bluuebunny/crossref_metadata_2025 huggingface dataset:
Pegvisomant-Induced Cholestatic Hepatitis in an Acromegalic Patient with UGT1A1 ​⁎ 28 Mutation
Authors: Mallea-Gil Maria Susana , Bernabeu Ignacio , Spiraquis Adriana , Avangina Alejandra , Loidi Lourdes , Ballarino Carolina
Published: February 2016

Pegvisomant (PEGv) is a growth hormone receptor antagonist approved for the treatment of acromegaly; one of its documented adverse effects is reversible elevation of hepatic enzymes. We report a 39-year-old male acromegalic patient with a pituitary macroadenoma who underwent transsphenoidal surgery. The patient’s condition improved but GH and IGF-I levels did not normalize; as a consequence, we first administered dopamine agonists and then somatostatin receptor ligands (SRLs) with poor response. PEGv 15 mg every other day was added to lanreotide 120 mg monthly. The patient developed a severe hepatitis five months after starting the combination therapy. Elevated ferritin, iron, and transferrin saturation suggested probable hepatitis due to haemochromatosis. We performed a liver biopsy which showed an acute cholestatic hepatitis consistent with toxic etiology. A heterozygous genotypeUGT1A1​⁎28polymorphism associated with Gilbert’s syndrome was also found in this Argentine patient. The predominant clinical presentation resembled an acute cholestatic hepatitis associated with severe hemosiderosis, a different and new pattern of PEGv hepatotoxicity.
Robust Fusion Filtering for Multisensor Time-Varying Uncertain Systems: The Finite Horizon Case
Authors: Feng Xiaoliang , Zhou Funa , Wen Chenglin
Published: February 2016

The robustH∞fusion filtering problem is considered for linear time-varying uncertain systems observed by multiple sensors. A performance index function for this problem is defined as an indefinite quadratic inequality which is solved by the projection method in Krein space. On this basis, a robust centralized finite horizonH∞fusion filtering algorithm is proposed. However, this centralized fusion method is with poor real time property, as the number of sensors increases. To resolve this difficulty, within the sequential fusion framework, the performance index function is described as a set of quadratic inequalities including an indefinite quadratic inequality. And a sequential robust finite horizonH∞fusion filtering algorithm is given by solving this quadratic inequality group. Finally, two simulation examples for time-varying/time-invariant multisensor systems are exploited to demonstrate the effectiveness of the proposed methods in the respect of the real time property and filtering accuracy.
Medical Students’ Perceptions of Dementia after Participation in Poetry Workshop with People with Dementia
Authors: Garrie Alaina J. , Goel Shruti , Forsberg Martin M.
Published: February 2016

Purpose. Researchers assessed whether medical students’ participation in a poetry workshop with people with Alzheimer’s disease and related dementias (ADRD) affected their attitudes towards persons with ADRD.Objective. To add to the growing body of research summarizing the impact of nonclinical interventions on medical students’ perspectives about people with ADRD.Design. Researchers used dementia attitudes scale (DAS) and interpretive phenomenological analysis (IPA) to analyze participants’ attitudes.Setting. Osteopathic medical school and dementia care unit in the state of New Jersey.Participants. Eleven out of fourteen medical students completed the study.Measurements. Emerging themes were classified from the postintervention semistructured interviews and descriptive statistics were used to compare the preintervention to postintervention DAS.Results. Researchers found statistically significant differences between preintervention and postintervention DAS scores. Study participants scored a preintervention DAS mean, 107.09 (SD = 11.85), that changed positively and significantly to the postintervention DAS mean, 121.82 (SD = 10.38). DAS subdomains, “comfort” (P=0.002) and “knowledge”(P=0.01), and eleven of the twenty DAS items underwent a positive and statistically significant shift from preintervention to postintervention. IPA of the interviews yielded five primary and five secondary themes, supporting the measured statistical outcomes.Conclusion. Medical students’ participation in a poetry workshop, with people with ADRD, positively impacts their attitudes.
An Improved Global Harmony Search Algorithm for the Identification of Nonlinear Discrete-Time Systems Based on Volterra Filter Modeling
Authors: Li Zongyan , Li Deliang
Published: February 2016

This paper describes an improved global harmony search (IGHS) algorithm for identifying the nonlinear discrete-time systems based on second-order Volterra model. The IGHS is an improved version of the novel global harmony search (NGHS) algorithm, and it makes two significant improvements on the NGHS. First, the genetic mutation operation is modified by combining normal distribution and Cauchy distribution, which enables the IGHS to fully explore and exploit the solution space. Second, an opposition-based learning (OBL) is introduced and modified to improve the quality of harmony vectors. The IGHS algorithm is implemented on two numerical examples, and they are nonlinear discrete-time rational system and the real heat exchanger, respectively. The results of the IGHS are compared with those of the other three methods, and it has been verified to be more effective than the other three methods on solving the above two problems with different input signals and system memory sizes.
Zn Electrodeposition on Single-Crystal GaN(0001) Surface: Nucleation and Growth Mechanism
Authors: Peng Fei , Qin Shuang-Jiao , Zhao Yu , Pan Ge-Bo
Published: February 2016

The electrochemical deposition of zinc on single-crystaln-type GaN(0001) from a sulphate solution has been investigated on the basis of electrochemical techniques including cyclic voltammetry, chronoamperometry, and Tafel plot. The morphology and crystal structure of zinc deposits have been characterized by means of scanning electron microscopy, X-ray diffraction, and energy-dispersive X-ray analysis. The result has revealed that the deposition of Zn on GaN electrode commenced at a potential of −1.12 V versus Ag/AgCl. According to the Tafel plot, an exchange current density of ~0.132 mA cm−2was calculated. In addition, the current transient measurements have shown that Zn deposition process followed the instantaneous nucleation in 10 mM ZnSO4+ 0.5 M Na2SO4+ 0.5 M H3BO3(pH = 4).
Cross Talk of Proteostasis and Mitostasis in Cellular Homeodynamics, Ageing, and Disease
Authors: Gumeni Sentiljana , Trougakos Ioannis P.
Published: February 2016

Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cell. Therefore, maintenance of mitochondria activity is necessary for the proper cellular function and survival. To this end, several mechanisms that act at different levels and time points have been developed to ensure mitochondria quality control. An interconnected highly integrated system of mitochondrial and cytosolic chaperones and proteases along with the fission/fusion machinery represents the surveillance scaffold of mitostasis. Moreover, nonreversible mitochondrial damage targets the organelle to a specific autophagic removal, namely, mitophagy. Beyond the organelle dynamics, the constant interaction with the ubiquitin‐proteasome‐system (UPS) has become an emerging aspect of healthy mitochondria. Dysfunction of mitochondria and UPS increases with age and correlates with many age‐related diseases including cancer and neurodegeneration. In this review, we discuss the functional cross talk of proteostasis and mitostasis in cellular homeodynamics and the impairment of mitochondrial quality control during ageing, cancer, and neurodegeneration.
Selective Inhibition of Bakuchicin Isolated from Psoralea corylifolia on CYP1A in Human Liver Microsomes
Authors: Kim Sun Joo , Oh Heung Chan , Kim Youn-Chul , Jeong Gil-Saeng , Lee Sangkyu
Published: February 2016

Bakuchicin is a furanocoumarin isolated from Psoralea corylifolia and shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinant cDNA-expressed CYP. Bakuchicin strongly inhibited CYP1A‐mediated phenacetin O‐deethylation with an IC50 value of 0.43 μM in HLMs. It was confirmed by human recombinant cDNA-expressed CYP1A1 and CYP1A2 with a Ki value of 0.11 μM and 0.32 μM, respectively. A Lineweaver‐Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs.
Male Involvement in Maternal Health Planning Key to Utilization of Skilled Birth Services in Malindi Subcounty, Kenya
Authors: Nyandieka Lilian Nyamusi , Njeru Mercy Karimi , Ng’ang’a Zipporah , Echoka Elizabeth , Kombe Yeri
Published: February 2016

Background.In Malindi, rural populations face challenges in accessing skilled birth services. Consequently, the majority of women deliver at home and only seek help when they have complications. This paper reports part findings from a study conducted to assess health priority setting process and its implication on availability, access, and use of emergency obstetric care services in Malindi.Methods. The study utilized qualitative methods to collect data from health personnel and maternal health stakeholders including community members. Source and method triangulation was used to strengthen the credibility of study findings. Data was categorized manually into themes around issues relating to utilization of skilled birth services discussed in this paper.Findings. Various barriers to utilization of skilled birth services were cited. However, most were linked tomwenye(the husband) who decides on the place of birth for the wife.Conclusion.Husbands are very influential in regard to decisions on skilled birth service utilization in this community. Their lack of involvement in maternal health planning may contribute as a barrier to utilization of skilled care by pregnant women. There is need to address themwenyefactor in an attempt to mitigate some of the barriers cited for nonutilization of skilled birth services.
The Th17/Treg Immune Imbalance in Ulcerative Colitis Disease in a Chinese Han Population
Authors: Gong Yang , Lin Yifan , Zhao Ning , He Xiaojuan , Lu Aiping , Wei Wei , Jiang Miao
Published: February 2016

Objective. To investigate the Th17/Treg immune balance in the ulcerative colitis (UC) patients in a Chinese Han population. Methods. Ninety UC patients and 30 healthy subjects were enrolled. The serum IL-17 and TGF-β1 levels of these participants were measured with ELISA; the percentage of Th17 and Treg cells in peripheral blood was determined with flow cytometry. Results. In UC patients, the levels of IL-17 and Th17 were significantly higher compared with healthy subjects; the percentage of Th17 and IL-17 level in moderate and severe subgroup was significantly higher than in mild subgroup; a positive correlation existed between these two indexes and clinical activity index and endoscopic evaluation. TGF-β1 level and Treg cells in UC patients were lower than healthy subjects. TGF-β1 level in moderate and severe subgroup was lower than in mild subgroup. There was a negative linear correlation between Treg cells and clinical activity index, endoscopic evaluation. A positive correlation was detected between Treg cells and TGF-β1 level. Conclusions. Th17/Treg immune imbalance might play a crucial role in the development of UC. To induce the production of Treg cells and TGF-β1, inhibit the level of Th17 and IL-17, and thus recover the Th17/Treg immune balance might imply new therapeutic targets in UC management.
Epigallocatechin‐3‐gallate Protects against Hydrogen Peroxide‐Induced Inhibition of Osteogenic Differentiation of Human Bone Marrow‐Derived Mesenchymal Stem Cells
Authors: Wang Dawei , Wang Yonghui , Xu Shihong , Wang Fu , Wang Bomin , Han Ke , Sun Daqing , Li Lianxin
Published: February 2016

Oxidative stress induces bone loss and osteoporosis, and epigallocatechin‐3‐gallate (EGCG) may be used to combat these diseases due to its antioxidative property. Herein, oxidative stress in human bone marrow‐derived mesenchymal stem cells (BM‐MSCs) was induced by H2O2, resulting in an adverse effect on their osteogenic differentiation. However, this H2O2‐induced adverse effect was nullified when the cells were treated with EGCG. In addition, treatment of BM‐MSCs with EGCG alone also resulted in the enhancement of osteogenic differentiation of BM‐MSCs. After EGCG treatment, expressions of β‐catenin and cyclin D1 were upregulated, suggesting that the Wnt pathway was involved in the effects of EGCG on the osteogenic differentiation of BM‐MSCs. This was also confirmed by the fact that the Wnt pathway inhibitor, Dickkopf‐1 (DKK‐1), can nullify the EGCG‐induced enhancement effect on BM‐MSC’s osteogenic differentiation. Hence, our results suggested that EGCG can reduce the effects of oxidative stress on Wnt pathway in osteogenic cells, which supported a potentially promising therapy of bone disorders induced by oxidative stress. Considering its positive effects on BM‐MSCs, EGCG may also be beneficial for stem cell‐based bone repair.
Robotic Partial Nephrectomy with the Da Vinci Xi
Authors: Kallingal George J. S. , Swain Sanjaya , Darwiche Fadi , Punnen Sanoj , Manoharan Murugesan , Gonzalgo Mark L. , Parekh Dipen J.
Published: February 2016

Purpose.The surgical expertise to perform robotic partial nephrectomy is heavily dependent on technology. The Da Vinci Xi (XI) is the latest robotic surgical platform with significant advancements compared to its predecessor. We describe our operative technique and experience with the XI system for robotic partial nephrectomy (RPN).Materials and Methods.Patients with clinical T1 renal masses were offered RPN with the XI. We used laser targeting, autopositioning, and a novel “in-line” port placement to perform RPN.Results.15 patients underwent RPN with the XI. There were no intraoperative complications and no operative conversions. Mean console time was 101.3 minutes (range 44–176 minutes). Mean ischemia time was 17.5 minutes and estimated blood loss was 120 mLs. 12 of 15 patients had renal cell carcinoma. Two patients had oncocytoma and one had benign cystic disease. All patients had negative surgical margins and pathologic T1 disease. Two postoperative complications were encountered, including one patient who developed a pseudoaneurysm and one readmitted for presumed urinary tract infection.Conclusions.RPN with the XI system can be safely performed. Combining our surgical technique with the technological advancements on the XI offers patients acceptable pathologic and perioperative outcomes.
A Comparative Study of Spreadsheet Applications on Mobile Devices
Authors: Chintapalli Veera V. S. M. , Tao Wenyuan , Meng Zhaopeng , Zhang Kang , Kong Jun , Ge Yue
Published: February 2016

Advances in mobile screen sizes and feature enhancement for mobile applications have increased the number of users accessing spreadsheets on mobile devices. This paper reports a comparative usability study on four popular mobile spreadsheet applications: OfficeSuite Viewer 6, Documents To Go, ThinkFree Online, and Google Drive. We compare them against three categories of usability criteria: visibility; navigation, scrolling, and feedback; and interaction, satisfaction, simplicity, and convenience. Measures for each criterion were derived in a survey. Questionnaires were designed to address the measures based on the comparative criteria provided in the analysis.
Genomic Landscape of Somatic Alterations in Esophageal Squamous Cell Carcinoma and Gastric Cancer
Authors: Hu Nan , Kadota Mitsutaka , Liu Huaitian , Abnet Christian C. , Su Hua , Wu Hailong , Freedman Neal D. , Yang Howard H. , Wang Chaoyu , Yan Chunhua , Wang Lemin , Gere Sheryl , Hutchinson Amy , Song Guohong , Wang Yuan , Ding Ti , Qiao You-Lin , Koshiol Jill , Dawsey Sanford M. , Giffen Carol , Goldstein Alisa M. , Taylor Philip R. , Lee Maxwell P.
Published: February 2016

Gastric cancer and esophageal cancer are the second and sixth leading causes of cancer-related death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma. Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR. Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development. Cancer Res; 76(7); 1714–23. ©2016 AACR.
Immunologic and Metabolic Features of Pancreatic Ductal Adenocarcinoma Define Prognostic Subtypes of Disease
Authors: Hutcheson Jack , Balaji Uthra , Porembka Matthew R. , Wachsmann Megan B. , McCue Peter A. , Knudsen Erik S. , Witkiewicz Agnieszka K.
Published: February 2016

Purpose: Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive microenvironment that supports the growth of the malignancy as well as immune system evasion. Here we examine markers of immunosuppression in PDA within the context of the glycolytic tumor microenvironment, their interrelationship with tumor biology and association with overall survival.

Experimental Design: We utilized tissue microarrays consisting of 223 PDA patients annotated for clinical stage, tumor size, lymph node involvement, and survival. Expression of CD163, FoxP3, PD-L1, and MCT4 was assessed by IHC and statistical associations were evaluated by univariate and multivariate analysis. Multimarker subtypes were defined by random forest analysis. Mechanistic interactions were evaluated using PDA cell lines and models for myeloid differentiation.

Results: PDA exhibits discrete expression of CD163, FoxP3, and PD-L1 with modest individual significance. However, combined low expression of these markers was associated with improved prognosis (P = 0.02). PDA tumor cells altered macrophage phenotype and function, which supported enhanced invasiveness in cell-based models. Lactate efflux mediated by MCT4 was associated with, and required for, the selective conversion of myeloid cells. Correspondingly, MCT4 expression correlated with immune markers in PDA cases, and increased the significance of prognostic subtypes (P = 0.002).

Conclusions: There exists a complex interplay between PDA tumor cells and the host immune system wherein immunosuppression is associated with negative outcome. MCT4 expression, representative of the glycolytic state of PDA, contributes to the phenotypic conversion of myeloid cells. Thus, metabolic status of PDA tumors is an important determinant of the immunosuppressive environment. Clin Cancer Res; 22(14); 3606–17. ©2016 AACR.
The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials
Authors: Li Guifang , Gao Shunji , Sheng Zhixin , Li Bin
Published: February 2016

Objective: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. Method: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Results: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. Conclusions: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients.
Routine Use of Probiotics in Preterm Infants: Longitudinal Impact on the Microbiome and Metabolome
Authors: Abdulkadir Bashir , Nelson Andrew , Skeath Tom , Marrs Emma C.L. , Perry John D. , Cummings Stephen P. , Embleton Nicholas D. , Berrington Janet E. , Stewart Christopher J.
Published: February 2016

Background: Probiotics are live microbial supplements that colonize the gut and potentially exert health benefit to the host. Objectives: We aimed to determine the impact of a probiotic (Infloran®: Lactobacillus acidophilus-NCIMB701748 and Bifidobacterium bifidum-ATCC15696) on the bacterial and metabolic function of the preterm gut while in the neonatal intensive care unit (NICU) and following discharge. Methods: Stool samples (n = 88) were collected before, during, and after probiotic intake from 7 patients, along with time-matched controls from 3 patients. Samples were also collected following discharge home from the NICU. Samples underwent bacterial profiling analysis by 16S rRNA gene sequencing and quantitative PCR (qPCR), as well as metabolomic profiling using liquid chromatography mass spectrometry. Results: Bacterial profiling showed greater Bifidobacterium (15.1%) and Lactobacillus (4.2%) during supplementation compared to the control group (4.0% and 0%, respectively). While Lactobacillus became reduced after the probiotic had been stopped, Bifidobacterium remained high following discharge, suggestive of successful colonisation. qPCR analysis showed a significant increase (p ≤ 0.01) in B. bifidum in infants who received probiotic treatment compared to controls, but no significant increase was observed for L. acidophilus (p = 0.153). Metabolite profiling showed clustering based on receiving probiotic or matched controls, with distinct metabolites associated with probiotic administration. Conclusions: Probiotic species successfully colonise the preterm gut, reducing the relative abundance of potentially pathogenic bacteria, and effecting gut functioning. Bifidobacterium (but not Lactobacillus) colonised the gut in the long term, suggesting the possibility that therapeutically administered probiotics may continue to exert important functional effects on gut microbial communities in early infancy.
Very Low Birth Weight Monochorionic Diamniotic Twins as a Risk Factor for Symptomatic Patent Ductus Arteriosus
Authors: Yamaguchi Hiroshi , Wada Keiko , Nagasawa Miho , Kikusui Takefumi , Sakai Hitomi , Mizobuchi Masami , Yoshimoto Seiji , Nakao Hideto
Published: February 2016

Background: Some prior studies have shown that symptomatic patent ductus arteriosus (sPDA) is highly familial. Although it is estimated that both genetic and environmental factors may contribute to sPDA, evidence is still lacking. Objective: The aim of this study was to determine the risk factors for sPDA, focusing on the genetic and in utero environment by analyzing very low birth weight (VLBW) singletons and twins. Methods: This retrospective case-control study reviewed the medical records of 445 VLBW infants (25 weeks ≤ gestational age <32 weeks, 600 g ≤ birth weight <1,500 g) and compared the incidence of sPDA among monochorionic diamniotic (MD) twins (n = 65), dichorionic diamniotic (DD) twins (n = 66), and singletons (n = 314). Results: Stepwise multiple regression analysis showed that twin siblings (p = 0.001), gestational week (p < 0.001), antenatal steroid use (p = 0.021), and premature rupture of membranes (p = 0.002) were independent predictors of sPDA. Incidence of sPDA in MD twin siblings was significantly higher than that in singletons (p < 0.01), whereas no significant difference was found between singletons and DD twins or between MD and DD twins. Conclusions: The current results show that being a VLBW MD twin is an independent risk factor for sPDA, and that both genetic and in utero environmental factors may contribute to its development.
Decrease of Store-Operated Ca2+ Entry and Increase of Na+/Ca2+ Exchange by Pharmacological JAK2 Inhibition
Authors: Yan Jing , Hosseinzadeh Zohreh , Zhang Bingbing , Froeschl Mirjam , Schulze-Osthoff Klaus , Stournaras Christos , Lang Florian
Published: February 2016

Background/Aims: Cell proliferation and migration are regulated by cytosolic Ca2+ activity ([Ca2+]i). Mechanisms modifying [Ca2+]i include store-operated Ca2+-entry (SOCE) accomplished by the pore-forming ion channel unit Orai1 and its regulator STIM1, as well as Ca2+ extrusion by Na+/Ca2+ exchanger NCX1. Kinases participating in the orchestration of cell proliferation include the Janus activated kinase JAK2. The present study explored the impact of pharmacological JAK2 inhibition on SOCE and Na+/Ca2+ exchange. Methods: MCF-7 breast carcinoma cells were studied in the absence and presence of the JAK2 inhibitors TG101348 (250 nM - 1 µM) or of AG490 (20 - 40 µM). Transcript levels were quantified with RT-PCR, protein abundance with immunoblotting, [Ca2+]i with Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and Na+/Ca2+ exchanger activity from increase of [Ca2+]i as well as Ca2+ current in whole cell patch clamp following extracellular Na+ removal. Migratory activity was determined by a wound healing assay. Results: JAK2 inhibitor TG101348 (1 µM) decreased Orai1 and STIM1 protein abundance, increased NCX1 transcript levels, decreased Ca2+ release from intracellular stores, decreased SOCE, increased Ca2+ entry as well as Ca2+-current following extracellular Na+-removal, and decreased migration. Similar effects on Ca2+ release, SOCE, and Ca2+-entry following extracellular Na+-removal were observed following treatment with AG490. Conclusion: The present observations disclose a novel powerful mechanism regulating intracellular Ca2+ release, cellular Ca2+ entry, cellular Ca2+ extrusion and cell migration.
Anti-Inflammatory and Antioxidant Actions of N-Arachidonoyl Serotonin in RAW264.7 Cells
Authors: Jeon Hye Lyun , Yoo Jae-Myung , Lee Bo Dam , Lee Su Jin , Sohn Eun Jung , Kim Mee Ree
Published: February 2016

The purpose of this study is to evaluate the effect of N-arachidonoyl serotonin (NA-5HT) on inflammatory response or oxidative stress in RAW264.7 cells exposed to lipopolysaccharide (LPS). When RAW264.7 cells were pre-incubated with NA-5HT before LPS treatment, NA-5HT was found to suppress LPS-induced formation of nitric oxide (NO), tumor necrosis factor-a or interleukins as well as expression of inducible NO synthase and cyclooxygenase-2 at non-cytotoxic concentrations. Consistent with this, NA-5HT efficiently reversed LPS-induced phosphorylative activation of nuclear factor-κB pathway probably through the suppression of mitogen-activated protein kinases (MAPKs) pathway or phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Separately, NA-5HT enhanced the antioxidant capacity accompanied by nuclear translocation of nuclear factor-E2-related factor-2 (Nrf2) in RAW264.7 cells. Additionally, NA-5HT-induced nuclear translocation of Nrf2 was suppressed significantly by the inhibition of c-Jun N-terminal kinase1/2 or PI3K/Akt pathways, although NA-5HT phosphorylated signal molecules in MAPKs and PI3K/Akt pathways. Taken together, NA-5HT is proposed to exert anti-inflammatory and antioxidant actions in RAW264.7 cells.
An Appraisal of Inflammatory Markers in Distinguishing Acute Uncomplicated and Complicated Appendicitis
Authors: Beecher Suzanne M. , Hogan John , O'Leary DP , McLaughlin Ray
Published: February 2016

Background: It remains difficult to distinguish between complicated appendicitis (CAP) and uncomplicated appendicitis (UAP). There is a paucity of studies utilizing inflammatory markers to stratify the severity of acute appendicitis. This study aimed to evaluate and demonstrate the potential clinical utility of inflammatory markers as adjuncts in distinguishing CAP and UAP. Methods: A comparative observational study was performed. Patients diagnosed with acute appendicitis were categorized as (a) complicated (necrosis, perforation, abscess) and (b) uncomplicated (inflamed, edematous). Hematological indices were combined to generate the following ratios: white cell lymphocyte ratio (WLR), white cell neutrophil ratio (WNR) and neutrophil lymphocyte ratio (NLR). Parameter accuracy was assessed using summary receiver operating characteristic (sROC) curves, classification and regression tree analysis and confusion matrix generation. Results: On sROC analysis, neutrophils (area under the curve (AUC) 0.79, p < 0.001), WLR (AUC 0.79, p < 0.001) and NLR (AUC 0.79, p < 0.001) were the most accurate parameters in distinguishing CAP and UAP. White cell count (WCC; AUC 0.76, p < 0.001) and C-reactive protein (AUC 0.75, p < 0.001) were less accurate. WCC >12.25 (sensitivity 70%, specificity 68%) and NLR >5.47 (sensitivity 78%, specificity 70%) were the most accurate in identifying CAP. Conclusion: Inflammatory marker cutoff points can be generated and utilized to differentiate between UAP and CAP. This may be useful when deciding between conservative and operative management.
A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca
2+
Clock
Authors: Wu Yuejin , Valdivia Héctor H. , Wehrens Xander H.T. , Anderson Mark E.
Published: February 2016

Background—

Fight or flight heart rate (HR) increases depend on protein kinase A (PKA)– and calmodulin kinase II (CaMKII)–mediated enhancement of Ca
2+
uptake and release from sarcoplasmic reticulum (SR) in sinoatrial nodal cells (SANC). However, the impact of specific PKA and CaMKII phosphorylation sites on HR is unknown.

Methods and Results—

We systematically evaluated validated PKA and CaMKII target sites on phospholamban and the ryanodine receptor using genetically modified mice. We found that knockin alanine replacement of ryanodine receptor PKA (S2808) or CaMKII (S2814) target sites failed to affect HR responses to isoproterenol or spontaneous activity in vivo or in SANC. Similarly, selective mutation of phospholamban amino acids critical for enhancing SR Ca
2+
uptake by PKA (S16) or CaMKII (T17) to alanines did not affect HR in vivo or in SANC. In contrast, CaMKII inhibition by expression of AC3-I has been shown to slow SANC rate responses to isoproterenol and decrease SR Ca
2+
content. Phospholamban deficiency rescued SR Ca
2+
content and SANC rate responses to isoproterenol in mice with AC3-I expression, suggesting that CaMKII affects HR by modulation of SR Ca
2+
content. Consistent with this, mice expressing a superinhibitory phospholamban mutant had low SR Ca
2+
content and slow HR in vivo and in SANC.

Conclusions—

SR Ca
2+
depletion reduces HR and SR Ca
2+
repletion restores physiological SANC rate responses, despite CaMKII inhibition. PKA and CaMKII do not affect HR by a unique target site governing SR Ca
2+
uptake or release. HR acceleration may require an SR Ca
2+
content threshold.
Catheter Ablation of Nonparoxysmal Atrial Fibrillation Using Electrophysiologically Guided Substrate Modification During Sinus Rhythm After Pulmonary Vein Isolation
Authors: Yang Gang , Yang Bing , Wei Youquan , Zhang Fengxiang , Ju Weizhu , Chen Hongwu , Li Mingfang , Gu Kai , Lin Yazhou , Wang Benqi , Cao Kejiang , Kojodjojo Pipin , Chen Minglong
Published: February 2016

Background—

The high incidence of postprocedural atrial tachycardia reduces the absolute arrhythmia-free success rate of extensive ablation strategies to treat nonparoxysmal atrial fibrillation (NPAF). We hypothesized that a strategy of targeting low-voltage zones and sites with abnormal electrograms during sinus rhythm (SR-AEs) in the left atrium after circumferential pulmonary vein isolation and cavotricuspid isthmus ablation in patients with NPAF is superior.

Methods and Results—

A total of 86 consecutive patients with NPAF were enrolled in study group. After circumferential pulmonary vein isolation, cavotricuspid isthmus ablation and cardioversion to SR, high-density mapping of left atrium was performed. Areas with low-voltage zone and SR-AE were targeted for further homogenization and elimination, respectively; 78 consecutive sex- and age-matched patients with NPAF who were treated with the stepwise approach served as the historical control group. In the study group, 92% (79/86) were successfully cardioverted after circumferential pulmonary vein isolation and cavotricuspid isthmus ablation. Among the patients converted to SR, 70% (55/79) had low-voltage zone and SR-AE and received additional ablation, whereas in 30% (24/79) without SR-AE or low-voltage zone, no further ablation was performed. During a follow-up period of >30 months, the Kaplan–Meier estimated probability to maintain SR at 24 months was 69.8% versus 51.3%. And after a single procedure, 3.5% (3/86) developed postprocedural atrial tachycardia in study group, compared with 30% (24/78) in control group (
P
=0.0003).

Conclusions—

A strategy of selective electrophysiologically guided atrial substrate modification in SR after circumferential pulmonary vein isolation and cavotricuspid isthmus ablation is clinically more effective than the stepwise approach for NPAF ablation.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT01716143.
Randomized Study of Persistent Atrial Fibrillation Ablation
Authors: Bassiouny Mohamed , Saliba Walid , Hussein Ayman , Rickard John , Diab Mariam , Aman Wahaj , Dresing Thomas , Callahan, Thomas , Bhargava Mandeep , Martin David O. , Shao Mingyuan , Baranowski Bryan , Tarakji Khaldoun , Tchou Patrick J. , Hakim Ali , Kanj Mohamed , Lindsay Bruce , Wazni Oussama
Published: February 2016

Background—

Achieving long-term successful outcomes with ablation of persistent atrial fibrillation (AF) remains a clinical and procedural challenge. We aimed to assess 2 ablation strategies for persistent AF: pulmonary vein antral isolation (PVAI) in sinus rhythm after direct current cardioversion versus PVAI and ablation targeting complex-fractionated atrial electrograms while in AF.

Methods and Results—

Between June 2009 and July 2013, patients with continuous persistent AF for ≥3 months were prospectively randomized to either direct current cardioversion before PVAI and posterior wall/septum ablation while in sinus rhythm (group 1), versus same ablation in group 1 in addition to complex-fractionated atrial electrogram ablation while in AF (group 2). The procedural profiles and clinical outcomes of the 2 strategies were compared. Ninety patients were randomized to group 1 (n=46) or group 2 (n=44). There were no differences in baseline characteristics between groups. Over 365 days of follow-up after the index procedure, 16 patients (35%) in group 1 and 13 patients (30%) in group 2 remained arrhythmia-free off antiarrhythmic medications. Over long-term follow-up (median, 867 days), arrhythmia-free survival off antiarrhythmic medications was more likely in group 1 than in group 2 in Kaplan–Meier analysis (Log Rank
P
=0.04). Group 1 ablation was associated with significantly shorter procedural duration and fluoroscopy time (231±72 versus 273±76 min;
P
=0.008 and 54 [Q1–Q3: 46–67] versus 66 (Q1–Q3: 53–83] min;
P
=0.018, respectively).

Conclusions—

In patients with persistent AF, PVAI in sinus rhythm after direct current cardioversion is associated with higher success and shorter procedural and fluoroscopy times compared with PVAI in AF with additional complex-fractionated atrial electrogram ablation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02429648.
Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats
Authors: Bertagnolli Mariane , Dios Anne , Béland-Bonenfant Sarah , Gascon Gabrielle , Sutherland Megan , Lukaszewski Marie-Amélie , Cloutier Anik , Paradis Pierre , Schiffrin Ernesto L. , Nuyt Anne Monique
Published: February 2016

Newborn rats exposed to high oxygen (O
2
), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O
2
-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O
2
exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O
2
or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O
2
exposure), P5, P10 (end of O
2
), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O
2
exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O
2
-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O
2
prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.
γ‐Glutamyltransferase and Risk of Sudden Cardiac Death in Middle‐Aged Finnish Men: A New Prospective Cohort Study
Authors: Kunutsor Setor K. , Khan Hassan , Laukkanen Jari A.
Published: February 2016

Background

γ‐Glutamyltransferase (
GGT
) has been linked to an increased risk of several cardiovascular outcomes; however, the relationship of
GGT
with sudden cardiac death (
SCD
) has not been investigated previously. We aimed to assess the association of
GGT
with risk of
SCD
.

Methods and Results

Serum
GGT
activity was assessed at baseline in the Kuopio Ischemic Heart Disease prospective cohort of 1780 men, and 136
SCD
s were recorded during 22 years of follow‐up. Correction for within‐person variability was made using data from repeated measurements taken several years apart. The regression dilution ratio of log
e
GGT
adjusted for age was 0.68 (95%
CI
0.61–0.74). Serum
GGT
was log‐linearly associated with risk of
SCD
. The hazard ratio for
SCD
per 1 SD higher baseline log
e
GGT
values (2‐fold higher) was 1.30 (95%
CI
1.10–1.54;
P
=0.002) after adjustment for several established risk factors and remained consistent with further adjustment for alcohol consumption, resting heart rate, lipids, and C‐reactive protein (hazard ratio 1.26, 95%
CI
1.05–1.50;
P
=0.014). The corresponding hazard ratios were 1.48 (95%
CI
1.15–1.89;
P
=0.002) and 1.40 (95%
CI
1.07–1.82;
P
=0.014) after correction for within‐person variability. Hazard ratios remained unchanged after accounting for incident coronary events and did not vary importantly by levels or categories of prespecified conventional risk factors.

Conclusions

GGT
is positively, log‐linearly, and independently associated with future risk of
SCD
in the general male population. Further research is needed to replicate these findings.
Challenges to Justice at Home: The Domestic Prosecution of Efrain Rios Montt
Authors: Robinson Alicia
Published: February 2016

In March 2013, at the age of 89, Efraín Ríos Montt became the first former head of state to ever be convicted of genocide by a national tribunal. After prior failed attempts to try him for this crime, his conviction to 80 years in prison was hailed as a victory both in Guatemala and abroad. Just ten days later, Guatemala’s Constitutional Court annulled the verdict and ordered a second trial. Having since been deemed mentally unfit to stand for trial, he will be tried in a closed quarters special proceeding in January 2016, but if found guilty, will not be sentenced. This article explains why Guatemalan national courts tried the case against Ríos Montt, and discusses the historical factors that led to the trial, questioning whether they are replicable in other countries. It argues that the necessary elements for a successful implementation of that conviction were present in Guatemala, but suggests that the political climate was inadequately negotiated in order to prevent the subsequent annulment of the verdict.
Is Targeting Naked Child Soldiers a War Crime?
Authors: Nicholson Joanna
Published: February 2016

International law prohibits the recruitment and use of children under the age of fifteen to participate actively in hostilities. Such child soldiers constitute military targets under international humanitarian law (ihl), and the prevailing view is that they may be targeted in the same way as their adult counterparts. Although there may be moral or pragmatic reasons for avoiding targeting child soldiers if possible, there is no obligation under international law to treat them differently from an adult fighter.
The Cooperation Provisions of the un Convention against Transnational Organised Crime: A ‘Toolbox’ Rarely Used?
Authors: Boister Neil
Published: February 2016

This article examines the provisions for international cooperation in the un Convention against Transnational Organised Crime (untoc) and their effectiveness in achieving the untoc’s goal of promoting effective cooperation in the prevention and combating of transnational organised crime. It is a response to the growing sense that the untoc is not as effective a tool as promised, which sense is exacerbated by the absence of a functional review mechanism for the untoc. The article notes the delimitation of the scope of the untoc based on organised crime groups that participate in serious transnational crime. It then goes on to describe the untoc’s provisions for informal law enforcement cooperation, mutual legal assistance, international cooperation in asset recovery and extradition, and examines what little evidence there is of the implementation of these provisions. It concludes that the untoc appears to be have been more successful as a tool for promoting informal rather than formal cooperation, and speculates as to why this may be so.
Transforming Time – the Maternal Church and the Pilgrimage of Faith
Authors: Beattie Tina
Published: February 2016

Two related themes running through Pope Francis’ theology form the focus of this article: the importance of time over space in the context of the unfolding story of salvation as a journey through history, and the motherhood of the Church, personified in Mary. On the face of it, these two different theological metaphors are not easy to combine to form a coherent ecclesiology. The first develops the Second Vatican Council’s imagery of the Church as the pilgrim people of God, and the other draws on the ancient metaphor of the Church as Mother. This article explores each of these in turn, in order to suggest ways in which they can be creatively integrated to offer a revitalised ecclesiology for our times. However, this can only happen if the church takes a leap of faith to acknowledge the sacramental significance of the female body.
From the Joy of the Gospel to the Joy of Christ
Authors: McCosker Philip
Published: February 2016

Many have perceived and reacted to the fresh presentation of the Christian gospel in the pontificate of Francis. It is tempting to read this as a switch in emphasis from content to form, or from ideas to action, and play Benedict XVI off against Francis I: the introverted scholarly theologian followed by the charismatic preacher. Ultimately undermining such a dichotomising approach, this article describes, analyses, situates, and draws out Francis’ christology. Exploring resonances between Francis’ thought and some ressourcement thinkers (Romano Guardini, Josef Jungmann, Yves Congar), it uncovers the christology underlying Evangelii Gaudium. Attention to the role of christology in Francis’ thought, as well as the inspiration he continues to draw from ressourcement thinkers, especially Guardini, uncovers surprisingly significant links between Bergoglio and Ratzinger.
Ecclesia et Pontifice: On Delivering on the Ecclesiological Implications of Evangelii Gaudium
Authors: Murray Paul D.
Published: February 2016

This article analyses the ecclesiological implications of Pope Francis’s 2013 Apostolic Exhortation Evangelii Gaudium from the perspective of critical-constructive systematic ecclesiology. The analysis proceeds in three stages. The first, expository, section identifies the key sites of ecclesiological significance in eg. The second section reflects on the broad implications of eg for the contemporary task of Roman Catholic ecclesiology – and Catholic theology more generally – concerning how these tasks should appropriately be pursued. The third section identifies something of the range of specific issues and potential ways ahead pertaining to the various sites of ecclesiological significance in eg and representing the focussed critical-constructive work now needing to be done.