bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trends in the incidence and mortality of multiple births by socioeconomic deprivation and maternal age in England: population-based cohort study
Authors: Smith Lucy K , Manktelow Bradley N , Draper Elizabeth S , Boyle Elaine M , Johnson Samantha J , Field David J 
Published: April 2014

ObjectiveTo investigate temporal trends in multiple birth rates and associated stillbirth and neonatal mortality by socioeconomic deprivation and maternal age in England.DesignPopulation cohort study.SettingEngland.ParticipantsAll live births and stillbirths (1 January 1997 to 31 December 2008).Main outcome measuresMultiple maternity rate, stillbirth and neonatal death rate by year of birth, decile of socioeconomic deprivation and maternal age.ResultsThe overall rate of multiple maternities increased over time (+0.64% per annum 95% CI (0.47% to 0.81%)) with an increase in twin maternities (+0.85% per annum 95% CI (0.67% to 1.0%)) but a large decrease in triplet and higher order maternities (−8.32% per annum 95% CI (−9.39% to −7.25%)). Multiple maternities were significantly lower in the most deprived areas, and this was most evident in the older age groups. Women over 40 years of age from the most deprived areas had a 34% lower rate of multiple births compared with similar aged women from the most deprived areas (rate ratio (RR) 0.66 95% CI (0.61 to 0.73)). Multiple births remain at substantially higher risk of neonatal mortality (RR 6.30 95% CI (6.07 to 6.53)). However, for stillbirths, while twins remain at higher risk, this has decreased over time (1997–2000: RR 2.89 (2.69 to 3.10); 2005–2008: RR 2.22 95% CI (2.06 to 2.40)). Socioeconomic inequalities existed in mortality for singletons and multiple births.ConclusionsThis period has seen increasing rates of twin pregnancies and decreasing rates of higher order births which have coincided with changes in recommendations regarding assisted reproductive techniques. Socioeconomic differences in multiple births may reflect differential access to these treatments. Improved monitoring of multiple pregnancies is likely to have led to the reductions in stillbirths over this time.
Relationship between target organ damage and blood pressure, retinal vessel calibre, oxidative stress and polymorphisms in VAV-2 and VAV-3 genes in patients with hypertension: a case–control study protocol (LOD-Hipertensión)
Authors: Gomez-Marcos Manuel A , Gonzalez-Sarmiento Rogelio , Recio-Rodríguez José I , Agudo-Conde Cristina , Gamella-Pozuelo Luis , Perretta-Tejedor Nuria , Martínez-Salgado Carlos , García-Ortiz Luis 
Published: April 2014

IntroductionTarget organ damage (TOD) is associated with increased cardiovascular risk. The study objectives were to analyse the relationship of TOD to blood pressure, size of retinal arteries and veins, oxidative stress and different polymorphisms in the VAV-2 and VAV-3 genes in participants with hypertension.Methods and analysisA case–control study to analyse the relationship between clinical, biochemical and genetic parameters and presence of cardiac, vascular and renal TOD in 486 patients with hypertension. Participants with TOD will be considered as cases, and those without TOD will be enrolled as controls. This will be a collaborative study conducted by the groups of Primary Care, Cardiovascular and Metabolic and Degenerative Diseases of the Instituto de Investigación Biomédica of Salamanca (IBSAL). Assessment of cardiac, renal and vascular TOD. Measurement of peripheral and central blood pressure, size of eye fundus arteries and veins, and oxidative stress, and polymorphisms in the VAV-2 and VAV-3 genes.Ethics and disseminationThe study will be conducted after approval is obtained from the Ethics Committee of Hospital Clínico Universitario of Salamanca. All study participants will sign an informed consent to agree to participate in the study, and another consent to agree on the genetic study, in compliance with the Declaration of Helsinki and the WHO standards for observational studies. The results of this study will allow for an understanding of the relationship of the different TODs with blood pressure, retinal artery and vein diameters, oxidative stress and polymorphisms in VAV-2 and VAV-3 genes.Trial registration numberClinical Trials. gov Identifier:NCT02022618.
Would you have laparoscopic Nissen fundoplication again? A patient satisfaction survey in a UK population
Authors: Courtney Michael J , Rao Milind , Teasdale Rebecca , Jain Rajesh , Gopinath Bussa 
Published: April 2014

ObjectiveLaparoscopic Nissen fundoplication (LNF) effectively reduces objective gastro-oesophageal reflux. It can however cause side effects which affect quality of life or fail to improve subjective reflux symptoms. This study aims to assess patient satisfaction following LNF by assessing whether patients would have the procedure again.DesignTelephone survey using a structured questionnaire. Participation was voluntary.SettingUK Foundation Trust (two university hospitals).PatientsAll patients who had LNF performed by a single surgeon between November 2008 and June 2012.Main outcome measuresPrimarily, current reflux symptoms, antiacid medication requirement and whether participants would choose to have the procedure again (should they still have their initial symptoms). Further measures were conversion to open procedure, need for redo or reversal, and mortality.Results99 patients underwent LNF in the quoted period; 71 were contactable and willing to participate. Of the 99, two required redo operations (neither of whom was contactable), and one had a reversal (primary operation included). Median time since the operation was 33 months (range 5–48 months). Compared with preoperatively, 72% rated their current reflux-symptom severity as ≤2/10, 23% as 3–6/10 and 4% as 7–10/10. 75% were not taking any antiacid medication. 89% of patients said that they would have the procedure again.ConclusionsThis study provides supporting evidence that LNF improves reflux symptoms and decreases medication use at intermediate-term follow-up. These results will aid counselling and reassurance of patients regarding the risks and benefits of LNF as the majority of postoperative patients were sufficiently satisfied to choose the operation again.
The potential for reducing differences in life expectancy between educational groups in five European countries: the effects of obesity, physical inactivity and smoking
Authors: Mäki Netta E , Martikainen Pekka T , Eikemo Terje , Menvielle Gwenn , Lundberg Olle , Östergren Olof , Mackenbach Johan P ,   the EURO-GBD-SE consortium members
Published: April 2014

IntroductionThis study assesses the effects of obesity, physical inactivity and smoking on life expectancy (LE) differences between educational groups in five European countries in the early 2000s.MethodsWe estimate the contribution of risk factors on LE differences between educational groups using the observed risk factor distributions and under a hypothetically more optimal risk factor distribution. Data on risk factor prevalence were obtained from the Survey of Health, Ageing and Retirement in Europe study, and data on mortality from census-linked data sets for the age between 50 and 79 according to sex and education.ResultsSubstantial differences in LE of up to 2.8 years emerged between men with a low and a high level of education in Denmark, Austria and France, and smaller differences among men in Italy and Spain. The educational differences in LE were not as large among women. The largest potential for reducing educational differences was in Denmark (25% among men and 41% among women) and Italy (14% among men).ConclusionsThe magnitude of the effect of unhealthy behaviours on educational differences in LE varied between countries. LE among those with a low or medium level of education could increase in some European countries if the behavioural risk factor distributions were similar to those observed among the highly educated.
Low-profile Visualized Intraluminal Support device (LVIS Jr) as a novel tool in the treatment of wide-necked intracranial aneurysms: initial experience in 32 cases
Authors: Behme Daniel , Weber Anushe , Kowoll Annika , Berlis Ansgar , Burke Thomas H , Weber Werner 
Published: April 2014

Background and purposeThe focus of this study was to determine ease of deployment, safety and effectiveness of the LVIS Jr device.MethodsA retrospective analysis was performed of 32 cases comprising 34 aneurysms in which the LVIS Jr device was used for stent-assisted coil embolization of intracranial aneurysms from February to October 2012, including all clinical and angiographic data as well as mid-term follow-up (1–12 months of treatment).ResultsThe median age of the patients was 54 years (range 21–76) and 19 (59%) were women. The aneurysms were ruptured in 12/34 cases (35.3%); 26 (76.4%) were located within the anterior circulation and the remaining 8 (23.5%) were located in the posterior circulation. Eleven of the 34 aneurysms (32.3%) were treated with a Y-stent configuration. Immediate total occlusion was observed in 16/34 (47%), near total occlusion (90–95%) in 5/34 (14.7%) and a ‘dog ear’ or subtotal occlusion in 12/34 (35.2%). A single aneurysm was treated without coil embolization. Complications occurred in 5/34 cases (15%), including two cases of in-stent thrombosis.ConclusionsImplantation of the LVIS Jr device as a support device for stent-assisted coil embolization seems to be safe and effective. The LVIS Jr device can also be implanted in a Y-stent configuration, offering a novel technique with a potentially lower risk of thromboembolic complications compared with other devices.
FRACTAL ANALYSIS OF THE ELECTROCARDIOGRAM SIGNAL
Authors: SEDJELMACI IBTICEME , BEREKSI-REGUIG F. 
Published: April 2014

In this paper, the analysis of the electrocardiogram (ECG) signal is carried out according a non-linear approach. This concerns the eventual fractal behavior of such signal and the correlation of such behavior with normal and pathological ECG signals. The analysis is carried out on different ECG signals taken from the MIT-BIH arrhythmia database. In fact these signals are those of six subjects with different ages and presenting both normal and abnormal arrhythmias situations. The abnormal situations are atrial premature beat (APB), premature ventricular contraction (PVC), right bundle branch block (RBBB) and left bundle branch block (LBBB). The fractal behavior of these signals is analyzed according to the determination of the multifractal spectrum and the fractal dimension variations and looking for eventually a fractal signature of each heart disease and age of the subject. The obtained results show a fractal signature according to the age and the pathologies for the studied cases. However further investigations are required on larger databases to confirm such results.
Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET
Authors: Xiang Qingfeng , Chen Weiqiang , Ren Meng , Wang Jingnan , Zhang Hongwu , Deng David Y.B. , Zhang Lei , Shang Changzhen , Chen Yajin 
Published: April 2014

Abstract
Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.
Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.
Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G1-phase arrest. Cabozantinib inhibited tumor growth in p-MET–positive and p-MET–negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET–positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)–stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.
Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker. Clin Cancer Res; 20(11); 2959–70. ©2014 AACR.
Germline Polymorphisms in RNF31 Regulate Linear Ubiquitination and Oncogenic Signaling
Authors: Grumati Paolo , Dikic Ivan 
Published: April 2014

Abstract
Summary: A new study proposes that the cancerous behavior of B cells in a subtype of diffuse large B-cell lymphoma is caused by excessive activity of the linear ubiquitin chain assembly complex (LUBAC) complex, which underlies abnormal NF-κB signaling. Two rare germline single-nucleotide polymorphisms in the RNF31 gene have been identified as being responsible. The use of a small inhibiting peptide may downregulate the abnormal LUBAC activity and counteract neoplastic cell growth. Cancer Discov; 4(4); 394–6. ©2014 AACR.
See related article by Yang et al., p. 480
Oncolytic Viruses and Their Application to Cancer Immunotherapy
Authors: Chiocca E. Antonio , Rabkin Samuel D. 
Published: April 2014

Abstract
Oncolytic viruses (OV) selectively replicate and kill cancer cells and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer selective or can be genetically engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines and can be armed with immunomodulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV–tumor/host interaction are important in delineating the effectiveness of therapy: (i) innate immune responses and the degree of inflammation induced; (ii) types of virus-induced cell death; (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture; and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers [MHC, costimulatory, and natural killer (NK) receptors], and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing granulocyte macrophage colony-stimulating factor (GM-CSF), have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between antivirus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs. Cancer Immunol Res; 2(4); 295–300. ©2014 AACR.
The Biology and Medical Implications of Interleukin-6
Authors: Tanaka Toshio , Kishimoto Tadamitsu 
Published: April 2014

Abstract
Cytokines are soluble mediators, which aid cell-to-cell communication in immune responses, and interleukin-6 (IL-6) is a prototypical cytokine featuring redundant and pleiotropic activity. The complete elucidation of the IL-6–mediated signal transduction system has provided a molecular basis for the characteristic features of cytokines. When tissue damage or inflammation due to infections or injuries occurs, IL-6 synthesis is promptly induced, contributing to the host defense through the stimulation of acute-phase immune reactions and hematopoiesis. The production of IL-6 is terminated when tissue homeostasis is restored. The synthesis of IL-6 is tightly regulated transcriptionally and posttranscriptionally. However, the dysregulated continual synthesis of IL-6 has been implicated in the development of various diseases, including autoimmune and chronic inflammatory diseases and cancers. Clinical trials using the humanized anti–IL-6 receptor monoclonal antibody tocilizumab have demonstrated the efficacy of IL-6 blockade for the treatment of refractory inflammatory diseases, such as rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman disease. Moreover, favorable results from the off-label use of tocilizumab strongly suggest that it may be applicable for the treatment of other refractory immune-mediated diseases, including cancer. Therefore, the mechanisms for the dysregulated synthesis of IL-6 need to be elucidated to understand the pathogenesis of the resultant diseases and to facilitate the development of effective therapeutic strategies. Cancer Immunol Res; 2(4); 288–94. ©2014 AACR.
Endothelial PFKFB3 Plays a Critical Role in Angiogenesis
Authors: Xu Yiming , An Xiaofei , Guo Xin , Habtetsion Tsadik Ghebreamlak , Wang Yong , Xu Xizhen , Kandala Sridhar , Li Qinkai , Li Honggui , Zhang Chunxiang , Caldwell Ruth B. , Fulton David J. , Su Yunchao , Hoda Md Nasrul , Zhou Gang , Wu Chaodong , Huo Yuqing 
Published: April 2014

Objective—
Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo.

Approach and Results—
Under hypoxic conditions or after treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration.

Conclusions—
The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.
Determinants of Flow-Mediated Outward Remodeling in Female Rodents
Authors: Tarhouni Kahena , Guihot Anne-Laure , Vessières Emilie , Toutain Bertrand , Procaccio Vincent , Grimaud Linda , Loufrani Laurent , Lenfant Francoise , Arnal Jean-Francois , Henrion Daniel 
Published: April 2014

Objective—
Flow (shear stress)-mediated outward remodeling (FMR) of resistance arteries is a key adaptive process allowing collateral growth after arterial occlusion but declining with age. 17-β-estradiol (E2) has a key role in this process through activation of estrogen receptor α (ERα). Thus, we investigated the impact of age and timing for estrogen efficacy on FMR.

Approach and Results—

Female rats, 3 to 18 months old, were submitted to surgery to increase blood flow locally in 1 mesenteric artery in vivo. High-flow and normal-flow arteries were collected 2 weeks later for in vitro analysis. Diameter increased by 27% in high-flow arteries compared with normal-flow arteries in 3-month-old rats. The amplitude of remodeling declined with age (12% in 18-month-old rats) in parallel with E2 blood level and E2 substitution failed restoring remodeling in 18-month-old rats. Ovariectomy of 3-, 9-, and 12-month-old rats abolished FMR, which was restored by immediate E2 replacement. Nevertheless, this effect of E2 was absent 9 months after ovariectomy. In this latter group, ERα and endothelial nitric oxide synthase expression were reduced by half compared with age-matched rats recently ovariectomized. FMR did not occur in ERα
−/−
mice, whereas it was decreased by 50% in ERα
+/−
mice, emphasizing the importance of gene dosage in high-flow remodeling.

Conclusions—
E2 deprivation, rather than age, leads to decline in FMR, which can be prevented by early exogenous E2. However, delayed E2 replacement was ineffective on FMR, underlining the importance of timing of this estrogen action.
Bim Regulates Alloimmune-Mediated Vascular Injury Through Effects on T-Cell Activation and Death
Authors: von Rossum Anna , Enns Winnie , Shi Yu P. , MacEwan Grace E. , Malekesmaeli Mehrnoush , Brinkman Ryan , Choy Jonathan C. 
Published: April 2014

Objective—
Bim is a proapoptotic Bcl-2 protein known to downregulate immune responses and to also be required for antigen-induced T-cell activation. However, it is not known how the effect of Bim on these offsetting processes determines the outcome of allogeneic immune responses. We have defined the role of Bim in regulating alloantigen-driven T-cell responses in a model of vascular rejection.

Approach and Results—

Bim was required for proliferation of CD4 and CD8 T cells, and for interleukin-2 production, in T cells stimulated with alloantigen in vitro. Moreover, a partial reduction in Bim expression was sufficient to attenuate T-cell activation, whereas a complete elimination of Bim was required to prevent CD4 T-cell death in response to cytokine withdrawl. When alloimmune-mediated vascular rejection was examined using an aortic interposition model, there was significantly less intimal thickening in Bim
+/−
, but not Bim
−/−
, graft recipients. T-cell proliferation in response to allograft arteries was significantly reduced in both Bim
+/−
and Bim
−/−
mice, but cell death was attenuated only in Bim
−/−
animals.

Conclusions—
Bim controls both T-cell activation and death in response to alloantigen stimulation. These processes act cooperatively to determine the outcome of immune responses in allograft arteries.