bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneity of Polyneuropathy Associated with Anti-MAG Antibodies
Authors: Magy Laurent , Kaboré Raphaël , Mathis Stéphane , Lebeau Prisca , Ghorab Karima , Caudie Christiane , Vallat Jean-Michel
Published: May 2015

Polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (MAG) antibodies is an immune-mediated demyelinating neuropathy. The pathophysiology of this condition is likely to involve anti-MAG antibody deposition on myelin sheaths of the peripheral nerves and it is supposed to be distinct from chronic inflammatory demyelinating neuropathy (CIDP), another immune-mediated demyelinating peripheral neuropathy. In this series, we have retrospectively reviewed clinical and laboratory findings from 60 patients with polyneuropathy, IgM gammopathy, and anti-MAG antibodies. We found that the clinical picture in these patients is highly variable suggesting a direct link between the monoclonal gammopathy and the neuropathy. Conversely, one-third of patients had a CIDP-like phenotype on electrodiagnostic testing and this was correlated with a low titer of anti-MAG antibodies and the absence of widening of myelin lamellae. Our data suggest that polyneuropathy associated with anti-MAG antibodies is less homogeneous than previously said and that the pathophysiology of the condition is likely to be heterogeneous as well with the self-antigen being MAG in most of the patients but possibly being another component of myelin in the others.
Robust Recursive Algorithm under Uncertainties via Worst-Case SINR Maximization
Authors: Song Xin , Wang Feng , Wang Jinkuan , Ren Jingguo
Published: May 2015

The performance of traditional constrained-LMS (CLMS) algorithm is known to degrade seriously in the presence of small training data size and mismatches between the assumed array response and the true array response. In this paper, we develop a robust constrained-LMS (RCLMS) algorithm based on worst-case SINR maximization. Our algorithm belongs to the class of diagonal loading techniques, in which the diagonal loading factor is obtained in a simple form and it decreases the computation cost. The updated weight vector is derived by the descent gradient method and Lagrange multiplier method. It demonstrates that our proposed recursive algorithm provides excellent robustness against signal steering vector mismatches and the small training data size and, has fast convergence rate, and makes the mean output array signal-to-interference-plus-noise ratio (SINR) consistently close to the optimal one. Some simulation results are presented to compare the performance of our robust algorithm with the traditional CLMS algorithm.
The Coupled Effect of Temperature and Carbonation on the Corrosion of Rebars in the Simulated Concrete Pore Solutions
Authors: Hu Jiezhen , Cheng Xuequn , Li Xiaogang , Deng Peichang , Wang Gui
Published: May 2015

The reinforced concrete structures have to survive high temperature and carbonation at low latitude region. The research on the effect of temperature and the effect of carbonation are vital to the corrosion of the rebars in concrete structures. The coupled effect of temperature and carbonation on the corrosion of rebars was researched by using the open circuit potential (OCP), the electrochemical impedance spectroscopy (EIS), and the potentiodynamic polarization (PP) measurement in the simulated concrete pore solutions (SPSs). The high temperature environment is conducive to the formation of passivated surface of rebars in SPSs, but the dissolution velocity of passivated surface is higher. The rebars have the greater capacity of passivity at lower temperature. The corrosion rate of rebars at higher temperature is smaller in moderate pH value (10.6) SPSs. The rebars suffer from serious corrosion in the pH = 9.6 SPSs at 318 K temperature.
Rectal Cancer Diagnosed after Cesarean Section in Which High Microsatellite Instability Indicated the Presence of Lynch Syndrome
Authors: Okuda Tomohiro , Ishii Hiroshi , Yamashita Sadao , Ijichi Sakura , Matsuo Seiki , Okimura Hiroyuki , Kitawaki Jo
Published: May 2015

We report a case of rectal cancer with microsatellite instability (MSI) that probably resulted from Lynch syndrome and that was diagnosed after Cesarean section. The patient was a 28-year-old woman (gravid 1, para 1) without a significant medical history. At 35 gestational weeks, vaginal ultrasonography revealed a 5 cm tumor behind the uterine cervix, which was diagnosed as a uterine myoma. The tumor gradually increased in size and blocked the birth canal, resulting in the patient undergoing an emergency Cesarean section. Postoperatively, the tumor was diagnosed as rectal cancer with MSI. After concurrent chemoradiation therapy, a lower anterior resection was performed. The patient’s family history revealed she met the criteria of the revised Bethesda guidelines for testing the colorectal tumor for MSI. Testing revealed that the tumor did indeed show high MSI and, combined with the family history, suggested this could be a case of Lynch syndrome. Our findings emphasize the importance of considering the possibility of Lynch syndrome in pregnant women with colorectal cancer, particularly those with a family history of this condition. We suggest that the presence of Lynch syndrome should also be considered for any young woman with endometrial, ovarian, or colorectal cancer.
Cellular Mechanisms of Oxidative Stress and Action in Melanoma
Authors: Venza Mario , Visalli Maria , Beninati Concetta , De Gaetano Giuseppe Valerio , Teti Diana , Venza Isabella
Published: May 2015

Most melanomas occur on the skin, but a small percentage of these life-threatening cancers affect other parts of the body, such as the eye and mucous membranes, including the mouth. Given that most melanomas are caused by ultraviolet radiation (UV) exposure, close attention has been paid to the impact of oxidative stress on these tumors. The possibility that key epigenetic enzymes cannot act on a DNA altered by oxidative stress has opened new perspectives. Therefore, much attention has been paid to the alteration of DNA methylation by oxidative stress. We review the current evidence about (i) the role of oxidative stress in melanoma initiation and progression; (ii) the mechanisms by which ROS influence the DNA methylation pattern of transformed melanocytes; (iii) the transformative potential of oxidative stress-induced changes in global and/or local gene methylation and expression; (iv) the employment of this epimutation as a biomarker for melanoma diagnosis, prognosis, and drug resistance evaluation; (v) the impact of this new knowledge in clinical practice for melanoma treatment.
Root Growth Optimizer with Self-Similar Propagation
Authors: He Xiaoxian , Chen Hanning , Niu Ben , Wang Jie
Published: May 2015

Most nature-inspired algorithms simulate intelligent behaviors of animals and insects that can move spontaneously and independently. The survival wisdom of plants, as another species of biology, has been neglected to some extent even though they have evolved for a longer period of time. This paper presents a new plant-inspired algorithm which is called root growth optimizer (RGO). RGO simulates the iterative growth behaviors of plant roots to optimize continuous space search. In growing process, main roots and lateral roots, classified by fitness values, implement different strategies. Main roots carry out exploitation tasks by self-similar propagation in relatively nutrient-rich areas, while lateral roots explore other places to seek for better chance. Inhibition mechanism of plant hormones is applied to main roots in case of explosive propagation in some local optimal areas. Once resources in a location are exhausted, roots would shrink away from infertile conditions to preserve their activity. In order to validate optimization effect of the algorithm, twelve benchmark functions, including eight classic functions and four CEC2005 test functions, are tested in the experiments. We compared RGO with other existing evolutionary algorithms including artificial bee colony, particle swarm optimizer, and differential evolution algorithm. The experimental results show that RGO outperforms other algorithms on most benchmark functions.
Health Status Monitoring of Cuplock Scaffold Joint Connection Based on Wavelet Packet Analysis
Authors: Zhang Liuyu , Wang Chenyu , Song Gangbing
Published: May 2015

The cuplock scaffolds are widely used as a temporary facility in the bridge and other constructions. The looseness of cuplock scaffold connection plays a significant role in the stability of the structure. Contemporary structural health monitoring method is reviewed in this paper at first, and then we proposed wavelet packet analysis based method. In order to detect the looseness of cuplock connection, three stress PZTs and three shear PZTs used as transducers are mounted onto vertical bar and cross bars of cuplok scaffold. Wavelet packet analysis is applied to analyze the transmitted signal energy between two PZTs through cuplok connection. Experimental results show that shear PZT has better performance than stress PZT to be used as actuator and sensor for the wavelet packet analysis based structural health monitoring. Besides, a sensor looseness index matrix (SLIM) is derived to indicate the looseness of the cuplock connection. The experimental results show that looseness index increases as the connection gets loose.
A 2-Week Course of Enteral Treatment with a Very Low-Calorie Protein-Based Formula for the Management of Severe Obesity
Authors: Castaldo Giuseppe , Monaco Luigi , Castaldo Laura , Sorrentino Paolo
Published: May 2015

Background. Multiple weight loss failures among obese patients suggest the design of new therapeutic strategies. We investigated the role of 2-week course of enteral treatment with a very low-calorie protein-based formula in the management of severe obesity.Methods. We evaluated the feasibility, safety, and efficacy of 2-week continuous administration of a protein-based formula (1.2 g/kg of ideal body weight/day) by nasogastric tube in severely obese adults (body mass index (BMI) ≥ 40 kg/m2).Results. In total, 364 patients (59% women; BMI =46.6±7.2 kg/m2) were recruited. The intervention was discontinued within 48 hours in 26 patients, due to nasogastric tube intolerance. No serious adverse events occurred. During the first and the second week, 65% and 80% patients, respectively, reported no side effects. All biochemical safety parameters were affected by the intervention, particularly uric acid (+45%) and aminotransferases (+48%). In the other cases the change was negligible. We observed significant weight loss (5.7±2.3%) and improvement in blood pressure and glucose and lipid metabolism parameters (P<0.001).Conclusions. A 2-week course of enteral treatment with a very low-calorie protein-based formula appeared a feasible, likely safe, and efficacious therapeutic option to be considered for inclusion into a composite weight loss program for the management of severe obesity. This trial is registered with ClinicalTrials.gov Identifier:NCT01965990.
Positive Coexistence of Steady States for a Diffusive Ratio-Dependent Predator-Prey Model with an Infected Prey
Authors: Kim Kwangjoong , Ahn Inkyung
Published: May 2015

We examine a diffusive ratio-dependent predator-prey system with disease in the prey under homogeneous Dirichlet boundary conditions with a hostile environment at its boundary. We investigate the positive coexistence of three interacting species (susceptible prey, infected prey, and predator) and provide nonexistence conditions of positive solutions to the system. In addition, the global stability of the trivial and semitrivial solutions to the system is studied. Furthermore, the biological interpretation based on the result is also presented. The methods are employed from a comparison argument for the elliptic problem as well as the fixed-point theory as applied to a positive cone on a Banach space.
QRFXFreeze: Queryable Compressor for RFX
Authors: Senthilkumar Radha , Nandagopal Gomathi , Ronald Daphne
Published: May 2015

The verbose nature of XML has been mulled over again and again and many compression techniques for XML data have been excogitated over the years. Some of the techniques incorporate support for querying the XML database in its compressed format while others have to be decompressed before they can be queried. XML compression in which querying is directly supported instantaneously with no compromise over time is forced to compromise over space. In this paper, we propose the compressor, QRFXFreeze, which not only reduces the space of storage but also supports efficient querying. The compressor does this without decompressing the compressed XML file. The compressor supports all kinds of XML documents along with insert, update, and delete operations. The forte of QRFXFreeze is that the textual data are semantically compressed and are indexed to reduce the querying time. Experimental results show that the proposed compressor performs much better than other well‐known compressors.
Prevalence of Peri‐Implant Mucositis and Peri‐Implantitis in Patients Treated with a Combination of Axial and Tilted Implants Supporting a Complete Fixed Denture
Authors: Cavalli Nicolò , Corbella Stefano , Taschieri Silvio , Francetti Luca
Published: May 2015

Objectives. The aim of this retrospective study was to assess the incidence and prevalence of peri‐implant mucositis and peri‐implantitis in patients with a fixed full‐arch prosthesis supported by two axial and two tilted implants. Materials and Methods. Sixty‐nine patients were included in the study. Each patient received a fixed full‐arch prosthesis supported by two mesial axial and two distal tilted implants to rehabilitate the upper arch, the lower arch, or both. Three hundred thirty‐six implants for 84 restorations were delivered. Patients were scheduled for follow‐up visits every 6 months in the first 2 years and yearly after. At each follow‐up visit peri‐implant mucositis and peri‐implantitis were diagnosed if present. Results. The overall follow‐up range was from 12 to 130 months (mean 63,2 months). Three patients presented peri‐implantitis. The prevalence of peri‐implant mucositis ranged between 0 and 7,14% of patients (5,06% of implants) while the prevalence of peri‐implantitis varied from 0 to 4,55% of patients (3,81% of implants). Conclusions. The prevalence and incidence of peri‐implant mucositis and peri‐implantitis are lower than most of the studies in literature. Therefore this kind of rehabilitation could be considered a feasible option, on the condition of adopting a systematic hygienic protocol.
Retinal Nerve Fibre Layer and Macular Thicknesses in Adults with Hyperopic Anisometropic Amblyopia
Authors: Yakar Konuralp , Kan Emrah , Alan Aydın , Alp Mehmet Hanifi , Ceylan Tolga
Published: May 2015

Objectives. This study compared the macular and retinal nerve fibre layer (RNFL) thicknesses and optic nerves of eyes with reduced vision due to anisometropia with the contralateral healthy eyes in adults using optical coherence tomography (OCT).Methods. This cross-sectional study was conducted in Atatürk State Hospital, Sinop, Turkey. Macular and RNFL thicknesses, optic nerve disc area, cup area, and horizontal and vertical cup-to-disc ratios obtained using a NIDEK RS-3000 SLO spectral domain OCT device were compared between the amblyopic and fellow eyes in 30 adults with anisometropic amblyopia 18–55 years old who were seen in our clinic with unilateral poor vision.Results. The mean macular thickness was 266.90 ± 23.22 µm in the amblyopic eyes and 263.90 ± 22.84 µm in the fellow eyes, and the mean RNFL thickness was 111.90 ± 12.9 and 109.70 ± 9.42 µm, respectively. The two thicknesses did not differ significantly between the amblyopic and fellow eyes. There were also no significant differences between the eyes in disc area, cup area, and horizontal-vertical cup/disc ratios.Conclusion. There does not seem to be a difference in macular thickness, peripapillary RNFL, or optic disc structures between the amblyopic and fellow eyes in adults.
Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18)(q21;q21), and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature
Authors: Akoum Riad , Serhal Wassim , Farhat Hussein
Published: May 2015

Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin’s lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL) has rarely been reported.Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18)(q21;q21). The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45.Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma.
Conductive Cotton Textile from Safely Functionalized Carbon Nanotubes
Authors: Rahman Mohammad Jellur , Mieno Tetsu
Published: May 2015

Electroconductive cotton textile has been prepared by a simple dipping‐drying coating technique using safely functionalized multiwalled carbon nanotubes (f‐MWCNTs). Owing to the surface functional groups, the f‐MWCNTs become strongly attached with the cotton fibers forming network armors on their surfaces. As a result, the textile exhibits enhanced electrical properties with improved thermal conductivity and therefore is demonstrated as a flexible electrothermal heating element. The fabricated f‐MWCNTs/cotton textile can be heated uniformly from room temperature to ca. 100°C within few minutes depending on the applied voltage. The textile shows good thermal stability and repeatability during a long‐term heating test.
First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors
Authors: Starodub Alexander N. , Ocean Allyson J. , Shah Manish A. , Guarino Michael J. , Picozzi Vincent J. , Vahdat Linda T. , Thomas Sajeve S. , Govindan Serengulam V. , Maliakal Pius P. , Wegener William A. , Hamburger Steven A. , Sharkey Robert M. , Goldenberg David M.
Published: May 2015

Purpose: Sacituzumab govitecan (IMMU-132) is an antibody–drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers.

Experimental Design: Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed.

Results: Twenty-five patients (52–60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done.

Conclusions: Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies. Clin Cancer Res; 21(17); 3870–8. ©2015 AACR.
Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma
Authors: Waters Alicia M. , Stewart Jerry E. , Atigadda Venkatram R. , Mroczek-Musulman Elizabeth , Muccio Donald D. , Grubbs Clinton J. , Beierle Elizabeth A.
Published: May 2015

Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell-cycle analysis, migration, and invasion were studied using AlamarBlue assays, FACS, and Transwell assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion, and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment. Mol Cancer Ther; 14(7); 1559–69. ©2015 AACR.
BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume
Authors: Theodosakis Nicholas , Held Matthew A. , Marzuka-Alcala Alexander , Meeth Katrina M. , Micevic Goran , Long Georgina V. , Scolyer Richard A. , Stern David F. , Bosenberg Marcus W.
Published: May 2015

BRAF kinase inhibitors have dramatically affected treatment of BRAFV600E/K-driven metastatic melanoma. Early responses assessed using [18F]fluorodeoxyglucose uptake-positron emission tomography (FDG-PET) have shown dramatic reduction of radiotracer signal within 2 weeks of treatment. Despite high response rates, relapse occurs in nearly all cases, frequently at sites of treated metastatic disease. It remains unclear whether initial loss of 18FDG uptake is due to tumor cell death or other reasons. Here, we provide evidence of melanoma cell volume reduction in a patient cohort treated with BRAF inhibitors. We present data demonstrating that BRAF inhibition reduces melanoma glucose uptake per cell, but that this change is no longer significant following normalization for cell volume changes. We also demonstrate that volume normalization greatly reduces differences in transmembrane glucose transport and hexokinase-mediated phosphorylation. Mechanistic studies suggest that this loss of cell volume is due in large part to decreases in new protein translation as a consequence of vemurafenib treatment. Ultimately, our findings suggest that cell volume regulation constitutes an important physiologic parameter that may significantly contribute to radiographic changes observed in clinic. Mol Cancer Ther; 14(7); 1680–92. ©2015 AACR.
Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody
Authors: Stewart Ross , Morrow Michelle , Hammond Scott A. , Mulgrew Kathy , Marcus Danielle , Poon Edmund , Watkins Amanda , Mullins Stefanie , Chodorge Matthieu , Andrews John , Bannister David , Dick Emily , Crawford Nicola , Parmentier Julie , Alimzhanov Marat , Babcook John S. , Foltz Ian N. , Buchanan Andrew , Bedian Vahe , Wilkinson Robert W. , McCourt Matthew
Published: May 2015

Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti–PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti–CTLA-4, anti–PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR. Cancer Immunol Res; 3(9); 1052–62. ©2015 AACR.
Single Institution Experience of Ipilimumab 3 mg/kg with Sargramostim (GM-CSF) in Metastatic Melanoma
Authors: Luke Jason J. , Donahue Hilary , Nishino Mizuki , Giobbie-Hurder Anita , Davis Meredith , Bailey Nancy , Ott Patrick A. , Hodi F. Stephen
Published: May 2015

Ipilimumab, 10 mg/kg with sargramostim (GM-CSF; GM), improved overall survival (OS) and safety of patients with advanced melanoma over ipilimumab in a randomized phase II trial. The FDA-approved dose of ipilimumab of 3 mg/kg has not been assessed with GM (IPI-GM). Consecutive patients treated with IPI-GM at a single institution were reviewed. Treatment included ipilimumab every 3 weeks × 4 and GM, 250-μg s.c. injection days 1 to 14 of each ipilimumab cycle. Efficacy, clinical characteristics, toxicities, and blinded radiology review of tumor burden were evaluated. Thirty-two patients were identified with 25 (78%) having immune-related response criteria (irRC) measurable disease and 41% with central nervous system metastases. A total of 88.6% of GM doses were administered. Response rate by irRC and disease control rate at 12 weeks were 20% and 44%, respectively (median follow-up 37 weeks). Immune-related adverse events (irAE) were observed in 10 (31.3%) patients, with 3 (9.4%) grade 3 events. Patients with grade 3 irAEs had prior autoimmunity, advanced age, and poor performance status. The median OS from first dose of ipilimumab was 41 weeks. Ipi-GM treatment is feasible and in this poor-risk advanced melanoma population, efficacy appeared similar but safety appeared improved relative to historical ipilimumab alone. Cancer Immunol Res; 3(9); 986–91. ©2015 AACR.
Prophylactic Application of an Intra-Aortic Balloon Pump in High-Risk Patients Undergoing Off-Pump Coronary Artery Bypass Grafting
Authors: Ding WenJun , Ji Qiang , Wei Qiang , Shi YunQing , Ma RunHua , Wang ChunSheng
Published: May 2015

Background: An intra-aortic balloon pump (IABP) is the most commonly used circulatory assist device in cardiac surgery. We hypothesized that prophylactic application of an IABP improves early clinical outcome of high-risk patients undergoing scheduled off-pump coronary artery bypass grafting (OPCABG). Methods: From January 2010 to December 2013, hemodynamically stable, high-risk patients undergoing scheduled OPCABG with preincision use of an IABP were recruited to the IABP group. Using the propensity score-matching method, every patient in the IABP group was matched with another patient (the control group) with a similar propensity score who received an IABP on an as-needed basis during or after OPCABG. Surgical mortality and major morbidity rates were compared between groups. Results: A total of 116 patient pairs were included in this study. In patients in the IABP group, postoperative low cardiac output and respiratory as well as renal failure were less frequent, intensive care unit stay was shorter, and surgical mortality was lower compared to patients in the control group. In multivariate logistic regression, timing of IABP implantation, as an independent risk factor, was associated with postoperative low cardiac output (OR = 2.02, 95% CI 1.28-5.76), respiratory failure (OR = 1.86, 95% CI 1.19-4.27), renal failure (OR = 2.96, 95% CI 1.51-6.63) and surgical mortality (OR = 2.45, 95% CI 1.42-6.07). Conclusions: Prophylactic application of an IABP improves postoperative cardiac performance, reduces respiratory and renal complications, and consequently lowers surgical mortality in high-risk patients undergoing scheduled OPCABG.
Cognitive Impairment Is Not a Predictor of Failure to Adhere to Anticoagulation of Stroke Patients with Atrial Fibrillation
Authors: Horstmann Solveig , Rizos Timolaos , Saribas Michaela , Efthymiou Evdokia , Rauch Geraldine , Veltkamp Roland
Published: May 2015

Background: Oral anticoagulation (OAC) with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) is an effective strategy that is used for stroke prevention in patients with atrial fibrillation (AF). However, OAC is underused particularly in elderly patients, who are often physically disabled or cognitively impaired. We aimed at evaluating the effect of cognitive status and disability on OAC adherence 1 year after stroke or TIA. Methods: In this prospective, single-center, observational study patients with ischemic stroke or TIA were consecutively included between 3/2011 and 9/2012. The detailed medical history, basic demographic variables, cardiovascular risk factors, stroke severity according to the National Institutes of Health Stroke Scale (NIHSS), medication including OAC were all recorded. Cognitive performance was measured using the Montreal Cognitive Assessment (MoCA) score at baseline. The functional status was assessed by recording activities and instrumental activities of daily living, respectively (ADL, IADL). After 12 months, patients had a follow-up visit to reassess the cognitive and functional status (MoCA, ADL and IADL) and to document the current use of OAC. Results: In total, 12 months after the ischemic stroke or TIA AF had been diagnosed in 160/586 (27.3%). Of these, 151 patients (94.4%) were treated with OAC. OAC was performed using VKA in 79/151 (52.3%) and DOACs in 72/151 (47.7%). Cognitive impairment at 12 months follow-up was not associated with the absence of OAC treatment. However, regression analysis revealed that patients with AF with physical (ADL) and functional disability (IADL) were less likely to be treated with OAC (p = 0.08 and p = 0.04, respectively) 12 months after a stroke. None of these two factors, however, was independently associated with nonadherence to OAC 12 months after stroke. Although cognitive performance was similar in patients receiving VKA and direct anticoagulants (DOAC), adherence to VKA tended to be lower (82.6 vs. 94.6%, p = 0.12). Conclusions: In stroke and TIA patients with AF, the multifactorial medical and functional constellation rather than cognitive impairment specifically can be an obstacle for long-term OAC.
Familial versus Sporadic Essential Tremor: What Patterns Can One Decipher in Age of Onset?
Authors: Louis Elan D. , Clark Lorraine N. , Ottman Ruth
Published: May 2015

Background: Essential tremor (ET) is a very prevalent neurological disease. Although familial and sporadic ET cases are assumed to have different age at onset distributions, no detailed study of this question has been carried out. Methods: Using a carefully characterized sample of 376 ET cases (232 (61.7%) familial) enrolled in a clinical-epidemiological study, we contrasted the age of onset distributions in familial versus sporadic ET. Results: Familial ET had a lower age at onset distribution, regardless of the current age. The majority (71 (86.6%) of 82) of ET cases that appeared during childhood were familial rather than sporadic. Additionally, the onset of ET occurred after age 40 in a majority of cases (125 (53.9%) of 232 with familial ET and 118 (81.9%) of 144 with sporadic ET), and in approximately one-quarter to one-half of cases, after age 60. Conclusions: The age of onset of ET differs between familial and sporadic ET and furthermore, is variable within each of these groups. The onset of ET during childhood is usually familial, and the small number of identified exceptions could be due to de novo mutations. Understanding the heterogeneity in onset age will provide insights into the nature of underlying etiological and patho-biological processes about which little is presently known.
Cross talk between serine/threonine and tyrosine kinases regulates ADP-induced thromboxane generation in platelets
Authors: Bhavanasi Dheeraj , Badolia Rachit , Manne Bhanu Kanth , Janapati Sumalaxmi , Dangelmaier Carol , Mazharian Alexandra , Jin Jianguo , Kim Soochong , Zhang Xiaoying , Chen Xiongwen , Senis Yotis , Kunapuli Satya
Published: May 2015

ADP-induced thromboxane generation depends on Src family kinases (SFKs) and is enhanced with pan-protein kinase C (PKC) inhibitors, but it is not clear how these two events are linked. The aim of the current study is to investigate the role of Y311 phosphorylated PKCδ in regulating ADP-induced platelet activation. In the current study, we employed various inhibitors and murine platelets from mice deficient in specific molecules to evaluate the role of PKCδ in ADP-induced platelet responses. We show that, upon stimulation of platelets with 2MeSADP, Y311 on PKCδ is phosphorylated in a P2Y1/Gq and Lyn-dependent manner. By using PKCδ and Lyn knockout murine platelets, we also show that tyrosine phosphorylated PKCδ plays a functional role in mediating 2MeSADP-induced thromboxane generation. 2MeSADP-induced PKCδ Y311 phosphorylation and thromboxane generation were potentiated in human platelets pre-treated with either a pan-PKC inhibitor, GF109203X or a PKC α/β inhibitor and in PKC α or β knockout murine platelets compared to controls. Furthermore, we show that PKC α/β inhibition potentiates the activity of SFK, which further hyper-phosphorylates PKCδ and potentiates thromboxane generation. These results show for the first time that tyrosine phosphorylated PKCδ regulates ADP-induced thromboxane generation independent of its catalytic activity and that classical PKC isoforms α/β regulate the tyrosine phosphorylation on PKCδ and subsequent thromboxane generation through tyrosine kinase, Lyn, in platelets.
Danger signal-dependent activation of human dendritic cells by plasma-derived factor VIII products
Authors: Miller Lilija , Weissmüller Sabrina , Ringler Eva , Crauwels Peter , van Zandbergen Ger , Seitz Rainer , Waibler Zoe ,   the ABIRISK consortium
Published: May 2015

Treatment of haemophilia A by infusions of the clotting factor VIII (FVIII) results in the development of inhibitors/anti-drug antibodies in up to 25 % of patients. Mechanisms leading to immunogenicity of FVIII products are not yet fully understood. Amongst other factors, danger signals as elicited upon infection or surgery have been proposed to play a role. In the present study, we focused on effects of danger signals on maturation and activation of dendritic cells (DC) in the context of FVIII application. Human monocyte-derived DC were treated with FVIII alone, with a danger signal alone or a combination of both. By testing more than 60 different healthy donors, we show that FVIII and the bacterial danger signal lipopolysaccharide synergise in increasing DC activation, as characterised by increased expression of co-stimulatory molecules and secretion of pro-inflammatory cytokines. The degree and frequency of this synergistic activation correlate with CD86 expression levels on immature DC prior to stimulation. In our assay system, plasma-derived but not recombinant FVIII products activate human DC in a danger signal-dependent manner. Further tested danger signals, such as R848 also induced DC activation in combination with FVIII, albeit not in every tested donor. In our hands, human DC but not human B cells or macrophages could be activated by FVIII in a danger signal-dependent manner. Our results suggest that immunogenicity of FVIII is a result of multiple factors including the presence of danger, predisposition of the patient, and the choice of a FVIII product for treatment.
Prognostic Implications of Level-of-Care at Tertiary Heart Centers Compared With Other Hospitals After Resuscitation From Out-of-Hospital Cardiac Arrest
Authors: Søholm Helle , Kjaergaard Jesper , Bro-Jeppesen John , Hartvig-Thomsen Jakob , Lippert Freddy , Køber Lars , Nielsen Niklas , Engsig Magaly , Steensen Morten , Wanscher Michael , Karlsen Finn Michael , Hassager Christian
Published: May 2015

Background—

Studies have found higher survival rates after out-of-hospital cardiac arrest and admission to tertiary heart centers. The aim was to examine the level-of-care at tertiary centers compared with nontertiary hospitals and the association with outcome after out-of-hospital cardiac arrest.

Methods and Results—

Consecutive out-of-hospital cardiac arrest patients (n=1078) without ST-segment–elevation myocardial infarction admitted to tertiary centers (54%) and nontertiary hospitals (46%) were included (2002–2011). Patient charts were reviewed focusing on level-of-care and comorbidity. Survival to discharge differed significantly with 45% versus 24% of patients discharged alive (
P
<0.001), and after adjustment for prognostic factors admissions to tertiary centers were still associated with lower 30-day mortality (hazard ratio, 0.78 [0.64–0.96;
P
=0.02]), independent of comorbidity. The adjusted odds of predefined markers of level-of-care were higher in tertiary centers: admission to intensive care unit (odds ratio [OR], 1.8 [95% confidence interval, 1.2–2.5]), temporary pacemaker (OR, 6.4 [2.2–19]), vasoactive agents (OR, 1.5 [1.1–2.1]), acute (<24 hours) and late coronary angiography (OR, 10 [5.3–22] and 3.8 [2.5–5.7]), neurophysiological examination (OR, 1.8 [1.3–2.6]), and brain computed tomography (OR, 1.9 [1.4–2.6]), whereas no difference in therapeutic hypothermia was noted. Patients at tertiary centers were more often consulted by a cardiologist (OR, 8.6 [5.0–15]), had an echocardiography (OR, 2.8 [2.1–3.7]), and survivors more often had implantable cardioverter defibrillator’s implanted (OR, 2.1 [1.2–3.6]).

Conclusions—

Admissions to tertiary centers were associated with significantly higher survival after out-of-hospital cardiac arrest in patients without ST-segment–elevation myocardial infarction in the Copenhagen area even after adjustment for prognostic factors including comorbidity. Level-of-care seems higher in tertiary centers both in the early phase, during the intensive care unit admission, and in the workup before discharge. The varying level-of-care may contribute to the survival difference; however, differences in comorbidity do not seem to matter significantly.
Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction
Authors: Twerenbold Raphael , Wildi Karin , Jaeger Cedric , Gimenez Maria Rubini , Reiter Miriam , Reichlin Tobias , Walukiewicz Astrid , Gugala Mathias , Krivoshei Lian , Marti Nadine , Moreno Weidmann Zoraida , Hillinger Petra , Puelacher Christian , Rentsch Katharina , Honegger Ursina , Schumacher Carmela , Zurbriggen Felicitas , Freese Michael , Stelzig Claudia , Campodarve Isabel , Bassetti Stefano , Osswald Stefan , Mueller Christian
Published: May 2015

Background—

It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined.

Methods and Results—

In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease–estimated glomerular filtration rate <60 mL·min
−1
·1.73 m
−2
). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%–80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve–derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9–3.4).

Conclusions—

More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00470587.
Cypher and Enigma Homolog Protein Are Essential for Cardiac Development and Embryonic Survival
Authors: Mu Yongxin , Jing Ran , Peter Angela K. , Lange Stephan , Lin Lizhu , Zhang Jianlin , Ouyang Kunfu , Fang Xi , Veevers Jennifer , Zhou Xinmin , Evans Sylvia M. , Cheng Hongqiang , Chen Ju
Published: May 2015

Background

The striated muscle Z‐line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z‐line‐associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Cypher and its close homologue, Enigma homolog protein (
ENH
), are 2 Z‐line proteins previously shown to be individually essential for maintenance of postnatal cardiac function and stability of the Z‐line during muscle contraction, but dispensable for cardiac myofibrillogenesis and development.

Methods and Results

The current studies were designed to test whether Cypher and
ENH
play redundant roles during embryonic development. Here, we demonstrated that mice lacking both
ENH
and Cypher exhibited embryonic lethality and growth retardation. Lethality in double knockout embryos was associated with cardiac dilation and abnormal Z‐line structure. In addition, when
ENH
was ablated in conjunction with selective ablation of either Cypher short isoforms (CypherS), or Cypher long isoforms (CypherL), only the latter resulted in embryonic lethality.

Conclusions

Cypher and
ENH
redundantly play an essential role in sustaining Z‐line structure from the earliest stages of cardiac function, and are redundantly required to maintain normal embryonic heart function and embryonic viability.
Human–Bovine Plagues in the Early Middle Ages
Authors: Newfield Timothy P.
Published: May 2015

Two independent molecular clock analyses (mcas) reveal that measles (mv) diverged from rinderpest (rpv) c. 1000 c.e. This evidence, when conjoined with written accounts of non-Justinianic plagues in 569–570 and 986–988 and zoo-archaeological discoveries regarding early medieval mass bovine mortalities, suggests that a now-extinct morbillivirus, ancestral to mv and rpv, broke out episodically in the early Middle Ages, causing large mortalities in both species. Tentative diagnoses of an mv–rpv ancestor help to untangle early medieval accounts of human–bovine disease and facilitate an assessment of the consequences of the 569–570 and 986–988 plagues.
Comparative Sociology of 11 to 18 Examinations in Thailand, England, and Japan
Authors: Onaka Fumiya
Published: May 2015

This study compares 11 to 18 examinations and the changes they have undergone in Thailand, England, and Japan. Using socio-cultural network analysis supported by the interpretive understanding of local newspaper articles and interview transcripts, this study will reveal a process that has not been detected by previous single-case studies. First, there are three compounds across time periods and countries. Second, the analyses of local newspapers show that there is a tendency toward interconnection among the three compounds. Third, the analyses of interview transcripts that are selected as interconnected show that this type can be found in various kinds of people, especially among education administrators and business persons. These results enable us to predict the future of examinations in these areas.
Empire and Mission
Authors: Sweetman Will
Published: May 2015

The historiography of the entanglement of mission and empire in India has often taken the inclusion of the so-called “pious clause” in the East India Company’s 1813 charter to mark the end of a ban on missions in Company territories, and the beginning of a period of co-operation between church and company. This neglects the importance in this debate of the mission founded by German Lutherans in the Danish settlement of Tranquebar in south India in 1706. The mission received direct patronage from the Company for almost a full century before 1813, and was invoked by both sides in the debate over the pious clause. A work published anonymously in 1812, purporting to be a new translation of dialogues between the first missionaries in Tranquebar and their Hindu and Muslim interlocutors, is shown here to be a skilful and savage satire on the dialogues published by the first missionaries.
1621
Authors: Tilg Stefan
Published: May 2015

Nach dem Muster des angeblichen jüdischen Ritualmords an Simon von Trient hat der Haller Stadtarzt und Schriftsteller Hippolytus Guarinonius in den Jahren seit 1619 die Legende des Anderl von Rinn konstruiert. Das erste rezeptionsgeschichtlich relevante Zeugnis für diese Legende ist ein in Hall 1621 aufgeführtes Jesuitendrama, an dessen Entstehung Guarinonius ohne Zweifel beteiligt war. Der bald darauf einsetzende und bis ins Ende des 20. Jhs. reichende religiöse Kult um Anderl von Rinn wurde wahrscheinlich durch diese Aufführung in Gang gebracht. Der Spieltext des Dramas ist verloren. Zwei vollständige Exemplare der Perioche sind jedoch erhalten. Der Periochentext wird hier erstmals veröffentlicht.