in SCr to < 1.5 × baseline (hazard ratio [HR] 1.50; 95% CI 1.29–1.75) and if renal recovery was limited to a fall in SCr to 1.25–1.5 × baseline (HR 1.32; 95% CI 1.12–1.57) within 30 days. The definition of renal recovery that best predicted survival was a reduction in SCr to < 1.5 × baseline within 30 days. One-year survival of patients whose SCr decreased to < 1.5 × baseline within 30 days was significantly better than that of a propensity score-matched control group that did not achieve renal recovery (85 vs. 71%, p < 0.001). Conclusions: These findings should be considered when a consensus definition of renal recovery after AKI is established.
Observational Study to Assess Quality of Life in Patients with Pancreatic Neuroendocrine Tumors Receiving Treatment with Everolimus: The OBLIQUE Study (UK Phase IV Trial)
Authors: Ramage John K. , Punia Pankaj , Faluyi Olusola , Frilling Andrea , Meyer Tim , Saharan Ruby , Valle Juan W.
Published: January 2019

Background/Aims: To assess health-related quality of life (HRQoL), treatment patterns, and clinical outcomes of adult (≥18 years) patients with advanced (unresectable or metastatic) pancreatic neuroendocrine neoplasms (PanNENs) treated with everolimus in routine clinical practice. Methods: In a prospective, non-interventional, multi-center study patients administered at least one 10 mg dose of everolimus were evaluated for change in HRQoL (EORTC QLQ-C30 Global Health Status scale) from baseline after 6 months treatment (primary endpoint). Secondary endpoints included disease-specific HRQoL measures (EORTC QLQ-G.I.NET21), clinical outcomes, everolimus treatment patterns, and safety. Results: Forty-eight patients were recruited (between August 2013 and March 2015); the median treatment duration was 27.8 months. EORTC QLQ-C30 Global Health score was not significantly different from baseline after 6 months of treatment (mean difference –1.9 points, p = 0.660, n = 30). In pairwise analyses, the only significant changes in HRQoL from baseline were for EORTC QLQ-C30 physical functioning score at month 3 (adjusted mean difference –8.8 points, p = 0.002, n = 36) and the EORTC QLQ-G.I.NET21 disease-related worries scores at months 1 and 2 (adjusted mean differences: –11.5 points [p = 0.001, n = 44] and –8.8 points [p = 0.017, n = 43], respectively). Disease progression or death was recorded in 44.4% (n = 20/45) patients during follow-up; median progression-free survival was 25.1 months and the cumulative survival rate at 3 years was 71%. No new safety signals were detected. Conclusions: The OBLIQUE study demonstrates that HRQoL is maintained in patients with PanNENs during treatment with everolimus in a UK real-world setting. This study adds to the limited HRQoL data available in this patient group.
Quinidine-Responsive Polymorphic Ventricular Tachycardia in Patients With Coronary Heart Disease
Authors: Viskin Sami , Chorin Ehud , Viskin Dana , Hochstadt Aviram , Halkin Amir , Tovia-Brodie Oholi , Lee John K. , Asher Elad , Laish-Farkash Avishag , Amit Guy , Havakuk Ofer , Belhassen Bernard , Rosso Raphael
Published: January 2019

Background:

Polymorphic ventricular tachycardia (VT) without QT prolongation is well described in patients without structural heart disease (mainly idiopathic ventricular fibrillation and Brugada syndrome) and in patients with acute ST-elevation myocardial infarction.

Methods:

Retrospective study of patients with polymorphic VT related to coronary artery disease, but without evidence of acute myocardial ischemia.

Results:

The authors identified 43 patients in whom polymorphic VT developed within days of an otherwise uncomplicated myocardial infarction or coronary revascularization procedure. The polymorphic VT events were invariably triggered by extrasystoles with short (364±36 ms) coupling interval. Arrhythmic storms (4–16 events of polymorphic VT deteriorating to ventricular fibrillation) occurred in 23 (53%) patients. These arrhythmic storms were always refractory to conventional antiarrhythmic therapy, including intravenous amiodarone, but invariably responded to quinidine therapy. In-hospital mortality was 17% for patients with arrhythmic storm. Patients treated with quinidine invariably survived to hospital discharge. During long-term follow-up (of 5.6±6 years; range, 1 month to 18 years), 3 (16%) of patients discharged without quinidine developed recurrent polymorphic VT. There were no recurrent arrhythmias during quinidine therapy

Conclusions:

Arrhythmic storm with recurrent polymorphic VT in patients with coronary disease responds to quinidine therapy when other antiarrhythmic drugs (including intravenous amiodarone) fail.
Abstract 100: In-Hospital Delirium and Long-Term Cognitive Outcomes Among Patients With Ischemic Stroke: A Population-Based Cohort Analysis
Authors: Bambhroliya Arvind B , Meeks Jennifer R , Tyson Jon E , Miller Charles C , Khan Babar A , Sheth Sunil A , McCullough Louise D , Grotta James C , Aronowski Jaroslaw , Savitz Sean I , Vahidy Farhaan S
Published: January 2019

Introduction:
Evidence of association between delirium during initial hospitalization of ischemic stroke (IS) patients, and development of long-term mild cognitive impairment or dementia (MCID) is lacking. We examined the prospective incident risk of MCID among IS patients who experienced in-hospital delirium in a large multi-state population-based cohort.

Methods:
We utilized NY, CA, and FL (2005 - 2014) State Inpatient and Emergency Department Databases, and established a cohort by selecting MCID free patients with a primary diagnosis of IS (ICD-9: 433.x1, 434.x1, 436) during a 2yr period. Delirium during the initial IS event was tagged using a validated algorithm with high specificity for the confusion assessment method. The cohort was followed for MCID diagnoses. Patients that died within 90 days of initial IS event were excluded. We conducted time-to-event analyses and report cumulative incidence, 95% Confidence Interval (CI) and hazard ratios (HR) for risk of MCID among IS patients with and without delirium.

Results:
A total of 133,815 IS patients (age: 70.5, female: 51.7%, white: 65.5%) were followed for up to 8yrs, resulting in 357,500 person-years. Patients who experienced delirium were significantly older and had a higher comorbidity burden. A significantly smaller proportion of delirium patients underwent IV or IA thrombolysis. Cumulative incidence (95% CI) for development of MCID was significantly higher among delirium patients (9.01, 8.32 - 9.74) as compared to non-delirium patients (3.99, 3.93 - 4.06). Likewise, the HR for MCID among delirium patients was statistically significant (1.86, 1.71 - 2.02) in the fully adjusted Cox proportional model (Figure).

Conclusion:
In-hospital delirium was independently associated with a higher risk of developing MCID in this large population-based cohort. Further investigation is warranted to elucidate the mechanistic basis for the role of delirium in long-term cognitive decline among IS patients.
Abstract 101: ApoE4 Disrupts Cerebrovascular Microcirculation and Undermines White Matter Integrity and Cognitive Function
Authors: Hattori Yorito , Ahn Sung Ji , Koizumi Kenzo , Schaffer Chris , Park Laibaik , Iadecola Costantino
Published: January 2019

Background:
Small vessel disease leading to subcortical white matter lesions (WML) is the major cause of vascular cognitive impairment. The apolipoprotein E4 (ApoE4) allele, a well-known risk factor for Alzheimer’s disease, is also a risk factor for WML, but the mechanisms of the effect remain unclear. We set out to determine whether the ApoE4 genotype disrupts the cerebral microcirculation and promotes WML and cognitive impairment.

Methods:
We studied male ApoE4 targeted replacement mice (ApoE4-TR; age 3-4 months). ApoE3 (ApoE3-TR) were used as controls. Cerebral blood flow (CBF) was assessed by ASL-MRI; the CBF increase induced by whisker stimulation (WS) or the endothelium-dependent agent acetylcholine (ACh) was assessed in cranial window preparations by laser-Doppler flowmetry. The corpus callosum (CC) microcirculation was examined by three-photon microscopy (3PM). Bilateral carotid artery stenosis (BCAS) was induced with 0.18 mm microcoils. WML and cognition were tested 4 weeks after BCAS.

Results:
In ApoE4-TR mice resting cortical CBF was attenuated compared to ApoE3-TR (-13%), as well the increase in CBF produced by WS (-47±3%) or ACh (-38±3%; p<0.05; n=5/group). In the CC, red blood cell (RBC) speed was slower in ApoE4-TR (1.6±0.1) than in ApoE3 mice (1.9±0.1 mm/s; p<0.05; n=5/group). Following 4 weeks of BCAS, cortical CBF was reduced more in ApoE4-TR (-35±4%) than in ApoE3-TR mice (-23±2%; p<0.05; n=8/group). Similarly, in the CC RBC speed was reduced more in ApoE4-TR (-33±3%) than in ApoE3-TR mice (-23±3%; p<0.05; n=5/group). In ApoE4-TR mice BCAS resulted in more marked CC WML (SMI312/MBP ratio, 48%) and cognitive dysfunction (novel object recognition: 18%; Y-maze arm alternation: 14%) than in ApoE3-TR mice (p<0.05; n=8/group).

Conclusions:
The findings unveil a previously unrecognized ApoE4-dependent failure of critical neurovascular regulatory mechanisms, sufficient to promote white matter damage in the setting of cerebral hypoperfusion. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.
Abstract 103: Cortical tau Pathology in Cerebral Amyloid Angiopathy
Authors: Gurol Edip M , Becker J. Alex , Gokcal Elif , Fotiadis Panagiotis , Schwab Kristin M , Goldstein Joshua N , Rosand Jonathan , Viswanathan Anand , Johnson Keith A , Greenberg Steve M
Published: January 2019

Introduction:
Cerebral amyloid angiopathy (CAA), a condition related to Alzheimer’s Disease, causes ischemic and hemorrhagic brain injury and contributes to cognitive impairment. Vascular amyloid, the hallmark of CAA, can be detected using amyloid PET imaging. We used selective tau imaging to understand the degree and associations of tau aggregation and deposition in patients with CAA.

Methods:
Thirty-four patients with probable CAA but without cognitive impairment were prospectively enrolled. Selective tau imaging was performed using PET tracer flortaucipir (FTP) and amyloid imaging was obtained with Pittsburgh Compound B PET. Global and region of interest based (ROI) standardized uptake value ratios (SUVR) were calculated from PET acquisitions. High resolution multimodal MRIs were obtained for each patient and markers of CAA-related structural injury were quantified.

Results:
The mean age (
+
SD) of the patients was 69
+
6, 38% were female. Thirteen patients (38%) enrolled without intracerebral hemorrhage (ICH). Mean cortical FTP uptake was 1.18
+
0.11 (tau load, in SUVR). Five patients were tau positive based on FTP SUVR > 1.28 from a posterior cingulate cortex ROI, a previously validated method. Mean global cortical FTP uptake correlated with cortical amyloid load (r=0.37, p=0.04), centrum semiovale perivascular spaces (cs-PVS, r=0.49, p=0.004), extent of cortical superficial siderosis (cSS, r=0.44, p=0.01), and showed a trend for correlation with extent of leukoaraiosis (r=0.33, p=0.059). The associations with amyloid load and cs-PVS remained significant in multivariable models. Cortical FTP uptake was not associated with age, sex, vascular risk factors, presence of ICH or any of the CAA-related focal lesions (cerebral microbleeds, microinfarcts, lacunes), all p>0.2.

Conclusions:
Our results show that many patients with CAA have some degree of cortical tau deposition, but severe tau positivity was not frequent (15%) in this cognitively normal CAA cohort, considering that 30% of healthy older adults were positive in other studies. The associations of cortical tau with brain amyloid and CAA-specific markers of global brain injury suggest that vascular amyloid might trigger tau deposition which, in turn, might increase parenchymal damage.
Abstract 110: Pre-Endovascular Therapy Change in BP is Associated With Outcome: A post-Hoc Analysis of the Blood Pressure After Endovascular Treatment (BEST) Prospective Cohort Study
Authors: Mistry Eva , Dakay Katarina , Peterson Nils , Jayaraman Mahesh , McTaggart Ryan , Furie Karen , Mehta Tapan , Arora Niraj , Starosciak Amy , De Los Rios La Rosa Felipe , Siegler James , Barnhill Natasha , Mistry Akshitkumar , Patel Kishan , Assad Salman , Tarboosh Amjad , Wagner Jeff , Bennett Alicia , Cruz Aurora , Fortuny Enzo , James Robert , Jagadeesan Bharathi , Streib Christopher , Weber Stewart , Kasner Scott , Chitale Rohan , Volpi John , Mayer Stephan , Khatri Pooja , Yaghi Shadi
Published: January 2019

Background:
Higher blood pressure on admission is associated with worse outcomes in stroke patients undergoing endovascular therapy (EVT). However, if BP changes pre-EVT affects outcomes remains unknown. We sought to determine this association in the prospective multi-institutional cohort study, Blood Pressure after EVT in Stroke (BEST).

Methods:
We enrolled consecutive adult patients in BEST with acute ischemic stroke who underwent clot retrieval from ICA, M1, or M2 from Nov 2017 to May 2018 at 12 comprehensive stroke centers. Study variables included change in mean arterial pressure (MAP) from admission to immediately pre-EVT. Primary outcomes was dichotomous 90-day modified Rankin score [mRS] 0-2 (good outcome) vs. 3-6 (bad outcome). We determined the association between any decrease or increase in MAP (delta MAP = Pre-EVT MAP – Admission MAP) and poor outcome (defined by mRS 0-2) using univariate and multivariable analysis (adjusted for age, NIHSS score, TICI score, and time to reperfusion).

Results:
Among 443 patients, 218 patients had data on pre-EVT BP (missing: n = 61) and 90-day mRS (missing: n = 164). The mean age was 68.8±14.6; 52.3% were women; median NIHSS was 16.5 (IQR 12-21). Baseline characteristics and outcomes are reported in table 1. In multivariable models, each mmHg increase or decrease in MAP was associated with higher odds of worse outcome (OR 1.05, 95% CI 1.002-1.10, p=0.042 and OR 1.06, 95% CI 1.01-1.11, p=0.021, respectively). (Table 2)

Conclusion:
We found a “U” shape association between pre-EVT change in MAP and poor outcome (Figure). While a drop in MAP may lead to infarct growth, an increase in MAP maybe a sign of failing collaterals and worsening ischemia. Future studies are needed to determine the best BP target pre-endovascular treatment.
Abstract 130: Histamine Increase After Ischemic Stroke Leads to Gut Barrier Breakdown Related Post-Stroke Inflammation in Aging
Authors: Ganesh Bhanu Priya , Conesa Maria P Blasco , Ahnstedt Hilda , Chauhan Anjali , Major Angela , Bryan Robert , McCullough Louise
Published: January 2019

Human aging is characterized by chronic, low-grade inflammation, a phenomenon termed “inflammaging”. Aging is a non-modifiable risk factor for stroke and inflammatory processes are a major contributor to ischemic brain damage. Mast cell (MC) degranulation and the subsequent release of histamine (HA) may contribute to chronic inflammation, BBB leakage and neutrophil accumulation. Over the past decade, the histaminergic system has been implicated in the modulation of cell death in brain disorders including stroke. However, the exact mechanisms underlying HA actions on ischemia-induced damage have not yet been defined. Stroke leads to gut dysfunction and dysbiosis, which might trigger MC infiltration. Since previous studies have shown that the gut/microbiome has a significant impact on stroke outcomes, we hypothesized that stroke increases HA levels, histamine receptors (HR) and MC infiltration in the gut leading to gut barrier breakdown further contributing to post-stroke inflammation (PSI) and damage.

Methods:
Aged (Ag) C57BL/6 (20-22 months old) and young (Yg) (3 months old) male mice were subjected to 60 min transient middle cerebral artery occlusion (MCAO) or sham surgery. Mice were sacrificed after 6-hours (h), 12-h, 24-h, 3-days (d) and 7-d post-MCAO. Brain, blood, gut and spleen were harvested and used for flow cytometry, mRNA and immunohistochemistry (IHC) before behavior analysis. Luminal contents were collected and subjected to 16s sequencing and metabolomics analysis.

Results:
Stroke increased HR2 expression in the intestine of 7-d PS Ag mice compared to the Ag controls. HA levels in Ag brain and blood was 2-fold higher than in Yg mouse at 6-h after stroke and remained high at 24-h. In addition, locomotor activity was significantly reduced in post stroke mice. Increased MCs were seen in the gut of PS compared to control mice. The protective gut mucus layer was depleted with increased HR activation and with a pro-inflammatory bio-marker elevation. This was correlated with imbalanced gut microbiota. This work suggests that there is a role of gut HR and systemic HA in modulating brain health. Controlling HA release and suppressing HR activation in the periphery especially in the gut PS might improve recovery after stroke.
Abstract 139: Inpatient Nursing Stroke Champions Improve Stroke Education Retention at 7 Days and 90 Days Post Discharge
Authors: Punsalang Lorina , McDaniels Christina , Gaffney Denise , Sta Maria Ariane , Perez Claudine , Mkrtumyan Alvina , Ajani Zahra , Le Duy , Sangha Navdeep
Published: January 2019

Background:
Patients with deficient stroke knowledge characteristically present to the hospital outside the treatment window. Providing effective inpatient stroke education motivates patients to change their modifiable risk factors, hence reducing the threat of a secondary stroke.

Purpose:
The purpose of this study is to validate the effectiveness of the American Heart Association’s Get with the Guidelines Stroke Champion (SC) Program. Inpatient Nursing SC (INSC) endeavored to optimize patients’ retention of stroke education. This study is one of the first to provide data supporting the use of INSC to improve stroke education retention post discharge.

Methods:
The INSC initiative was implemented in 2017. Data was compared 6 months pre and post intervention. INSC conducted chart reviews, provided peer to peer feedback, implemented “1 Learner 1 Topic” education theme per shift, and ensured education throughout the care continuum. The aggregate data was collected from 7day survey calls (n=340) and stroke-specific HCAHPS topbox survey scores completed by the patient at 90 days post discharge (n=155). Statistical analysis was performed using a chi-squared test.

Results:
At 7 days, more patients were able to recall stroke risk factors and prevention (54% pre vs. 85% post intervention; p<0.003), and stroke symptoms (54% pre vs. 95% post; p<0.003). At their 90day HCAHPS survey, more patients were able to recall the stroke risk factors and prevention (52% pre vs. 67% post intervention; p<0.05) and stroke symptoms (61% pre vs. 71% post; p=0.003). A trend towards more patients recalling the knowledge and diagnosis of their stroke based on their HCAHPS was seen (59% pre vs. 66% post intervention; p=0.07).

Conclusions:
Implementation of an INSC can improve patients’ retention of stroke symptoms, risk factors, prevention, and cause at 7 days and 90 days post discharge.
Abstract 147: Individualized Blood Pressure Management After Subarachnoid Hemorrhage Using Real-time Autoregulation Monitoring: A Pilot Study Using NIRS and ICP-derived Limits of Autoregulation
Authors: Silverman Andrew , Wang Anson , Kodali Sreeja , Strander Sumita , Cord Branden , Hebert Ryan , Matouk Charles , Gilmore Emily , Sheth Kevin , Petersen Nils H
Published: January 2019

Introduction:
Optimal blood pressure (BP) targets in the early stages of aneurysmal subarachnoid hemorrhage (aSAH) prior to occurrence of clinical vasospasm have not been well established. It is unclear which patients are ideal candidates for therapeutic BP manipulation. To determine the association of individualized autoregulation-based BP targets on functional outcome, we continuously measured limits of autoregulation (LA) in SAH patients.

Methods:
We prospectively enrolled 7 patients with aSAH who underwent multimodality neuromonitoring. Autoregulatory function was continuously measured by interrogating changes in arterial BP and intracranial pressure (ICP) or the near-infrared spectroscopy (NIRS) derived tissue-oxygenation index. Resulting indices of autoregulation were used to identify the BP of individual patients at which autoregulation was best preserved (MAPopt). A time trend of MAPopt with upper and lower limits of autoregulation (ULA, LLA) provided dynamically updated targets for BP control, and percent time within and outside LA was computed for each patient (Fig 1A). Functional outcome was assessed using the modified Rankin Scale (mRS) at discharge and 90 days.

Results:
Identification of MAPopt was possible in all patients (mean age 59, 3 male, mean WFNS 2.1) with an average monitoring time of 62.8h starting within 24h of SAH. A high degree of correlation was observed between invasive (ICP) and non-invasive (NIRS) modalities for calculation of MAPopt (r=0.91, p=0.01). The median time spent within optimal BP range was 51.4%, and percent time outside LA showed a linear association with worse functional outcomes (Fig 1B).

Conclusions:
Calculation of personalized autoregulation-based BP targets after SAH is feasible; BP management outside LA may increase the risk for worse functional outcomes. Non-invasive NIRS-based methods could provide a reasonable alternative for patients for whom invasive intracranial monitoring is not indicated.