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The relationship between cooling time (CT) variables and neurological outcomes is controversial. We evaluated the relationship between CT and neurological outcomes in out-of-hospital cardiac arrest (OHCA) patients treated with targeted temperature management (TTM).We conducted a multicenter, prospective, and registry-based study of OHCA survivors treated with TTM. CT was defined as the time from restoration of spontaneous circulation to achievement of the target temperature. The primary outcome was a favorable neurological outcome at 6 months. Multilevel logistic regression analysis was performed to test the relationship between CT and the primary outcome.Overall, the favorable neurological outcome rates at 6 months were 29.8% in 937 patients. When CT was stratified into categories of 0-3, 3.1-6, 6.1-9, 9.1-12, and12 h, according to 3-h intervals, the primary outcome rates were 8.2%, 22.7%, 35.5%, 44.7%, and 44.5%, respectively (p 0.001). Significant differences were not found in multilevel logistic regression analysis; the adjusted odds ratios (95% confidence interval) of each category for the primary outcome compared to the 0-3-h group were 0.81 (0.32 to 2.04), 0.77 (0.30 to 2.01), 1.26 (0.43 to 3.68), and 1.06 (0.37 to 3.06).We did not find a relationship between CT and neurological outcomes at 6 months.

BACKGROUND Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P

Summary Neoagarobiose (NA2) derived from agar marine biomass is a rare reagent that acts as an anti‐melanogenesis reagent and moisturizer. Here, for the economical manufacturing of NA2, we developed the co‐secretory production system of endo‐type β‐agarases (DagA) and exo‐type β‐agarases (EXB3) in Corynebacterium glutamicum. For this purpose, we first developed a secretory system of DagA via Tat pathway. To improve the secretion efficiency, we coexpressed two Tat pathway components (TatA and TatC), and to improve the purity of secreted DagA in the culture supernatant, two endogenous protein genes (Cg2052 and Cg1514) were removed. Using the engineered strain (C. glutamicum SP002), we confirmed that DagA as high as 1.53 g l‐1 was successfully produced in the culture media with high purity (72.7% in the supernatant protein fraction). Next, we constructed the expression system (pHCP‐CgR‐DagA‐EXB3) for the simultaneous secretion of EXB3 via Sec‐pathway together with DagA, and it was clearly confirmed that DagA and EXB3 were successfully secreted as high as 54% and 24.5%, respectively. Finally, using culture medium containing DagA and EXB3, we successfully demonstrated the conversion of high‐concentration agar (40 g l‐1) into NA2 via a two‐stage hydrolysis process.

Aims This study aimed to investigate differences in baseline and treatment characteristics, and in‐hospital mortality according to the aetiologies of cardiogenic shock in patients undergoing veno‐arterial‐extracorporeal membrane oxygenation (VA‐ECMO). Methods and results The RESCUE registry is a multicentre, observational cohort that includes 1247 patients with cardiogenic shock from 12 centres. A total of 496 patients requiring VA‐ECMO were finally selected, and the study population was stratified by cardiogenic shock aetiology [ischaemic cardiomyopathy (ICM, n = 342) and non‐ICM (NICM, n = 154)]. The primary outcome of interest was in‐hospital mortality. Sensitivity analyses including propensity‐score matching adjustments were performed. Mean age of the entire population was 61.8 ± 14.2, and 30.8% were women. There were significant differences in baseline characteristics; notable differences included the older age of patients with ICM (65.1 ± 13.7 vs. 58.2 ± 13.8, P

Background and objectives This study aimed to investigate the clinical course and prognostic factors after isolated local recurrence (iLR) and to identify the predictive factors for R0 resection of locally recurrent rectal cancer (LRRC). Methods We retrospectively reviewed the medical records of 76 patients with iLR who had undergone radical surgery for a primary tumor from 2003 to 2015. Results The iLR rate was 2.5%. From 76 patients, 39 patients underwent R0 resection for iLR. Multivariate analysis revealed that initial open surgery, neoadjuvant chemoradiation, and p/ypT ≥ 3 were poor prognostic factors after iLR as regard to the variables related to the primary tumor; and symptom presence at the time of iLR diagnosis, higher fixity, and no chemotherapy after iLR were associated with shorter overall survival after iLR, and R0 resection of LRRC was the only favorable prognostic factor for progression-free survival after iLR as regard to the variables related to LRRC. Higher tumor level, negative pathologic circumferential margin of the primary tumor, and low fixity of LRRC were favorable factors in achieving R0 resection of LRRC. Conclusions Early detection of iLR before symptom development, use of chemotherapy after iLR and R0 resection of LRRC should be considered to improve survival outcomes after iLR.

Although primary human hepatocytes (PHHs) are the gold standard in drug efficacy and metabolism studies, long-term survival of PHHs and maintenance of their hepatic function are still challenging. In this study, we focused on the effect of the initial microenvironment on upregulation and long-term preservation of hepatic function of PHHs encapsulated within biodegradable hydrogel systems. PHHs were encapsulated in RGD-functionalized hybrid hydrogels with various degrees of degradability, and their hepatic functionality was analyzed. Regardless of the hydrogel elastic modulus, the combination with nondegradable hydrogels had a predominantly negative effect on the prompt engraftment of PHHs, whereas a degradable hydrogel with intermediate initial degradability was most effective in maintaining hepatic function. Efficient network formation by PHHs and cocultured cells, along with the control of hydrogel degradation, governed the hepatic functionality at an early stage and upon long-term cultivation. Under optimized conditions, expression of genes involved in biological processes such as focal adhesions, cell survival, cytoskeleton formation, and extracellular matrix interactions was significantly higher than that in a control with relatively delayed initial degradation. Thus, we suggest that the orchestrated control of initial cellular remodeling may play an important role in the maintenance of hepatic function in a three-dimensional PHH culture.

Our objective was to determine how much PaO2 levels increase after normobaric oxygen (NBO) therapy and whether NBO therapy exerts therapeutic effects regardless of the PaO2 level. We suggest the optimal PaO2 level to use during NBO therapy for the acute treatment of carbon monoxide (CO) poisoning. This retrospective study included 311 patients who received oxygen administration after CO poisoning and had a measurable PaO2 level upon arrival. Baseline characteristics, clinical courses and long-term neurological outcome were collected and compared. The PaO2 level upon arrival was 192 (161-225) mm Hg, and 272 (87.5%) of the patients presented with hyperoxia. The incidence of poor long-term neurological outcome was 11.3% at a median follow-up period of 35 months. PaO2 levels upon arrival were higher in patients with good long-term neurological outcome than in those with poor outcome. The incidence of poor long-term neurological outcome was significantly dependent on the PaO2 level when patients were stratified at 100-mm Hg increments. A multivariate regression analysis showed that PaO2 levels, when considered a continuous, interval or ordinal variable, were associated with long-term neurological outcome in separate models. According to the three models, a PaO2 level of 200-300 mm Hg has the lowest risk of poor long-term neurological outcome. The results of the analysis of the predicted probability of poor long-term outcome according to the PaO2 level exhibited a U-shaped curve. Further large-scale studies are needed to confirm the association between 200-300 mm Hg of PaO2 and long-term neurological outcome and evaluate the impact of PaO2 levels above 300 mm Hg on acute CO poisoning outcome.

BACKGROUND A survival paradox of stage IIB/IIC and IIIA colon cancer has been consistently observed throughout revisions of the TNM system. This study aimed to understand this paradox with clinicopathological and molecular differences. METHODS Clinicopathological characteristics of patients with pathologically confirmed stage IIB/IIC or IIIA colon cancer were retrospectively reviewed from a database. Publicly available molecular data were retrieved, and intrinsic subtypes were identified and subjected to gene sets enrichment analysis (GSEA). RESULTS Among the 159 patients included in the clinicopathological analysis, those at stage IIB/IIC had worse 3-year disease-free and overall survival than those at stage IIIA (59.3% vs 91.7%, P

Spheroids, a widely used three-dimensional (3D) culture model, are standard in hepatocyte culture as they preserve long-term hepatocyte functionality and enhance survivability. In this study, we investigated the effects of three operation modes in 3D culture - static, orbital shaking, and under vertical bidirectional flow using spheroid forming units (SFUs) on hepatic differentiation and drug metabolism to propose the best for mass production of functionally enhanced spheroids. Spheroids in SFUs exhibited increased hepatic gene expression, albumin secretion, and cytochrome P450 3A4 (CYP3A4) activity during the differentiation period (12 days). SFUs advantages include facilitated mass production and a relatively earlier peak of CYP3A4 activity. However, CYP3A4 activity was not well maintained under dimethyl sulfoxide (DMSO)-free conditions (13-18 days), dramatically reducing drug metabolism capability. Continued shear stimulation without differentiation stimuli in assay conditions markedly attenuated CYP3A4 activity, which was less severe in static conditions. In this condition, SFU spheroids exhibited dedifferentiation characteristics, such as increased proliferation and Notch signaling genes. We found that the dedifferentiation could be overcome by using the serum-free medium formulation. Therefore, we suggest that SFUs represent the best option for the mass production of functionally improved spheroids and so the serum-free conditions should be maintained during drug metabolism analysis.

Introduction The incidence and predictors of tricuspid regurgitation (TR) after permanent pacemaker (PM) implantations have not been well evaluated. We attempted to determine TR's natural course and predictors, especially focusing on the influence of atrial fibrillation (AF). Methods Data from 530 patients with dual-chamber PMs were evaluated. The main study outcomes were moderate to severe TR and isolated TR (moderate to severe TR without other structural heart diseases [SHDs]) in follow-up echocardiography. Results Over a median follow-up period of 7.6 years, moderate to severe TR developed in 14.5% patients. Of those, concomitant SHD was observed in 51.9% of patients, and 48.1% presented with isolated TR. A multivariable analysis identified the independent predictors of moderate to severe TR (diabetes mellitus [DM], chronic lung disease, preexisting mild TR, peripheral artery disease, moderate to severe aortic regurgitation, and persistent AF [PeAF]) and isolated TR (DM, preexisting mild TR, and PeAF). PeAF (n = 67, 12.6%) was an independent predictor of both moderate to severe TR (hazard ratio [HR] 2.59, 95% confidence interval [CI]: 1.22-5.51) and isolated TR (HR 4.54, 95% CI: 1.60-12.90). The patients with PeAF exhibited a higher incidence of moderate to severe TR (21.8% vs 12.9% vs 11.6% PeAF, paroxysmal AF, and without AF, respectively) and isolated TR (18.6% vs 6.6% vs 4.2%, respectively) during the follow-up. Conclusion Moderate to severe TR after PM implantations developed with or without the influence of concomitant SHD. Patients with PeAF exhibited a higher risk of moderate to severe TR after PM implantations.

Growing evidence indicates that inflammation is associated with neurological sequelae after CO poisoning. Several scores incorporating the peripheral complete blood cell (CBC) count have been introduced as indicators of systemic inflammation. This study investigated whether these scores can improve the predictive accuracy for long-term neurological outcome of acute carbon monoxide (CO) poisoning. Two hundred seventy-nine patients who suffered from acute CO poisoning were included. Data on the demographic details, serial peripheral CBC counts and scores based on peripheral CBC counts (neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), systemic immune inflammation index [SII]) over the first 12 hours after presentation together with the clinical course during hospitalization and long-term neurological outcome were collected. Both a multivariate logistic regression model with only significant univariate predictors and a model with univariate predictors plus each score for long-term neurological outcome were constructed. Patients with a poor long-term neurological outcome had higher neutrophil and monocyte counts and lower lymphocyte counts over the first 12 hours after admission than patients with a good outcome. The diagnostic performance of the NLR, MLR and SII over the first 12 hours for predicting long-term neurological outcome was acceptable. These scores at presentation were independently associated with the long-term neurological outcome. Among these scores, only the SII at presentation significantly improved the predictive accuracy of the model when combined with clinical parameters (AUC 0.949, 95% CI 0.916-0.972 vs AUC 0.923, 95% CI 0.884-0.952 for the model with clinical parameters only, P = 0.0476). The optimal cut-off value for SII at presentation was 1012.2, resulting in a sensitivity of 97% (84.2%-99.9%) and specificity of 64.6% (58.2%-70.6%). The SII at presentation could significantly improve the prognostic accuracy for predicting the long-term neurological outcome in patients with acute CO poisoning. Because the SII is an inexpensive and easily measurable parameter, it might be used as a prognostic tool in clinical fields.

The complete hardware implementation of an optoelectronic neuromorphic computing system is considered as one of the most promising solutions to realize energy-efficient artificial intelligence. Here, a fully light-driven and scalable optoelectronic neuromorphic circuit with metal-chalcogenide/metal-oxide heterostructure phototransistor and photovoltaic divider is proposed. To achieve wavelength-selective neural operation and hardware-based pattern recognition, multispectral light modulated bidirectional synaptic circuits are utilized as an individual pixel for highly accurate and large-area neuromorphic computing system. The wavelength selective control of photo-generated charges at the heterostructure interface enables the bidirectional synaptic modulation behaviors including the excitatory and inhibitory modulations. More importantly, a 7 × 7 neuromorphic pixel circuit array is demonstrated to show the viability of implementing highly accurate hardware-based pattern training. In both the pixel training and pattern recognition simulation, the neuromorphic circuit array with the bidirectional synaptic modulation exhibits lower training errors and higher recognition rates, respectively.

Human intestinal organoids (hIOs) derived from human pluripotent stem cells (hPSCs) have immense potential as a source of intestines. Therefore, an efficient system is needed for visualizing the st...

Background: There is growing evidence that the serotonergic system, in particular serotonin 2A receptors, is involved in neuropsychiatric symptoms in Parkinson's disease (PD), including cognitive processing and visual hallucinations. However, the relationship between serotonin 2A receptor availability, visual hallucinations, and cognitive profile is unknown. The objective of this study was to investigate the level of serotonin 2A receptor availability in brain regions affected by visual hallucinations and to test the association with cognitive/behavioral changes in patients who have PD with visual hallucinations. Methods: Nondemented patients who had PD with (n = 11) and without (n = 8) visual hallucinations and age‐matched controls (n = 10) were recruited. All participants completed neuropsychological testing, which consisted of visuoperceptual, executive, memory, language, and frontal‐behavioral function. Positron emission tomography scans using [18F]setoperone, a serotonin 2A antagonist radioligand, were acquired in patients with PD, and a parametric binding potential map of [18F]setoperone was calculated with the simplified reference tissue model using the cerebellum as a reference. Results: Patients who had PD with visual hallucinations exhibited significantly lower scores on measures of executive and visuoperceptual functions compared with age‐matched controls. These changes were paralleled by decreased [18F]setoperone binding in the right insula, bilateral dorsolateral prefrontal cortex, right orbitofrontal cortex, right middle temporal gyrus, and right fusiform gyrus. The psychometric correlation analysis revealed significant relationships among tests associated with visuoperceptual function, memory and learning, and serotonin 2A binding in different prefrontal and ventral visual stream regions. There was also reduced serotonin 2A receptor binding in patients who had PD with depression. Conclusions: These findings support a complex interaction between serotonin 2A receptor function and cognitive processing in patients who have PD with visual hallucinations. Fil: Cho, Sang Soo. University of Toronto; Canadá Fil: Strafella, Antonio P.. University of Toronto; Canadá Fil: Duff Canning, Sarah. University of Toronto; Canadá Fil: Zurowski, Mateusz. University of Toronto; Canadá Fil: Vijverman, Anne Catherine. Onze‐Lieve‐Vrouw Hospital; Bélgica Fil: Bruno, Veronica Andrea. University of Toronto; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aquino, Camila C.. University of Toronto; Canadá Fil: Criaud, Marion. University of Toronto; Canadá Fil: Rusjan, Pablo M.. University of Toronto; Canadá Fil: Houle, Sylvain. University of Toronto; Canadá Fil: Fox, Susan H.. University of Toronto; Canadá

A small-cell network SCN constructed by splitting a macro-cell into numerous small cells using an active antenna array system is studied. A synchronization signal appropriate for the SCN, virtually generated by an eNodeB with 3D beamforming, is proposed for efficient handover in SCNs. The virtual cell synchronization signal VCSS carries a macro-cell ID MCID and virtual-cell ID VCID in a hierarchical manner, allowing us to distinguish between an intra-cell handover virtual cell handover within a cell without changing the serving eNodeB and inter-cell handover virtual cell handovers across cells while changing the serving eNodeB in SCNs. Using the signal metrics obtained by the VCSS, an efficient handover measurement technique is proposed which can significantly reduce the processing time and overhead by distinguishing between the intra-cell/inter-cell handovers. The performance of the proposed technique is evaluated by simulating two different deployment scenarios of LTE-based SCN with 3D beamforming. Copyright © 2017 John Wiley & Sons, Ltd.

Dielectric composite thick films containing a high dielectric constant CaCu3Ti4O12 (CCTO) filler in a UV-cured polymer matrix were investigated as flexible planar capacitors on Cu foils. Dielectric performance depended on the volume fraction and size of CCTO particles dispersed in the cured polymer matrix. As a result, the thick films containing 33.3 vol.% CCTO with an average particle size of 0.47 μm exhibited a dielectric constant of ~80 and a dielectric loss of ~0.06 at 10 kHz. The effective medium theory model incorporating a morphology fitting parameter has been proven to be most close to the experimental values.

Induction of endoplasmic reticulum (ER)-to-Golgi blockade or ER stress induces Golgi reassembly stacking protein (GRASP)-mediated, Golgi-independent unconventional cell-surface trafficking of the folding-deficient ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR). However, molecular mechanisms underlying this process remain elusive. Here, we show that phosphorylation-dependent dissociation of GRASP homotypic complexes and subsequent relocalization of GRASP to the ER play a critical role in the unconventional secretion of CFTR. Immunolocalization analyses of mammalian cells revealed that the Golgi protein GRASP55 was redistributed to the ER by stimuli that induce unconventional secretion of ΔF508-CFTR, such as induction of ER-to-Golgi blockade by the Arf1 mutant. Notably, the same stimuli also induced phosphorylation of regions near the C-terminus of GRASP55 and dissociation of GRASP homomultimer complexes. Furthermore, phosphorylation-mimicking mutations of GRASP55 induced the monomerization and ER relocalization of GRASP55, and these changes were nullified by phosphorylation-inhibiting mutations. These results provide mechanistic insights into how GRASP accesses the ER-retained ΔF508-CFTR and mediates the ER stress-induced unconventional secretion pathway.

Nonconventional ways to modify phosphor structures have been reported to enhance the overall luminous efficacy of white light-emitting diodes (LED). Here, a nanoscale texturing technique of a glass substrate with the simple printing process of yellow (Ba,Sr,Ca)2SiO4:Eu+2 silicate phosphor paste is combined to achieve enhanced white luminescence performance. It is demonstrated that the luminous efficacy of the resulting printed phosphor layer can be enhanced by ≈16% as a result of controlling surface roughness of the substrate up to 151 nm. The substantial improvement obtained by texturing both sides of the substrate is attributed to the reduction of total internal reflection of rays at the glass–air interface, combined with reduction of specular reflection at the phosphor–glass interface. For the surface-textured configuration, 3D ray tracing simulations reveal that more rays can be extracted with a widely scattered radiation pattern on the surface. Far-field luminance uniformity is also found to be significantly improved as a result of the texturing technique.

In this paper, a beam ID preamble (BIDP) technique, where the beam ID is transmitted in the physical layer, is proposed for efficient beam training in millimeter-wave (mmWave) cellular communication systems. In order to facilitate beam ID detection in a multicell environment with multiple beams, the BIDP is designed such that the beam ID is mapped onto a Zadoff–Chu sequence in association with its cell ID. By analyzing the correlation property of the BIDP, it is shown that multiple beams can be transmitted simultaneously with the proposed technique with minimal interbeam interference in a multicell environment, where beams have different time delays due to propagation delay or multipath channel delay. Through simulation with the spatial channel model (SCM), it is shown that the best beam pairs can be found with a significantly reduced processing time of beam training in the proposed technique.

Miniaturization of electronics demands electromagnetic interference (EMI) shielding of nanoscale dimension. The authors report a systematic exploration of EMI shielding behavior of 2D Ti3 C2 Tx MXene assembled films over a broad range of film thicknesses, monolayer by monolayer. Theoretical models are used to explain the shielding mechanism below skin depth, where multiple reflection becomes significant, along with the surface reflection and bulk absorption of electromagnetic radiation. While a monolayer assembled film offers ≈20% shielding of electromagnetic waves, a 24-layer film of ≈55 nm thickness demonstrates 99% shielding (20 dB), revealing an extraordinarily large absolute shielding effectiveness (3.89 × 106 dB cm2 g-1 ). This remarkable performance of nanometer-thin solution processable MXene proposes a paradigm shift in shielding of lightweight, portable, and compact next-generation electronic devices.

Objectives Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). The survival rates and mortality-predictive factors of a nationwide registry of Korean patients with CTD-PH measured by echocardiography were determined. Methods Patients with CTD-PH were enrolled between April 2008 and December 2012. Hemodynamic parameters and clinical data (WHO-functional class [FC], organ involvement, laboratory tests and treatment agents) were recorded. Survival rates were calculated by using the Kaplan–Meier method. Mortality-associated factors were examined by Cox proportional hazards regression analysis. Results In total, 174 incident PH cases (61 with systemic lupus erythematosus, 50 with systemic sclerosis, 10 with mixed CTD, 22 with rheumatoid arthritis (RA) and 31 with other CTDs) were diagnosed by Doppler echocardiography. Of these, 25 (14%) died during the 3.8 ± 2.7 year follow-up period after PH diagnosis. The 1- and 3-year survival rates were 90.7% and 87.3%, respectively. Compared to the other CTD-PHs, RA-PH had the lowest survival rates (56% 3 year survival; P = 0.022). Multiple regression analysis revealed that low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were poor prognostic factors (P = 0.008, 0.04 and 0.009, respectively). Anti-UI-RNP (ribonucleoprotein) antibody positivity was protective (P = 0.022). In patients with WHO-FC III/IV, patients who received vasodilators had lower mortality than those who did not (P = 0.038). Conclusions In Korean patients with CTD-PH, the 3-year survival rate was 87%. Low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were independent poor prognostic factors. Anti-UI-RNP antibody was protective. Prompt PAH-specific vasodilator therapy may improve the survival of patients with severe CTD-PH.

TRAIL (TNF-related apoptosis inducing ligand) is a promising anti-cancer drug target that selectively induces apoptosis in cancer cells. However, many cancer cells are resistant to TRAIL-induced apoptosis. Therefore, reversing TRAIL resistance is an important step for the development of effective TRAIL-based anti-cancer therapies. We previously reported that knockdown of the TOR signaling pathway regulator-like (TIPRL) protein caused TRAIL-induced apoptosis by activation of the MKK7-c-Jun N-terminal Kinase (JNK) pathway through disruption of the MKK7-TIPRL interaction. Here, we identified Taraxacum officinale F.H. Wigg (TO) as a novel TRAIL sensitizer from a set of 500 natural products using an ELISA system and validated its activity by GST pull-down analysis. Furthermore, combination treatment of Huh7 cells with TRAIL and TO resulted in TRAIL-induced apoptosis mediated through inhibition of the MKK7-TIPRL interaction and subsequent activation of MKK7-JNK phosphorylation. Interestingly, HPLC analysis identified chicoric acid as a major component of the TO extract, and combination treatment with chicoric acid and TRAIL induced TRAIL-induced cell apoptosis via JNK activation due to inhibition of the MKK7-TIPRL interaction. Our results suggest that TO plays an important role in TRAIL-induced apoptosis, and further functional studies are warranted to confirm the importance of TO as a novel TRAIL sensitizer for cancer therapy. © 2015 Wiley Periodicals, Inc.

NFAT5 (nuclear factor of activated T cells), a well-known osmoprotective factor, can be activated by isotonic stimuli such as Toll-like receptor (TLR) triggering. However, it is unclear how NFAT5 discriminates between isotonic and hypertonic stimuli to produce different functional and molecular outcomes. Here, we identified a novel XO-ROS-p38 MAPK-NFAT5 pathway (XO is xanthine oxidase, ROS is reactive oxygen species) that is activated in RAW 264.7 macrophages upon isotonic TLR stimulation. Unlike what is seen under hypertonic conditions, XO-derived ROS were selectively required for the TLR-induced NFAT5 activation and NFAT5 binding to the IL-6 promoter in RAW 264.7 macrophages under isotonic conditions. In mouse peritoneal macrophages and human macrophages, TLR ligation also induced NFAT5 activation, which was dependent on XO and p38 kinase. The involvement of XO in NFAT5 activation by TLR was confirmed in RAW 264.7 macrophages implanted in BALB/c mice. Moreover, allopurinol, an XO inhibitor, suppressed arthritis severity and decreased the expression of NFAT5 and IL-6 in splenic macrophages in C57BL/6 mice. Collectively, these data support a novel function of the XO-NFAT5 axis in macrophage activation and TLR-induced arthritis, and suggest that XO inhibitor(s) could serve as a therapeutic agent for chronic inflammatory arthritis.

Objective To identify factors influencing endothelial progenitor cell (EPC) counts in patients with rheumatoid arthritis (RA). Methods The number of circulating CD34+/vascular endothelial growth factor receptor 2–positive EPCs was measured in 126 RA patients and 46 non-RA control patients. Endothelial function was assessed by brachial flow-mediated dilation (FMD). Serum CXCL12 concentrations were determined using an enzyme-linked immunosorbent assay. EPCs and FMD were measured at baseline and after 24 weeks of anti–tumor necrosis factor α (TNFα) therapy in 29 patients with active RA. Results The numbers of circulating EPCs were significantly lower in the RA patients than in the non-RA controls. In multivariate analysis, older age, reduced levels of high-density lipoprotein cholesterol, and higher bone erosion scores were independent risk factors for reduced EPC counts in RA patients. Serum CXCL12 levels correlated negatively with EPC counts, but positively with bone erosion scores. FMD was impaired in RA patients, and a decreased FMD in RA was closely associated with a higher bone erosion score and a reduced EPC count. In addition, EPC counts were restored by anti-TNFα therapy, and this increase was paralleled by improvement in FMD. Interestingly, restoration of EPC counts was attenuated in patients with higher bone erosion scores than in those with lower scores, despite similar levels of improvement in disease activity. Conclusion The numbers of circulating EPCs in RA patients are reduced and are inversely correlated with serum levels of CXCL12. Reduced EPC counts are closely associated not only with bone erosion, but also with endothelial dysfunction.

Background The aim of this study was to compare the outcomes in colorectal cancer (CRC) patients with synchronous unresectable metastases who received either primary tumor resection (PTR) or chemotherapy as the first treatment and to investigate the clinical course of asymptomatic patients who received chemotherapy as the first treatment. Methods We retrospectively analyzed 324 CRC patients with synchronous unresectable metastases. Overall survival (OS) was analyzed for the two groups (upfront PTR group [n = 72] vs. upfront chemotherapy group [n = 252]). Surgical morbidity and mortality were recorded. In the asymptomatic patients who received upfront chemotherapy, the incidences of primary tumor-related complications were analyzed. Results In patients who underwent PTR as the first treatment, the median OS period was superior to those who received upfront chemotherapy (17.2 vs. 13.6 months, P = 0.002). In the PTR group, surgical morbidity and mortality were 11.6% and 1.9%, respectively. Of the 252 asymptomatic patients, the incidence of primary tumor-related complications was 35%. Emergent surgery was ultimately done in 14% of the 252 patients. Conclusion CRC patients with synchronous unresectable metastases who underwent PTR followed by chemotherapy had significantly longer survival times compared to patients who received chemotherapy as the first treatment. J. Surg. Oncol. 2014; 110:214–221. © 2014 Wiley Periodicals, Inc.

Background FOS has been implicated in the progression of renal disease including IgAN. In this study, we investigated whether polymorphisms of FOS family genes [FOS, FOSB, FOS-like antigen 1 (FOSL1), and FOSL2] were associated with immunoglobulin A nephropathy (IgAN) and the clinical phenotypes of IgAN patients. Methods We genotyped single nucleotide polymorphisms (SNPs) of FOS family genes (rs2239615 and rs7101 for FOS, rs12373539 and rs2282695 for FOSB, rs637571 for FOSL1, and rs925255 for FOSL2) using direct sequencing in 198 IgAN patients and 290 control subjects. Results No SNPs were associated with IgAN; however, in the analysis of clinical phenotypes, we found that rs637571 of FOSL1 was associated with podocyte foot process effacement of IgAN in additive (CT vs. TT vs. CC, P = 0.0031, OR = 2.08, 95% CI = 1.27–3.40) and dominant models (CT/TT vs. CC, P = 0.0034, OR = 2.50, 95% CI = 1.35–4.64). The frequency of genotypes containing the T allele was increased in IgAN patients with podocyte foot process effacement, compared to those without podocyte foot process effacement. Conclusion These results suggest that FOSL1 may be related to IgAN severity.

Aim To estimate the point prevalence of pulmonary hypertension (PH) and determine the associated factors for PH in patients with systemic lupus erythematosus (SLE). Methods A prospective cross-sectional study of 114 patients with SLE was conducted in a single tertiary center. Transthoracic echocardiography was performed to estimate the pulmonary arterial pressures. PH was defined as resting systolic pulmonary artery pressure (sPAP) ≥ 40 mmHg, in the absence of left heart disease. Results PH was identified in nine patients (7.9%) who had few cardiopulmonary symptoms. SLE patients with PH had higher SLE disease activity index score. In particular, serum uric acid (UA) was significantly higher in patients with PH than in those without PH. In multivariate analysis, UA remained significant for the presence of PH. Moreover, serum UA level correlated significantly with plasma NT-pro-B-type natriuretic peptide level as well as sPAP. At the cutoff level of 6.5 mg/dL, serum UA had reasonable accuracy for predicting the presence of PH in SLE patients (sensitivity 66.7% and specificity 96.2%). Conclusion A significant number of SLE patients in rheumatology practice have undiagnosed PH with few discernible symptoms. Serum UA level may be useful as a surrogate marker for screening of PH in patients with SLE.