bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin II‐Induced Hypertension Is Attenuated by Overexpressing Copper/Zinc Superoxide Dismutase in the Brain Organum Vasculosum of the Lamina Terminalis
Authors: Collister John P. , Taylor-Smith Heather , Drebes Donna , Nahey David , Tian Jun , Zimmerman Matthew C.
Published: January 2016

Angiotensin II (AngII) can access the brain via circumventricular organs (CVOs), including the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), to modulate blood pressure. Previous studies have demonstrated a role for both the SFO and OVLT in the hypertensive response to chronic AngII, yet it is unclear which intracellular signaling pathways are involved in this response. Overexpression of copper/zinc superoxide dismutase (CuZnSOD) in the SFO has been shown to attenuate the chronic hypertensive effects of AngII. Presently, we tested the hypothesis that elevated levels of superoxide () in the OVLT contribute to the hypertensive effects of AngII. To facilitate overexpression of superoxide dismutase, adenoviral vectors encoding human CuZnSOD or control adenovirus (AdEmpty) were injected directly into the OVLT of rats. Following 3 days of control saline infusion, rats were intravenously infused with AngII (10 ng/kg/min) for ten days. Blood pressure increased 33 ± 8 mmHg in AdEmpty rats (n = 6), while rats overexpressing CuZnSOD (n = 8) in the OVLT demonstrated a blood pressure increase of only 18 ± 5 mmHg after 10 days of AngII infusion. These results support the hypothesis that overproduction of in the OVLT plays an important role in the development of chronic AngII‐dependent hypertension.
Harmonic Transfer Function Based Damage Identification of Breathing Cracked Jeffcott Rotor
Authors: Zhao Jie , DeSmidt Hans , Peng Meng
Published: January 2016

This paper proposes a vibration-based damage identification method based on 6-dof Jeffcott rotor system, which is based on harmonic balance and Newton-Raphson methods. First, the equations of motion are derived by using energy method and Lagrange principle. The crack model is based on strain energy release rate (SERR) in fracture mechanics and modified to accommodate 6-dof Jeffcott rotor model. Then, Gear’s method is used to solve the vibration responses of nominal and damaged rotor systems. By processing vibration responses, the transfer function shifts between nominal and damaged systems are taken as the input of damage identification algorithm. Finally, damage severity can be correlated with the damage parameter estimated via developed damage identification model. Numerical examples are shown to demonstrate the effectiveness in identifying the breathing crack in the rotor system.
A Case of a 4-Year-Old Boy with a Mesenteric Chylous Cyst Infected withHistoplasma capsulatum
Authors: Kweyamba Vianney , Apiyo Mirraim , Olika Biratu , Kituuka Olivia
Published: January 2016

Mesenteric cysts are uncommon entities and chyle- (lymph-) containing cysts are the rarest of this group. This is a case report of a 4-year-old boy with a mesenteric chylous cyst who was later found to haveHistoplasma capsulatuminfection.
Lipogems Product Treatment Increases the Proliferation Rate of Human Tendon Stem Cells without Affecting Their Stemness and Differentiation Capability
Authors: Randelli Pietro , Menon Alessandra , Ragone Vincenza , Creo Pasquale , Bergante Sonia , Randelli Filippo , De Girolamo Laura , Alfieri Montrasio Umberto , Banfi Giuseppe , Cabitza Paolo , Tettamanti Guido , Anastasia Luigi
Published: January 2016

Increasing the success rate of rotator cuff healing remains tremendous challenge. Among many approaches, the possibility of activating resident stem cells in situ, without the need to isolate them from biopsies, could represent valuable therapeutic strategy. Along this line, it has been recently demonstrated that lipoaspirate product, Lipogems, contains and produces growth‐factors that may activate resident stem cells. In this study, human tendon stem cells (hTSCs) from the rotator cuff were cocultured in a transwell system with the Lipogems lipoaspirate product and compared to control untreated cells in terms of cell proliferation, morphology, stem cell marker and VEGF expression, and differentiation and migration capabilities. Results showed that the Lipogems product significantly increases the proliferation rate of hTSCs without altering their stemness and differentiation capability. Moreover, treated cells increase the expression of VEGF, which is crucial for the neovascularization of the tissue during the healing process. Overall, this study supports that directly activating hTSCs with the Lipogems lipoaspirate could represent a new practical therapeutic approach. In fact, obtaining a lipoaspirate is easier, safer, and more cost‐effective than harvesting cells from tendon or bone marrow biopsies, expanding them in GMP facility and then reinjecting them in the patient.
Solitary Wave Formation from a Generalized Rosenau Equation
Authors: Ramos J. I. , García-López C. M.
Published: January 2016

A generalized viscous Rosenau equation containing linear and nonlinear advective terms and mixed third- and fifth-order derivatives is studied numerically by means of an implicit second-order accurate method in time that treats the first-, second-, and fourth-order spatial derivatives as unknown and discretizes them by means of three-point, fourth-order accurate, compact finite differences. It is shown that the effect of the viscosity is to decrease the amplitude, curve the wave trajectory, and increase the number and width of the waves that emerge from an initial Gaussian condition, whereas the linear convective term pushes the wave front towards the downstream boundary. It is also shown that the effect of the nonlinear convective term is to increase the steepness of the leading wave front and the number of sawtooth waves that are generated behind it, while that of the first dispersive term is to increase the number of waves that break up from the initial condition as the coefficient that characterizes this term is decreased. It is also shown that, for reasons of stability, the second dispersion coefficient must be much smaller than the first one and its effects on wave propagation are relatively small.
Pharmacopuncture in Korea: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Park Jimin , Lee Hyangsook , Shin Byung-Cheul , Lee Myeong Soo , Kim Boryang , Kim Jong-In
Published: January 2016

Background. Pharmacopuncture is a new form of acupuncture combining acupuncture with herbal medicine, and it has been used under various conditions in Korea. The aim of this study is to establish clinical evidence for the safety and efficacy of pharmacopuncture in Korea. Methods. We searched 9 databases and two relevant journals up to December 2014 using keywords, such as pharmacopuncture. All randomized, controlled trials evaluating pharmacopuncture under any conditions in Korea were considered. Results. Twenty‐nine studies involving 1,211 participants were included. A meta‐analysis of two studies on obesity showed that 5 to 8 weeks of pharmacopuncture reduced weight, waist circumference, and body mass index (BMI) more than normal saline injections. In the 5 studies of musculoskeletal conditions, 7 to 30 days of pharmacopuncture had additional effects on the reduction of pain intensity, and this benefit was maintained by limiting analyses to studies with a low risk of bias for randomization and/or allocation concealment. Conclusions. This systematic review suggests the potential of pharmacopuncture for obesity and musculoskeletal diseases. However, it is difficult to recommend pharmacopuncture as an evidence‐based treatment because of methodological flaws and small sample sizes of the included studies. Further well‐designed trials are needed to draw a definitive conclusion.
Treatment with a Monoclonal Anti-IL-12p40 Antibody Induces Substantial Gut Microbiota Changes in an Experimental Colitis Model
Authors: Castro-Mejía Josué , Jakesevic Maja , Krych Łukasz , Nielsen Dennis S. , Hansen Lars H. , Sondergaard Bodil C. , Kvist Peter H. , Hansen Axel K. , Holm Thomas L.
Published: January 2016

Background and Aim. Crohn’s disease is associated with gut microbiota (GM) dysbiosis. Treatment with the anti-IL-12p40 monoclonal antibody (12p40-mAb) has therapeutic effect in Crohn’s disease patients. This study addresses whether a 12p40-mAb treatment influences gut microbiota (GM) composition in mice with adoptive transfer colitis (AdTr-colitis).Methods. AdTr-colitis mice were treated with 12p40-mAb or rat-IgG2a or NaCl from days 21 to 47. Disease was monitored by changes in body weight, stool, endoscopic and histopathology scores, immunohistochemistry, and colonic cytokine/chemokine profiles. GM was characterized through DGGE and 16S rRNA gene-amplicon high-throughput sequencing.Results. Following 12p40-mAb treatment, most clinical and pathological parameters associated with colitis were either reduced or absent. GM was shifted towards a higher Firmicutes-to-Bacteroidetes ratio compared to rat-IgG2a treated mice. Significant correlations between 17 bacterial genera and biological markers were found. The relative abundances of the RF32 order (Alphaproteobacteria) andAkkermansia muciniphilawere positively correlated with damaged histopathology and colonic inflammation.Conclusions. Shifts in GM distribution were observed with clinical response to 12p40-mAb treatment, whereas specific GM members correlated with colitis symptoms. Our study implicates that specific changes in GM may be connected with positive clinical outcomes and suggests preventing or correcting GM dysbiosis as a treatment goal in inflammatory bowel disease.
Inhibition of JAK‐STAT ERK/MAPK and Glycogen Synthase Kinase‐3 Induces a Change in Gene Expression Profile of Bovine Induced Pluripotent Stem Cells
Authors: Malaver-Ortega Luis F. , Sumer Huseyin , Liu Jun , Verma Paul J.
Published: January 2016

Pluripotent stem cells (PSCs) fall in two states, one highly undifferentiated, the naïve state, and the primed state, characterized by the inability to contribute to germinal lineage. Several reports have demonstrated that these states can be modified by changes to the cell culture conditions. With the advent of nuclear reprogramming, bovine induced pluripotent stem cells (biPSCs) have been generated. These cells represent examples of a transient‐intermediate state of pluripotency with remarkable characteristics and biotechnological potential. Herein, we generated and characterized biPSC. Next, we evaluated different culture conditions for the ability to affect the expression of the set of core pluripotent transcription factors in biPSC. It was found that the use of 6‐bromoindirubin‐3‐oxime and Sc1 inhibitors alone or in combination with 5‐AzaC induced significantly higher levels of expression of endogenous REX1, OCT4, NANOG, and SOX2. Furthermore, LIF increased the levels of expression of OCT4 and REX1, compared with those cultured with LIF + bFGF. By contrast, bFGF decreased the levels of expression for both REX1 and OCT4. These results demonstrate that the biPSC gene expression profile is malleable by modification of the cell culture conditions well after nuclear reprogramming, and the culture conditions may determine their differentiation potential.
The Effect of Culture on Human Bone Marrow Mesenchymal Stem Cells: Focus on DNA Methylation Profiles
Authors: Bentivegna Angela , Roversi Gaia , Riva Gabriele , Paoletta Laura , Redaelli Serena , Miloso Mariarosaria , Tredici Giovanni , Dalprà Leda
Published: January 2016

Human bone marrow mesenchymal stem cells (hBM‐MSCs) are the best characterized multipotent adult stem cells. Their self‐renewal capacity, multilineage differentiation potential, and immunomodulatory properties have indicated that they can be used in many clinical therapies. In a previous work we studied the DNA methylation levels of hBM‐MSC genomic DNA in order to delineate a kind of methylation signature specific for early and late passages of culture. In the present work we focused on the modification of the methylation profiles of the X chromosome and imprinted loci, as sites expected to be more stable than whole genome. We propose a model where cultured hBM‐MSCs undergo random modifications at the methylation level of most CGIs, nevertheless reflecting the original methylation status. We also pointed out global genome‐wide demethylation connected to the long‐term culture and senescence. Modification at CGIs promoters of specific genes could be related to the decrease in adipogenic differentiation potential. In conclusion, we showed important changes in CGIs methylation due to long‐term in vitro culture that may affect the differentiation potential of hBM‐MSCs. Therefore it is necessary to optimize the experimental conditions for in vitro expansion in order to minimize these epigenetic changes and to standardize safer procedures.
Challenges of Assessing Maltreated Children Coming into Foster Care
Authors: Pritchett Rachel , Hockaday Harriet , Anderson Beatrice , Davidson Claire , Gillberg Christopher , Minnis Helen
Published: January 2016

Children who have experienced early adversity have been known to be at risk of developing cognitive, attachment, and mental health problems; therefore, it is crucial that children entering foster care can be properly assessed as early as possible. There are known difficulties in assessing children in foster care, for example, in finding a reliable informant. An ongoing randomised controlled trial in Glasgow, Scotland, recruiting infants entering foster care, provides a unique opportunity to explore some of the issues which need to be considered when assessing these children. The assessment data of 70 infants entering care is described while exploring the reliability of foster carers as informants and the importance of infant engagement with tasks. This group of infants was shown to be having more problems than children from the general population. While correlations were found between a carer’s level of concern about a child and the severity of a child’s problem, there were still a number of children displaying worrying problem scores whom foster carers did not report concern. The child’s engagement in the cognitive task showed associations with the child’s attainment on the task. Findings emphasise the importance of a holistic assessment for these children and all should be considered as potential cases with Maltreatment-Associated Psychiatric Problems (MAPP).
Generalization of Fuzzy Laplace Transforms of Fuzzy Fractional Derivatives about the General Fractional Ordern-1<β<n
Authors: Haydar Amal Khalaf , Hassan Ruaa Hameed
Published: January 2016

The main aim in this paper is to use all the possible arrangements of objects such thatr1of them are equal to 1 andr2(the others) of them are equal to 2, in order to generalize the definitions of Riemann-Liouville and Caputo fractional derivatives (about order0<β<n) for a fuzzy-valued function. Also, we find fuzzy Laplace transforms for Riemann-Liouville and Caputo fractional derivatives about the general fractional ordern-1<β<nunder H-differentiability. Some fuzzy fractional initial value problems (FFIVPs) are solved using the above two generalizations.
Direct Midline Diastema Closure with Composite Layering Technique: A One-Year Follow-Up
Authors: Korkut Bora , Yanikoglu Funda , Tagtekin Dilek
Published: January 2016

Objective. Maxillary anterior spacing is a common aesthetic complaint of patients. Midline diastema has a multifactorial etiology such as labial frenulum, microdontia, mesiodens, peg-shaped lateral incisors, agenesis, cysts, habits such as finger sucking, tongue thrusting, or lip sucking, dental malformations, genetics, proclinations, dental-skeletal discrepancies, and imperfect coalescence of interdental septum. Appropriate technique and material for effective treatment are based on time, physical, psychological, and economical limitations. Direct composite resins in diastema cases allow dentist and patient complete control of these limitations and formation of natural smile.Clinical Considerations. In this case report a maxillary midline diastema was closed with direct composite resin restorations in one appointment without any preparation. One bottle total etch adhesive was used and translucent/opaque composite resin shades were layered on mesial surfaces of the teeth that were isolated with rubber dam and Teflon bands. Finishing and polishing procedures were achieved by using polishing discs. Patient was informed for recalls for every 6 months.Conclusions. At one-year recall no sensitivities, discolorations, or fractures were detected on teeth and restorations. Direct composite resins seemed to be highly aesthetic and durable restorations that can satisfy patients as under the conditions of case presented.
Protein Loosing Enteropathy Secondary to Strongyloidiasis: Case Report and Review of the Literature
Authors: El Hajj Weam , Nakad Gilbert , Abou Rached Antoine
Published: January 2016

Strongyloidiasis is a helminthic disease which affects millions around the world resulting in a significant burden in certain high risk groups. It is rarely reported in the Lebanese population probably due to the low index of suspicion in common practice. We are reporting a case of strongyloidiasis that was found in an elderly patient presenting initially with dyspnea followed by skin rash, protein loosing enteropathy, diarrhea, and abdominal pain while on corticosteroid therapy. The diagnosis was suspected based on clinical presentation in addition to peripheral eosinophilia. We will also describe the upper and lower endoscopic aspects of the disease, as well as histologic findings on duodenal and colonic biopsies.
Oscillatory and Steady Flows in the Annular Fluid Layer inside a Rotating Cylinder
Authors: Dyakova Veronika , Polezhaev Denis
Published: January 2016

The dynamics of a low-viscosity fluid inside a rapidly rotating horizontal cylinder were experimentally studied. In the rotating frame, the force of gravity induces azimuthal fluid oscillations at a frequency equal to the velocity of the cylinder’s rotation. This flow is responsible for a series of phenomena, such as the onset of centrifugal instability in the Stokes layer and the growth of the relief at the interface between the fluid and the granular medium inside the rotating cylinder. The phase inhomogeneity of the oscillatory fluid flow in the viscous boundary layers near the rigid wall and the free surface generates the azimuthal steady streaming. We studied the relative contribution of the viscous boundary layers in the generation of the steady streaming. It is revealed that the velocity of the steady streaming can be calculated using the velocity of the oscillatory fluid motion.
Inhibition of Viability, Proliferation, Cytokines Secretion, Surface Antigen Expression, and Adipogenic and Osteogenic Differentiation of Adipose‐Derived Stem Cells by Seven‐Day Exposure to 0.5 T Static Magnetic Fields
Authors: Wang Jian , Xiang Bo , Deng Jixian , Freed Darren H. , Arora Rakesh C. , Tian Ganghong
Published: January 2016

After seven‐day exposure to 0.5‐Tesla Static Magnetic Field (SMF), Adipose‐derived Stem Cells (ASCs) and those labeled by superparamagnetic iron oxide (SPIO) nanoparticles were examined for viability by methyl thiazol tetrazolium (MTT) assay, proliferation by cell counting and bromodeoxyuridine (BrdU) incorporation, DNA integrity by single cell gel electrophoresis, surface antigen by flow cytometry analysis, and the expression of cytokines and genetic markers by reverse transcription‐PCR and underwent adipogenic and osteogenic differentiation assessed by quantifying related specific genes expression. The SMF slightly reduced cell viability and proliferation and inhibited the expression of CD49d, CD54, and CD73 but did not damage DNA integrity. The SMF slightly downregulated the expression of cytokines including Vascular Endothelial Growth Factor (VEGF), Insulin‐like Growth Factor‐1 (IGF‐1), Transforming Growth Factor Beta 1 (TGF‐β1), genetic markers comprising Stem Cell Antigen‐1 (Sca1), Octamer‐4 (Oct‐4), ATP‐binding Cassette Subfamily B Member 1 (ABCB1), adipogenic marker genes containing Lipoprotein Lipase (LPL), Peroxisome Proliferator‐Activated Receptor Gamma (PPAR‐γ), and osteogenic marker genes including Secreted Phosphor‐protein 1 (SPP1) and Osterix (OSX). Exposure to 0.5 T SMF for seven days inhibited viability, proliferation, surface antigen expression, cytokine secretion, stem cell genetic marker expression, and adipogenic and osteogenic differentiation but did not affect the DNA integrity in ASCs with or without SPIO labeling.
Evaluation of Different Soil Salinity Mapping Using Remote Sensing Techniques in Arid Ecosystems, Saudi Arabia
Authors: Elhag Mohamed
Published: January 2016

Land covers in Saudi Arabia are generally described as salty soils with sand dunes and sand sheets. Waterlogging and higher soil salinity are major challenges to sustaining agricultural practices in Saudi Arabia principally within closed drainage basins. Agricultural practices in Saudi Arabia were flourishing in the last two decades. The newly reclaimed lands were added annually and distributed all over the country. Irrigation techniques are mostly modernized to fulfill water saving strategies. Nevertheless, water resources in Saudi Arabia are under stress and groundwater levels are depleted rapidly due to heavy abstraction that may exceed crop water requirements in most of the cases due to high evaporation rates. The excess use of irrigational water leads to severe soil salinity problems. Applications of remote sensing technique in agricultural practices became widely distinctive and cover multidisciplinary principal interests on both local and regional levels. The most important remote sensing applications in agricultural practices are vegetation indices which are related to vegetation and water especially in an arid environment. Soil salinity mapping in an arid ecosystem using remote sensing data is a demanding task. Several soil salinity indices were implemented and evaluated to detect soil salinity effectively and quantitatively. Thematic maps of soil salinity were satisfactorily produced and assessed.
Navigation System Heading and Position Accuracy Improvement through GPS and INS Data Fusion
Authors: Ryu Ji Hyoung , Gankhuyag Ganduulga , Chong Kil To
Published: January 2016

Commercial navigation systems currently in use have reduced position and heading error but are usually quite expensive. It is proposed that extended Kalman filter (EKF) and Unscented Kalman Filter (UKF) be used in the integration of a global positioning system (GPS) with an inertial navigation system (INS). GPS and INS individually exhibit large errors but they do complement each other by maximizing the advantage of each in calculating the heading angle and position through EKF and UKF. The proposed method was tested using low cost GPS, a cheap electronic compass (EC), and an inertial management unit (IMU) which provided accurate heading and position information, verifying the efficacy of the proposed algorithm.
A Potential Alternative against Neurodegenerative Diseases: Phytodrugs
Authors: Pérez-Hernández Jesús , Zaldívar-Machorro Víctor Javier , Villanueva-Porras David , Vega-Ávila Elisa , Chavarría Anahí
Published: January 2016

Neurodegenerative diseases (ND) primarily affect the neurons in the human brain secondary to oxidative stress and neuroinflammation. ND are more common and have a disproportionate impact on countries with longer life expectancies and represent the fourth highest source of overall disease burden in the high‐income countries. A large majority of the medicinal plant compounds, such as polyphenols, alkaloids, and terpenes, have therapeutic properties. Polyphenols are the most common active compounds in herbs and vegetables consumed by man. The biological bioactivity of polyphenols against neurodegeneration is mainly due to its antioxidant, anti‐inflammatory, and antiamyloidogenic effects. Multiple scientific studies support the use of herbal medicine in the treatment of ND; however, relevant aspects are still pending to explore such as metabolic analysis, pharmacokinetics, and brain bioavailability.
Experimental Colitis Is Attenuated by Cardioprotective Diet Supplementation That Reduces Oxidative Stress, Inflammation, and Mucosal Damage
Authors: Vargas Robles Hilda , Citalán Madrid Alí Francisco , García Ponce Alexander , Silva Olivares Angelica , Shibayama Mineko , Betanzos Abigail , Del Valle Mondragón Leonardo , Nava Porfirio , Schnoor Michael
Published: January 2016

Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD) are multifactorial, relapsing disorders of the gastrointestinal tract. However, the etiology is still poorly understood but involves altered immune responses, epithelial dysfunction, environmental factors, and nutrition. Recently, we have shown that the diet supplement corabion has cardioprotective effects due to reduction of oxidative stress and inflammation. Since oxidative stress and inflammation are also prominent risk factors in IBD, we speculated that corabion also has beneficial effects on experimental colitis. Colitis was induced in male mice by administration of 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for a period of 3 or 7 days with or without daily gavage feeding of corabion consisting of vitamin C, vitamin E, L‐arginine, and eicosapentaenoic and docosahexaenoic acid. We found that corabion administration attenuated DSS‐induced colon shortening, tissue damage, and disease activity index during the onset of colitis. Mechanistically, these effects could be explained by reduced neutrophil recruitment, oxidative stress, production of proinflammatory cytokines, and internalization of the junctional proteins ZO‐1 and E‐cadherin leading to less edema formation. Thus, corabion may be a useful diet supplement for the management of chronic inflammatory intestinal disorders such as IBD.
A New Methodology of Multicriteria Decision-Making in Supplier Selection Based onZ-Numbers
Authors: Kang Bingyi , Hu Yong , Deng Yong , Zhou Deyun
Published: January 2016

Supplier selection is a significant issue of multicriteria decision-making (MCDM), which has been heavily studied with classical fuzzy methodologies, but the reliability of the knowledge from domain experts is not efficiently taken into consideration.Z-number introduced by Zadeh has more power to describe the knowledge of human being with uncertain information considering both restraint and reliability. In this paper, a methodology for supplier selection usingZ-numbers is proposed considering information transformation. It includes two parts: one solves the issue of how to convertZ-number to the classic fuzzy number according to the fuzzy expectation; the other solves the problem of how to get the optimal priority weight for supplier selection with genetic algorithm (GA), which is an efficient and flexible method for calculating the priority weight of the judgement matrix. Finally, an example for supplier selection is used to illustrate the effectiveness the proposed methodology.
Postoperative Albumin Drop Is a Marker for Surgical Stress and a Predictor for Clinical Outcome: A Pilot Study
Authors: Hübner Martin , Mantziari Styliani , Demartines Nicolas , Pralong François , Coti-Bertrand Pauline , Schäfer Markus
Published: January 2016

Background. Surgical stress during major surgery may be related to adverse clinical outcomes and early quantification of stress response would be useful to allow prompt interventions. The aim of this study was to evaluate the acute phase protein albumin in the context of the postoperative stress response.Methods. This prospective pilot study included 70 patients undergoing frequent abdominal procedures of different magnitude. Albumin (Alb) and C-reactive protein (CRP) levels were measured once daily starting the day before surgery until postoperative day (POD) 5. Maximal Alb decrease (Alb Δ min) was correlated with clinical parameters of surgical stress, postoperative complications, and length of stay.Results. Albumin values dropped immediately after surgery by about 10 g/L (42.2±4.5 g/L preoperativelyversus33.8±5.3 g/L at day 1,P<0.001). Alb Δ min was correlated with operation length (Pearsonρ=0.470,P<0.001), estimated blood loss (ρ=0.605,P<0.001), and maximal CRP values (ρ=0.391,P=0.002). Alb Δ min levels were significantly higher in patients having complications (10.0±5.4versus6.1±5.2,P=0.005) and a longer hospital stay (ρ=0.285,P<0.020).Conclusion. Early postoperative albumin drop appeared to reflect the magnitude of surgical trauma and was correlated with adverse clinical outcomes. Its promising role as early marker for stress response deserves further prospective evaluation.
Upper Bounds on the Degeneracy of the Ground State in Quantum Field Models
Authors: Arai Asao , Funakawa Daiju
Published: January 2016

Axiomatic abstract formulations are presented to derive upper bounds on the degeneracy of the ground state in quantum field models including massless ones. In particular, given is a sufficient condition under which the degeneracy of the ground state of the perturbed Hamiltonian is less than or equal to the degeneracy of the ground state of the unperturbed one. Applications of the abstract theory to models in quantum field theory are outlined.
Risk of Gastrointestinal Bleeding with Rivaroxaban: A Comparative Study with Warfarin
Authors: Sherid Muhammed , Sulaiman Samian , Samo Salih , Husein Husein , Tupper Ruth , Spurr Charles , Sifuentes Humberto , Sridhar Subbaramiah
Published: January 2016

Introduction. The risk of gastrointestinal (GI) bleeding with rivaroxaban has not been studied extensively. The aim of our study was to assess this risk in comparison to warfarin.Methods. We examined the medical records for patients who were started on rivaroxaban or warfarin from April 2011 to April 2013.Results. We identified 300 patients (147 on rivaroxaban versus 153 on warfarin). GI bleeding occurred in 4.8% patients with rivaroxaban when compared to 9.8% patients in warfarin group(p=0.094). GI bleeding occurred in 8% with therapeutic doses of rivaroxaban (>10 mg/d) compared to 9.8% with warfarin(p=0.65). Multivariate analysis showed that patients who were on rivaroxaban for ≤40 days had a higher incidence of GI bleeding than those who were on it for >40 days (OR = 2.8,p=0.023). Concomitant use of dual antiplatelet agents was associated with increased risk of GI bleeding in the rivaroxaban group (OR = 7.4,p=0.0378). Prior GI bleeding was also a risk factor for GI bleeding in rivaroxaban group (OR = 15.5).Conclusion. The incidence of GI bleeding was similar between rivaroxaban and warfarin. The risk factors for GI bleeding with rivaroxaban were the first 40 days of taking the drug, concomitant dual antiplatelet agents, and prior GI bleeding.
Trichohepatoenteric Syndrome or Syndromic Diarrhea—Report of Three Members in a Family, First Report from Iran
Authors: Mahjoub F. E. , Imanzadeh F. , Mahdavi Izadi S. , Nahali Moghaddam A.
Published: January 2016

Introduction.Intractable diarrhea of infancy (IDI) includes several types of early onset diarrhea; one of the rare etiologies is trichohepatoenteric (THE) syndrome, also known as syndromic diarrhea (SD) which was primarily described by Stankler et al. Hereby we report a family with several affected members which to our knowledge is the first case report from Iran.Report of Cases.A three-year-old boy referred with short stature, poor weight gain, and intermittent steatotic diarrhea to our center. He was born to healthy, relative parents (cousins). He did not gain any weight after four months of age and began having intermittent steatotic diarrhea, abdominal distension, and fever. He was hospitalized several times. Two other children in the family also showed somewhat similar symptoms. Two sweat tests were negative for cystic fibrosis. Workup for Celiac disease was performed several times which was negative; however, gluten-free diet was tried several times which was not effective. Workup for Hirschsprung’s disease was performed but colon was ganglionic. Evidence of liver involvement was approved by elevated liver enzymes and coarse echo of liver on sonography.Discussion.Trichoenterohepatic syndrome should be put in mind in cases of intractable diarrhea presenting in a family with several affected members. Early diagnosis would save patients from unnecessary workups.
The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis
Authors: Vogelsang Matjaz , Martinez Carlos N. , Rendleman Justin , Bapodra Anuj , Malecek Karolina , Romanchuk Artur , Kazlow Esther , Shapiro Richard L. , Berman Russell S. , Krogsgaard Michelle , Osman Iman , Kirchhoff Tomas
Published: January 2016

Purpose: The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes.

Experimental Design: Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models.

Results: We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41–0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19–2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43–2.60; P = 2.38e-5).

Conclusions: Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268–80. ©2016 AACR.
Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha–Positive, PIK3CA-Mutant Breast Cancer
Authors: Yang Wei , Hosford Sarah R. , Dillon Lloye M. , Shee Kevin , Liu Stephanie C. , Bean Jennifer R. , Salphati Laurent , Pang Jodie , Zhang Xiaolin , Nannini Michelle A. , Demidenko Eugene , Bates Darcy , Lewis Lionel D. , Marotti Jonathan D. , Eastman Alan R. , Miller Todd W.
Published: January 2016

Purpose: Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)–positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER+ breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index.

Experimental Design: Antiestrogen-sensitive and antiestrogen-resistant ER+ human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured.

Results: Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone.

Conclusions: Continuous and metronomic PI3K inhibition elicits robust anticancer effects in ER+, PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens is warranted. Clin Cancer Res; 22(9); 2250–60. ©2016 AACR.

See related commentary by Toska and Baselga, p. 2099
Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics
Authors: Vitale Candida , Falchi Lorenzo , ten Hacken Elisa , Gao Hui , Shaim Hila , Van Roosbroeck Katrien , Calin George , O'Brien Susan , Faderl Stefan , Wang Xuemei , Wierda William G. , Rezvani Katayoun , Reuben James M. , Burger Jan A. , Keating Michael J. , Ferrajoli Alessandra
Published: January 2016

Purpose: We evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment.

Experimental Design: Thirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3–6, and once every other course during courses 7–24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed.

Results: The overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders.

Conclusions: The combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359–67. ©2016 AACR.
Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120
Authors: Chen Shih-Hsun , Zhang Youyan , Van Horn Robert D. , Yin Tinggui , Buchanan Sean , Yadav Vipin , Mochalkin Igor , Wong Swee Seong , Yue Yong Gang , Huber Lysiane , Conti Ilaria , Henry James R. , Starling James J. , Plowman Gregory D. , Peng Sheng-Bin
Published: January 2016

We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490–deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer–dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.

Significance: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer. Cancer Discov; 6(3); 300–15. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 217
Low Serum Vitamin D Levels May Contribute to Gastric Dysmotility in de novo Parkinson's Disease
Authors: Kwon Ki Young , Jo Kwang Deog , Lee Moon Kyu , Oh Minyoung , Kim Eyu Nyong , Park Jinse , Kim Ji Sun , Youn Jinyoung , Oh Engseok , Kim Hee-Tae , Oh Mi Young , Jang Wooyoung
Published: January 2016

Background and Objectives: Gastrointestinal dysfunction is a common non motor symptom in Parkinson's disease (PD). However, the potential association between vitamin D and gastroparesis in PD has not been previously investigated. The aim of this study was to compare vitamin D levels between drug-naive de novo PD patients with normal gastric emptying and those with delayed gastric emptying. Methods: Fifty-one patients with drug-naive de novo PD and 20 age-matched healthy controls were enrolled in this study. Gastric emptying time (GET) was assessed by scintigraphy, and gastric emptying half-time (T1/2) was determined. The PD patients were divided into a delayed-GET group and a normal-GET group. Results: The serum 25-hydroxyvitamin D3 levels were decreased in the delayed-GET group compared with the normal-GET and control groups (11.59 ± 4.90 vs. 19.43 ± 6.91 and 32.69 ± 4.93, respectively, p < 0.01). In the multivariate model, the serum 25-hydroxyvitamin D3 level was independently associated with delayed gastric emptying in PD patients. Conclusions: Vitamin D status may be an independent factor for gastric dysmotility in PD. Although the underlying mechanism remains to be characterized, vitamin D status may play a role in the pathogenesis of delayed gastric emptying in drug-naive PD.
Sequential Morphological Changes in the CNV Net after Intravitreal Anti-VEGF Evaluated with OCT Angiography
Authors: Marques João Pedro , Costa José Filipe , Marques Marco , Cachulo Maria Luz , Figueira João , Silva Rufino
Published: January 2016

Purpose: To assess and describe sequential morphological changes in the choroidal neovascularization (CNV) net using optical coherence tomography angiography (OCTA) in patients undergoing treatment with intravitreal antivascular endothelial growth factor (VEGF). Methods: Prospective cohort study. OCTA was performed sequentially: before (t0), 1 h (t1), 1 week (t2) and 1 month after the injection (t3), using Avanti RTVue XR equipped with the AngioVue® software (Optovue, Calif., USA). All images were classified by two independent graders. Results: Ten eyes of 10 patients, with a mean age of 72.4 ± 10.5 years, were included. CNV morphology was described as tree-like in 5 eyes, glomerular in 1 and fragmented in 4. A fibrovascular capsule surrounding the CNV net was found in 4 eyes and a feeder trunk was noticed in 6. No changes were observed at t1. Loss of peripheral capillaries, vessel fragmentation and decreased vessel density were evident in 8 eyes at t2. The CNV capillary density and the peripheral anastomosis increased in all of these at t3. Two eyes remained unchanged through the whole length of follow-up. Conclusions: Significant changes in the CNV net can be observable in OCTA at least 1 week after intravitreal anti-VEGF. The safety of frequent examinations may provide a method of gauging treatment effects.
Monitoring of Lung Involvement in Rheumatologic Disease
Authors: Paschalaki Koralia E. , Jacob Joseph , Wells Athol U.
Published: January 2016

The monitoring of lung involvement in patients with connective tissue diseases is central to optimal long-term management and is directed towards: (a) the detection of supervening lung involvement not present at presentation and (b) the identification of disease progression in established lung disease. For both goals, accurate surveillance requires multi-disciplinary evaluation with the integration of symptomatic change, serial pulmonary function trends and imaging data. Evaluated in isolation, each of these monitoring domains has significant limitations. Symptomatic change may be confounded by a wide variety of systemic factors. Pulmonary function tests provide the most reliable data, but are limited by measurement variability, the heterogeneity of functional patterns and the confounding effects of non-pulmonary factors. Chest radiography is insensitive to change but may provide rapid confirmation of major disease progression or alert the clinician to respiratory co-morbidities. Although high-resolution computed tomography has a central role in assessing disease severity, it should be used very selectively as a monitoring tool due to the associated radiation burden. Ancillary tests include echocardiography and exercise testing to proactively identify cases of pulmonary hypertension and worsening of oxygenation. In summary, a multi-disciplinary approach is essential for the identification of disease progression and prompt treatment of comorbidities that severely impact on the morbidity and mortality of disease.
Population Pharmacokinetics of Bisoprolol in Hemodialysis Patients with Hypertension
Authors: Nikolic Valentina N. , Jankovic Slobodan M. , Dimitrijevic Zorica M. , Sokolovic Miodrag J. , Andric Branislav R. , Petrovic Dejan S. , Jevtovic-Stoimenov Tatjana , Zivanovic Slavoljub , Milovanovic Jasmina R.
Published: January 2016

The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Parameters associated with plasma concentration of bisoprolol at steady state were analyzed in 63 patients (mean age 62.12 years, mean total weight 69.63 kg) who were hypertensive and on hemodialysis due to severe renal failure using non-linear mixed-effect modeling with ADVAN1 subroutine. The final regression model for the clearance of the drug included only creatinine clearance (CLcr) out of 12 tested covariates. The equation that describes CL of bisoprolol is the following: CL (l/h) = 0.12 + 6.33 * CLcr. These findings suggest that the routine measuring of serum creatinine level may be used to facilitate administration of bisoprolol in patients on hemodialysis.
Spies and Boats and Planes: An Examination of U.S. Decision-Making during the Pueblo Hostage Crisis of 1968
Authors: Houghton David Patrick
Published: January 2016

Hostage crises almost always involve a tradeoff between the “national honor”—bound up with national identity and a sense of self-esteem—and the desire to get hostages back safely and without loss of life. This was certainly the case in 1968, as President Lyndon Johnson and his advisers agonized over the crew of the USS Pueblo, which had been seized by North Korea while on an intelligence-gathering mission at the height of the Cold War. Such episodes also commonly lead to a frantic search for historical analogies and policy options that will attain one objective or another. Various historical analogies influenced the deliberations of U.S. policymakers as they looked beyond cases involving the seizure of intelligence-gathering ships to other types of hostage incident involving U.S. helicopters and spy planes. They gradually pieced together a solution to the problem at hand, much as one would a jigsaw puzzle.