bluuebunny/crossref_metadata_2025 huggingface dataset:
Recrudescence ofPlasmodium malariaeafter Quinine
Authors: Kugasia Irfanali R. , Polara Farhana K. , Assallum Hussein
Published: February 2014

Plasmodium malariaecauses uncommon benign malaria found in the malaria endemic regions mostly of Sub-Saharan Africa. AsPlasmodium malariaedoes not have a continued liver stage in humans the only way to have reinfection without reexposure is through recrudescence. However, reports of its recrudescence after antimalarials are rare with only a handful of case reports in the literature. Research in this field to date has not been able to establish definitively an emergence of resistance inPlasmodium malariaeto commonly used antimalarials. In the presented case, patient had a recrudescence ofP. malariaeafter full treatment with quinine and clindamycin. This recrudescence was treated with full course of chloroquine with clearance of parasite from blood immediately after treatment and at two months’ follow up. The recrudescence in this case cannot be explained by mechanisms explained in prior articles. We propose that the indolence of some of thePlasmodium malariaetrophozoites in the blood can shield them from the effect of the toxic effects of antimalarials and enable them to produce recrudescence later. However, when recrudescence happens, this should not be considered a case of development of resistance and a course of chloroquine should be considered.
NF-κB Mediated Regulation of Adult Hippocampal Neurogenesis: Relevance to Mood Disorders and Antidepressant Activity
Authors: Bortolotto Valeria , Cuccurazzu Bruna , Canonico Pier Luigi , Grilli Mariagrazia
Published: February 2014

Adult hippocampal neurogenesis is a peculiar form of process of neuroplasticity that in recent years has gained great attention for its potential implication in cognition and in emotional behavior in physiological conditions. Moreover, a vast array of experimental studies suggested that adult hippocampal neurogenesis may be altered in various neuropsychiatric disorders, including major depression, where its disregulation may contribute to cognitive impairment and/or emotional aspects associated with those diseases. An intriguing area of interest is the potential influence of drugs on adult neurogenesis. In particular, several psychoactive drugs, including antidepressants, were shown to positively modulate adult hippocampal neurogenesis. Among molecules which could regulate adult hippocampal neurogenesis the NF-κB family of transcription factors has been receiving particular attention from our and other laboratories. Herein we review recent data supporting the involvement of NF-κB signaling pathways in the regulation of adult neurogenesis and in the effects of drugs that are endowed with proneurogenic and antidepressant activity. The potential implications of these findings on our current understanding of the process of adult neurogenesis in physiological and pathological conditions and on the search for novel antidepressants are also discussed.
Construction and Characterization of Recombinant HSV-1 Expressing Early Growth Response-1
Authors: Bedadala Gautam , Chen Feng , Figliozzi Robert , Balish Matthew , Hsia Victor
Published: February 2014

Early Growth response-1 (Egr-1) is a transcription factor that possesses a variety of biological functions. It has been shown to regulate HSV-1 gene expression and replication in different cellular environments through the recruitment of distinct cofactor complexes. Previous studies demonstrated that Egr-1 can be induced by HSV-1 infection in corneal cells but the level was lower compared to other cell types. The primary goal of this report is to generate a recombinant HSV-1 constitutively expressing Egr-1 and to investigate the regulation of viral replication in different cell types or in animals with Egr-1 overexpression. The approach utilized was to introduce Egr-1 into the BAC system containing complete HSV-1 (F) genome. To assist in the insertion of Egr-1, a gene cassette was constructed that contains the Egr-1 gene flanked by loxP sites. In this clone Egr-1 is expressed under control of CMV immediate-early promoter followed by another gene cassette expressing the enhanced green fluorescent protein (EGFP) under the control of the elongation factor 1α (EF-1 α) promoter. The constructed recombinant viruses were completed containing the Egr-1 gene within the viral genome and the expression was characterized by qRT-PCR and Western blot analyses. Our results showed that Egr-1 transcript and protein can be generated and accumulated upon infection of recombinant virus in Vero and rabbit corneal cells SIRC. This unique virus therefore is useful for studying the effects of Egr-1 during HSV-1 replication and gene regulation in epithelial cells and neurons.
Preparation and Its Adsorptive Property of Modified Expanded Graphite Nanomaterials
Authors: Wang Liqin , Fu Xiujun , Chang E. , Wu Haitao , Zhang Kun , Lei Xianchao , Zhang Ruijun , Qi Xiaowen , Yang Yulin
Published: February 2014

Modified expanded graphite (MEG) samples were prepared by strong acid treatment modification. As-prepared MEG samples were characterized by the means of FE-SEM, XRD, FT-IR, N2physical adsorption measurements, and TG-DTA. The influences of expanded volume and oil viscosity on adsorptive property of MEG samples were investigated. The results suggest that MEG samples have high crystallinity. The pores of MEG samples can be divided into three levels from FE-SEM images. All of the functional groups of MEG samples are nonpolar. The expansion temperature of modified expansible graphite starts at about 700°C. The sorption capacity of MEG increases gradually with expanded volume and oil viscosity increase. When the expanded volume of MEG samples is 320 mL/g, its maximum sorption capacity is up to 84.681 g/g for gear oil with the highest viscosity.
Racial Disparities in Survival and Age-Related Outcome in Postsurgery Breast Cancer Patients in a New York City Community Hospital
Authors: Martindale Stacey , Singh Awinder , Wang Hua , Steinberg Ashley , Homsi Amer , Zhang Haidi , Go Alan , Pappas Peter
Published: February 2014

Breast cancer survival has significantly improved over the past two decades. However, the diagnosis of breast cancer is lower and the mortality rate remains higher, in African American women (AA) compared to Caucasian-American women. The purpose of this investigation is to analyze postoperative events that may affect breast cancer survival. This is a retrospective analysis of prospectively collected data from The Brooklyn Hospital Center cancer registry from 1997 to 2010. Of the 1538 patients in the registry, 1226 are AA and 269 are Caucasian. The study was divided into two time periods, 1997–2004 (period A) and 2005–2010 (period B), in order to assess the effect of treatment outcomes on survival. During period A, 5-year survival probabilities of 75.37%, 74.53%, and 78.70% were seen among all patients, AA women and Caucasian women, respectively. These probabilities increased to 87.62%, 87.15% and 89.99% in period B. Improved survival in AA women may be attributed to the use of adjuvant chemotherapy, radiation, and hormonal therapy. Improved survival in Caucasian patients was attributed to the use of radiation therapy, as well as earlier detection resulting in more favorable tumor grades and pathological stages.
Is CT Angiogram of the Abdominal Vessels Needed following the Diagnosis of Ischemic Colitis? A Multicenter Community Study
Authors: Sherid Muhammed , Samo Salih , Sulaiman Samian , Husein Husein , Sethuraman Sankara N. , Vainder John A.
Published: February 2014

Background. CT angiogram is frequently obtained after diagnosis of ischemic colitis (IC). Aims. To investigate the vascular findings of CT angiogram as compared to contrast-enhanced CT scan and whether this modality changes the management or prognosis of IC. Methods. We conducted a retrospective analysis of patients with IC from 2007 to 2013. Results. CT angiogram was performed in 34 patients (28.81%), whereas contrast-enhanced CT scan was performed in 54 patients (45.76%). In CT angiogram group, 8 patients (23.5%) had atherosclerotic changes. Stenosis was found in 12 patients (35.3%) (9: celiac trunk, 3: SMA). Among this group, one patient underwent colectomy and another underwent angioplasty of the celiac trunk who died within 30 days. Among contrast-enhanced CT scan group, 5 patients (9.3%) had atherosclerotic changes. Stenosis was found in 5 patients (9.3%) (3: celiac trunk, 1: SMA, and 1: IMA). Among this group, 3 patients had colectomy and one died within 30 days. There was no statistical difference between both groups in all vascular findings except the stenosis which was higher in CT angiogram group (P=0.0025). Neither the need for surgery nor all-cause mortality was different between both groups. Conclusion. CT angiogram did not provide any useful findings that altered the management or the prognosis of IC.
Development and Evaluation of Taste Masked Granular Formulation of Satranidazole by Melt Granulation Technique
Authors: Pawar Harshal Ashok , Joshi Pooja Rasiklal
Published: February 2014

Drugs from nitroimidazole category are generally bitter in taste. Oral formulation with bitter taste is not palatable. Geriatrics and pediatrics patients usually suffer from swallowing difficulties. Many other patients in some disease conditions avoid swallowing tablets. Satranidazole is a new nitro-imidazole derivative with bitter taste and is available in market as film coated tablet. The purpose of this research was to mask the bitter taste of Satranidazole by coating complexation with low melting point wax and Eudragit EPO. Different types of wax (glyceryl monostearate, stearic acid and cetyl alcohol) were tried for taste masking. The drug to stearic acid ratio 1 : 2 was found to be optimum on the basis of taste evaluation and in vitro release. The formulated granules were found to possess good flow property. FTIR studies confirmed that there was no interaction between drug and excipients. Scanning Electron Microscopy of drug and the optimized batch of granules was performed. The in vitro release of drug from granules was compared with marketed tablet formulation. The taste masked granules of optimized batch showed 87.65% release of drug in 1 hr which is comparable to that of marketed tablet formulation.
The Average Lower Connectivity of Graphs
Authors: Aslan Ersin
Published: February 2014

For a vertexvof a graphG, thelower connectivity, denoted bysv(G), is the smallest number of vertices that containsvand those vertices whose deletion fromGproduces a disconnected or a trivial graph. The average lower connectivity denoted byκav(G)is the value(∑v∈VGsvG)/VG. It is shown that this parameter can be used to measure the vulnerability of networks. This paper contains results on bounds for the average lower connectivity and obtains the average lower connectivity of some graphs.
Coupling Analysis of Fluid-Structure Interaction and Flow Erosion of Gas-Solid Flow in Elbow Pipe
Authors: Zhu Hongjun , Zhao Hongnan , Pan Qian , Li Xue
Published: February 2014

A numerical simulation has been conducted to investigate flow erosion and pipe deformation of elbow in gas-solid two-phase flow. The motion of the continuous fluid phase is captured based on calculating three-dimensional Reynolds-averaged-Navier-Stokes (RANS) equations, while the kinematics and trajectory of the discrete particles are evaluated by discrete phase model (DPM), and a fluid-structure interaction (FSI) computational model is adopted to calculate the pipe deformation. The effects of inlet velocity, pipe diameter, and the ratio of curvature and diameter on flow feature, erosion rate, and deformation of elbow are analyzed based on a series of numerical simulations. The numerical results show that flow field, erosion rate, and deformation of elbow are all sensitive to the structural changes and inlet condition changes. Higher inlet rate, smaller curvature diameter ratio, or smaller pipe diameter leads to greater deformation, while slower inlet rate, larger curvature diameter ratio, and larger pipe diameter can weaken flow erosion.
Cyclooxygenase Inhibitor Associated with Carboplatin in Treatment of Metastatic Nasal Carcinoma in Dog
Authors: Fonseca-Alves Carlos Eduardo , Gonçalves Corrêa Aline , Elias Fabiana , Gouveia Calazans Sabryna
Published: February 2014

A 10-year-old, intact male, pinscher was presented with unilateral bloodstained nasal discharge, sneezing, dyspnea, zygomatic arch deformity, submandibular lymph node increase, blindness in right eye, and exophthalmia. After clinical examination, it was found that the animal presented with upper respiratory tract dyspnea origin, possibly caused by an obstructive process. Complete blood count (CBC), ocular ultrasonography, thoracic radiographs, mandibular lymph node, and nasal sinus fine needle aspiration were performed. The right mandibular lymph node excisional biopsy was conducted and a tumor sample was obtained through the nasal fistula at hard palate. The material was processed, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Immunohistochemical staining for cytokeratin (AE1/AE3), vimentin, and COX-2 was performed. After histopathological evaluation nasal carcinoma diagnosis was obtained. Chemotherapy was established with carboplatin 300 mg/m2intravenously—four cycles with intervals of 21 days—and firocoxib 5 mg/kg orally every 24 hours for 7 months. After 7 months the treatment started, the animal presented with ataxia, vocalization, hyperesthesia, and anorexia. Due the clinical condition presented, the animal owner opted for performing euthanasia. The chemotherapy protocol was effective causing the disease stagnation, minimizing the clinical signs, and extending patient survival and quality of life.
Comparative Analysis of Changes of Myocardial Angiogenesis and Energy Metabolism in Postinfarction and Diabetic Damage of Rat Heart
Authors: Afanasiev Sergey A. , Egorova Margarita V. , Kondratyeva Dina S. , Batalov Roman E. , Popov Sergey V.
Published: February 2014

Comparative study of changes in myocardial activity of lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), and capillary density distribution in the experimental models of diabetic and postinfarction damage of rat heart was performed. Data showed that decrease in LDH and SDH activities was observed in both pathologies which can suggest abnormal processes of glycolysis and oxidative phosphorylation in cardiac mitochondria. Activity of LDH and SDH in combined pathologies was comparative with the corresponding values of these parameters in control group. The authors hypothesize that these differences can be caused by specifics of myocardial vascularization. The results of the study showed that an increase in capillary density was found in all groups of rats with pathologies compared with control group. However, no significant differences in the intensity of angiogenesis processes were found between groups with pathologies.
Drug Reaction with Eosinophilia and Systemic Symptoms: DRESS following Initiation of Oxcarbazepine with Elevated Human Herpesvirus-6 Titer
Authors: Cornell Seth L. , DiBlasi Daniel , Arora Navin S.
Published: February 2014

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and potentially fatal severe cutaneous reaction, which has a delayed onset after the initiation of an inciting medication. After recognition and withdrawal of the causative agent, along with aggressive management, a majority of patients will have complete recovery over several months. We present a rare case of DRESS secondary to oxcarbazepine with an elevated human herpesvirus-6 titer.
Phylogenetic Framework and Biosurfactant Gene Expression Analysis of Marine Bacillus spp. of Eastern Coastal Plain of Tamil Nadu
Authors: Swaathy Sreethar , Kavitha Varadharajan , Sahaya Pravin Arockiasamy , Sekaran Ganesan , Mandal Asit Baran , Gnanamani Arumugam
Published: February 2014

The present study emphasizes the diversity assessment of marine Bacillus species with special reference to biosurfactant production, respective gene expression, and discrimination among Bacillus licheniformis and Bacillus subtilis. Among the 200 individual species of eastern coastal plain of Tamil Nadu screened, five biosurfactant producing potential bacterial species with entirely different morphology were selected. Biochemical and 16S rRNA gene sequence analysis suggested that all the said five species belong to Bacillus genera but differ in species levels. Biosurfactant of all the five species fluctuates in greater levels with respect to activity as well as to constituents but showed partial similarity to the commercially available surfactin. The expression of srf gene was realized in all of the five species. However, the sfp gene expression was observed only in three species. In conclusion, both B. licheniformis and B. subtilis demonstrate srf gene; nevertheless, sfp gene was expressed only by Bacillus subtilis.
Clinical and Radiological Outcome of the Newest Generation of Ceramic-on-Ceramic Hip Arthroplasty in Young Patients
Authors: Reuven Avishai , Manoudis Grigorios N. , Aoude Ahmed , Huk Olga L. , Zukor David , Antoniou John
Published: February 2014

Ceramic-on-ceramic articulations have become an attractive option for total hip arthroplasty in young patients. In this study, we retrospectively evaluated the short- to midterm clinical and radiographic results in 51 consecutive patients (61 hips) using the newest generation of ceramic implants. Results obtained in our study showed positive clinical and radiological outcomes. Both HHS and UCLA activity scores doubled after surgery and tended to increase over time. There was one infection requiring a two-stage revision and a case of squeaking that began 2 years postoperatively after a mechanical fall. The overall survival rate of the implants was 98.4% at six years with revision for any reason as the end point. Based on these results, fourth generation ceramics offer a viable option for young and active patients.
Integrative Analysis of miRNA-mRNA and miRNA-miRNA Interactions
Authors: Guo Li , Zhao Yang , Yang Sheng , Zhang Hui , Chen Feng
Published: February 2014

MicroRNAs (miRNAs) are small, noncoding regulatory molecules. They are involved in many essential biological processes and act by suppressing gene expression. The present work reports an integrative analysis of miRNA-mRNA and miRNA-miRNA interactions and their regulatory patterns using high-throughput miRNA and mRNA datasets. Aberrantly expressed miRNA and mRNA profiles were obtained based on fold change analysis, and qRT-PCR was used for further validation of deregulated miRNAs. miRNAs and target mRNAs were found to show various expression patterns. miRNA-miRNA interactions and clustered/homologous miRNAs were also found to contribute to the flexible and selective regulatory network. Interacting miRNAs (e.g., miRNA-103a and miR-103b) showed more pronounced differences in expression, which suggests the potential “restricted interaction” in the miRNA world. miRNAs from the same gene clusters (e.g., miR-23b gene cluster) or gene families (e.g., miR-10 gene family) always showed the same types of deregulation patterns, although they sometimes differed in expression levels. These clustered and homologous miRNAs may have close functional relationships, which may indicate collaborative interactions between miRNAs. The integrative analysis of miRNA-mRNA based on biological characteristics of miRNA will further enrich miRNA study.
Molecular Pathways: HER3 Targeted Therapy
Authors: Gala Kinisha , Chandarlapaty Sarat
Published: February 2014

The HER family of receptor tyrosine kinases, including EGF receptor (EGFR), HER2, HER3, and HER4, transduce growth-promoting signals in response to ligand binding to their extracellular domains (ECD). This family is deregulated in numerous cancers, with mutations in EGFR and HER2 often serving as “driver” events to activate key growth factor signaling pathways such as the RAS-ERK and PI3K-AKT pathways. Less attention has been paid to the oncogenic functions of HER3 due to its lack of intrinsic kinase activity. Recent work, however, has placed HER3 in the spotlight as a key signaling hub in several clinical contexts. First, HER3 has been shown to play a major role in mediating resistance to HER2 and phosphoinositide 3-kinase (PI3K) pathway-directed therapies due to its feedback regulation via AKT signaling. Second, activating mutations in HER3 have been identified in multiple cancer types, including gastric, colon, bladder, and non–small cell lung cancers. As a result, HER3 is now being examined as a direct therapeutic target. In the absence of a strong enzymatic activity to target, the focus has been on strategies to prevent HER3 activation including blocking its most relevant dimerization partner's kinase activity (erlotinib, gefitinib, and lapatinib), blocking its most relevant dimerization partner's ability to dimerize with HER3 (trastuzumab and pertuzumab), and directly targeting the HER3 ECD (MM-121, U3-1287, and LJM716). Although drugs targeting EGFR and HER2 have proven effective even as single agents, the preclinical and clinical data on the antibodies directly targeting HER3 suggest more limited potential for single-agent activity. Possible reasons for this include the lack of a suitable biomarker for activated HER3, the lack of potency of the antibodies, and the lack of relevance of HER3 for growth of some of the cancer types analyzed. Nevertheless, clear improvements in activity are being observed for many of these compounds when they are given in combination. In this snapshot, we will highlight the basis for HER3 activation in cancer, the different pharmacologic strategies being used, and opportunities for further development. Clin Cancer Res; 20(6); 1410–6. ©2014 AACR.
Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer
Authors: Gong Jingjing , Xie Jianping , Bedolla Roble , Rivas Paul , Chakravarthy Divya , Freeman James W. , Reddick Robert , Kopetz Scott , Peterson Amanda , Wang Huamin , Fischer Susan M. , Kumar Addanki P.
Published: February 2014

Purpose: Near equal rates of incidence and mortality emphasize the need for novel targeted approaches for better management of patients with pancreatic cancer. Inflammatory molecules NF-κB and STAT3 are overexpressed in pancreatic tumors. Inhibition of one protein allows cancer cells to survive using the other. The goal of this study is to determine whether targeting STAT3/NF-κB crosstalk with a natural product Nexrutine can inhibit inflammatory signaling in pancreatic cancer.

Experimental Design: HPNE, HPNE-Ras, BxPC3, Capan-2, MIA PaCa-2, and AsPC-1 cells were tested for growth, apoptosis, cyclooxygenase-2 (COX-2), NF-κB, and STAT3 level in response to Nexrutine treatment. Transient expression, gel shift, chromatin immunoprecipitation assay was used to examine transcriptional regulation of COX-2. STAT3 knockdown was used to decipher STAT3/NF-κB crosstalk. Histopathologic and immunoblotting evaluation was performed on BK5–COX-2 transgenic mice treated with Nexrutine. In vivo expression of prostaglandin receptor E-prostanoid 4 (EP4) was analyzed in a retrospective cohort of pancreatic tumors using a tissue microarray.

Results: Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of STAT3, NF-κB, and their crosstalk led to transcriptional suppression of COX-2 and subsequent decreased levels of prostaglandin E2 (PGE2) and PGF2. STAT3 knockdown studies suggest STAT3 as negative regulator of NF-κB activation. Nexrutine intervention reduced the levels of NF-κB, STAT3, and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors.

Conclusions: Dual inhibition of STAT3–NF-κB by Nexrutine may overcome problems associated with inhibition of either pathway. Clin Cancer Res; 20(5); 1259–73. ©2014 AACR.
Combination Immunotherapy after ASCT for Multiple Myeloma Using MAGE-A3/Poly-ICLC Immunizations Followed by Adoptive Transfer of Vaccine-Primed and Costimulated Autologous T Cells
Authors: Rapoport Aaron P. , Aqui Nicole A. , Stadtmauer Edward A. , Vogl Dan T. , Xu Yin Yan , Kalos Michael , Cai Ling , Fang Hong-Bin , Weiss Brendan M. , Badros Ashraf , Yanovich Saul , Akpek Gorgun , Tsao Patricia , Cross Alan , Mann Dean , Philip Sunita , Kerr Naseem , Brennan Andrea , Zheng Zhaohui , Ruehle Kathleen , Milliron Todd , Strome Scott E. , Salazar Andres M. , Levine Bruce L. , June Carl H.
Published: February 2014

Purpose: Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.

Experimental Design: In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28–costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8+ T cells, and ELISA performed serially after transplant.

Results: T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3–specific CD8 T cells in 7 of 8 evaluable HLA-A2+ patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%–100%] and 2-year event-free survival was 56% (95% CI, 37%–85%).

Conclusions: A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF–primed MAGE-A3 vaccine. Clin Cancer Res; 20(5); 1355–65. ©2013 AACR.
CD4+ T Lymphocyte Ablation Prevents Pancreatic Carcinogenesis in Mice
Authors: Zhang Yaqing , Yan Wei , Mathew Esha , Bednar Filip , Wan Shanshan , Collins Meredith A. , Evans Rebecca A. , Welling Theodore H. , Vonderheide Robert H. , di Magliano Marina Pasca
Published: February 2014

Pancreatic cancer, one of the deadliest human malignancies, is associated with oncogenic Kras and is most commonly preceded by precursor lesions known as pancreatic intraepithelial neoplasias (PanIN). PanIN formation is accompanied by the establishment of an immunotolerant microenvironment. However, the immune contribution to the initiation of pancreatic cancer is currently poorly understood. Here, we genetically eliminate CD4+ T cells in the iKras* mouse model of pancreatic cancer, in the context of pancreatitis, to determine the functional role of CD4+ T cells during mutant Kras-driven pancreatic carcinogenesis. We show that oncogenic Kras-expressing epithelial cells drive the establishment of an immunosuppressive microenvironment through the recruitment and activity of CD4+ T cells. Furthermore, we show that CD4+ T cells functionally repress the activity of CD8+ T cells. Elimination of CD4+ T cells uncovers the antineoplastic function of CD8+ T cells and blocks the onset of pancreatic carcinogenesis. Thus, our studies uncover essential and opposing roles of immune cells during PanIN formation and provide a rationale to explore immunomodulatory approaches in pancreatic cancer. Cancer Immunol Res; 2(5); 423–35. ©2014 AACR.
Physical Activity Measured With Implanted Devices Predicts Patient Outcome in Chronic Heart Failure
Authors: Conraads Viviane M. , Spruit Martijn A. , Braunschweig Frieder , Cowie Martin R. , Tavazzi Luigi , Borggrefe Martin , Hill Michael R.S. , Jacobs Sandra , Gerritse Bart , van Veldhuisen Dirk J.
Published: February 2014

Background—

Physical activity (PA) predicts cardiovascular mortality in the population at large. Less is known about its prognostic value in patients with chronic heart failure (HF).

Methods and Results—

Data from 836 patients with implantable cardioverter defibrillator without or with cardiac resynchronization therapy enrolled in the Sensitivity of the InSync Sentry OptiVol feature for the prediction of Heart Failure (SENSE-HF)

1

study and the Diagnostic Outcome Trial in Heart Failure (DOT-HF) were pooled. The devices continuously measured and stored total daily active time (single-axis accelerometer). Early PA (average daily activity over the earliest 30-day study period) was studied as a predictor of time to death or HF-related hospital admission (primary end point). Data from 781 patients were analyzed (65±10 years; 85% men; left ventricular ejection fraction, 26±7%). Older age, shorter height, ischemic cause, peripheral artery disease, atrial fibrillation, diabetes mellitus, rales, peripheral edema, higher New York Heart Association class, lower diastolic blood pressure, and no angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were associated with reduced early PA. The primary end point occurred in 135 patients (15±7 months of follow-up). In multivariable analysis including baseline variables, early PA predicted death or HF hospitalization, with a 4% reduction in risk for each 10 minutes per day additional activity (hazard ratio [HR], 0.96; confidence interval [CI], 0.94–0.98;
P
=0.0002 compared with a model with the same baseline variables but without PA). PA also predicted death (HR, 0.93; CI, 0.90–0.96;
P
<0.0001) and HF hospitalization (HR, 0.97; CI, 0.95–0.99;
P
=0.011).

Conclusions—

Early PA, averaged over a 30-day window early after defibrillator implantation or cardiac resynchronization therapy in patients with chronic HF, predicted death or HF hospitalization, as well as mortality and HF hospitalization separately, accounting for baseline HF severity.

Clinical Trial Registration Information—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00400985, NCT00480077.
Cyclooxygenase-2 in Endothelial and Vascular Smooth Muscle Cells Restrains Atherogenesis in Hyperlipidemic Mice
Authors: Tang Soon Yew , Monslow James , Todd Leslie , Lawson John , Puré Ellen , FitzGerald Garret A.
Published: February 2014

Background—

Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages.

Methods and Results—

In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I
2
and prostaglandin E
2
, elevated blood pressure, and accelerated atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, α-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants.

Conclusions—

Although atherogenesis is accelerated in global COX-2 knockouts, consistent with evidence of risk transformation during chronic nonsteroidal anti-inflammatory drug administration, this masks the contrasting effects of enzyme depletion in macrophages versus vascular smooth muscle cells and endothelial cells. Targeting delivery of COX-2 inhibitors to macrophages may conserve their efficacy while limiting cardiovascular risk.
Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca
2+
Handling Dysfunction in Heart Failure
Authors: Zhang Caimei , Chen Biyi , Guo Ang , Zhu Yanqi , Miller Jordan D. , Gao Shan , Yuan Can , Kutschke William , Zimmerman Kathy , Weiss Robert M. , Wehrens Xander H. T. , Hong Jiang , Johnson Frances L. , Santana Luis F. , Anderson Mark E. , Song Long-Sheng
Published: February 2014

Background—

Cardiac dysfunction in failing hearts of human patients and animal models is associated with both microtubule densification and transverse-tubule (T-tubule) remodeling. Our objective was to investigate whether microtubule densification contributes to T-tubule remodeling and excitation–contraction coupling dysfunction in heart disease.

Methods and Results—

In a mouse model of pressure overload–induced cardiomyopathy by transaortic banding, colchicine, a microtubule depolymerizer, significantly ameliorated T-tubule remodeling and cardiac dysfunction. In cultured cardiomyocytes, microtubule depolymerization with nocodazole or colchicine profoundly attenuated T-tubule impairment, whereas microtubule polymerization/stabilization with taxol accelerated T-tubule remodeling. In situ immunofluorescence of heart tissue sections demonstrated significant disorganization of junctophilin-2 (JP2), a protein that bridges the T-tubule and sarcoplasmic reticulum membranes, in transaortic banded hearts as well as in human failing hearts, whereas colchicine injection significantly preserved the distribution of JP2 in transaortic banded hearts. In isolated mouse cardiomyocytes, prolonged culture or treatment with taxol resulted in pronounced redistribution of JP2 from T-tubules to the peripheral plasma membrane, without changing total JP2 expression. Nocodazole treatment antagonized JP2 redistribution. Moreover, overexpression of a dominant-negative mutant of kinesin 1, a microtubule motor protein responsible for anterograde trafficking of proteins, protected against JP2 redistribution and T-tubule remodeling in culture. Finally, nocodazole treatment improved Ca
2+
handling in cultured myocytes by increasing the amplitude of Ca
2+
transients and reducing the frequency of Ca
2+
sparks.

Conclusion—

Our data identify a mechanistic link between microtubule densification and T-tubule remodeling and reveal microtubule-mediated JP2 redistribution as a novel mechanism for T-tubule disruption, loss of excitation–contraction coupling, and heart failure.
Intakes of Potassium, Magnesium, and Calcium and Risk of Stroke
Authors: Sluijs Ivonne , Czernichow Sebastien , Beulens Joline W.J. , Boer Jolanda M.A. , van der Schouw Yvonne T. , Verschuren W. Monique M. , Grobbee Diederick E.
Published: February 2014

Background and Purpose—

We aimed to investigate the associations of dietary and total potassium, magnesium, and calcium intakes with stroke occurrence.

Methods—

A prospective cohort study was conducted among 36 094 participants aged 21 to 70 years. Dietary intake was assessed with a food frequency questionnaire.

Results—

During 12 years of follow-up, 631 strokes occurred. After adjustment for confounders, magnesium intake was associated with reduced stroke risk (hazard ratio [95% confidence interval] per 100 mg/d, 0.80 [0.67–0.97] dietary magnesium; 0.78 [0.65–0.93] total magnesium). Potassium and calcium intakes were not associated with stroke.

Conclusions—

This study supports an association between high magnesium intake and a reduced stroke risk.
A new species of sponge-dwelling Oukuriella (Chironomidae) from Brazil
Authors: FUSARI LÍVIA MARIA , BELLODI CAROLINA FERRAZ , LAMAS CARLOS JOSÉ EINICKER
Published: February 2014

Oukuriella Epler, 1986 is an exclusively Neotropical genus that comprises two well supported clades: inhabitants of freshwater sponges and inhabitants of immersed wood (saproxylophilic). In this work, males of a new chironomid species, Oukuriella froehlichi sp. n., are described and illustrated.  Specimens were collected near  stream in the Brazilian Atlantic Forest. Phylogenetic analyses performed in this study show that the newly discovered species belongs in the clade of freshwater sponge inhabitants.
Neophyllobius lorestanicus sp. nov. and N. ostovani sp.nov. (Acari: Camerobiidae) from Iran
Authors: KHANJANI MOHAMMAD , HOSEINI MOHAMMAD AHMAD , YAZDANPANAH SHIMA , MASOUDIAN FARSHAD
Published: February 2014

Two new species of the genus Neophyllobius Berlese, 1886 are described: Neophyllobius lorestanicus sp. nov. collected from soil under Prunus domestica L. (Rosaceae) in Markazi province and Neophyllobius ostovani sp. nov. from soil and rotten leaves of oak trees in Fars province, Iran. A key to all known Iranian and Turkish species of Neophyllobius is provided.
Lanzavecchia mangrovi sp. n. (Nematoda, Dorylaimida) from mangroves of Red River Estuary, Vietnam.
Authors: GAGARIN VLADIMIR G.
Published: February 2014

A new nematode species found in the Red River Estuary of Vietnam is described. Lanzavecchia mangrovi sp. n. is morphologically close to L. coomansi Nicholas, Stewart, 1984, but differs in its longer body (L = 2.71–3.76 µm versus L = 2.2–2.9 µm), shorter spicules (63–65 mm versus 72–88), longer prerectum (500–675 mm versus 262–310 µm) and shorter distal portion of tail in relation to the proximal portion (0.6–0.8 versus 0.9–2.3).
Finding a Home away from Home
Authors: Hernandez Exequiel
Published: February 2014

Using data from a sample of foreign subsidiaries established in the U.S. by firms from 27 countries between 1998 and 2003, this study examines the relationship between immigrants and the foreign expansion of organizations from their home countries. I propose that common country bonds to immigrants can become unique channels of knowledge, providing firms with idiosyncratic benefits in foreign places. Such connections to co-national immigrants should positively influence location choice and survival through processes of local learning and knowledge transfer. The results support these predictions. The probability of locating operations and surviving in a state increases with the concentration of same-nationality immigrants in that state, but not with the presence of immigrants of other nationalities. To highlight the knowledge-related mechanisms, I show that these relationships are particularly strong for firms lacking prior experience in the country, for locations in which immigrants can help firms capitalize on industry-specific knowledge spillovers, and for firms with highly knowledge-intensive operations.
The Paradox of Publicity
Authors: Kovács Balázs , Sharkey Amanda J.
Published: February 2014

Although increases in status often lead to more favorable inferences about quality in subsequent evaluations, in this paper, we examine a setting in which an increase to an actor’s status results in less favorable quality evaluations, contrary to what much of sociological and management theory would predict. Comparing thousands of reader reviews on Goodreads.com of 64 English-language books that either won or were short-listed for prestigious book awards between 2007 and 2011, we find that prizewinning books tend to attract more readers following the announcement of an award and that readers’ ratings of award-winning books tend to decline more precipitously following the announcement of an award relative to books that were named as finalists but did not win. We explain this surprising result, focusing on two mechanisms whereby signals of quality that tend to promote adoption can subsequently have a negative impact on evaluation. First, we propose that the audience evaluating a high-status actor or object tends to shift as a result of a public status shock, like an award, increasing in number but also in diverse tastes. We outline how this shift might translate into less favorable evaluations of quality. Second, we show that the increase in popularity that tends to follow a status shock is off-putting to some, also resulting in more negative evaluations. We show that our proposed mechanisms together explain the negative effect of status on evaluations in the context of the literary world.
When Does Prior Experience Pay? Institutional Experience and the Multinational Corporation
Authors: Perkins Susan E.
Published: February 2014

This study reexamines organizational learning theories to reconcile the conditions under which prior internationalization experience leads to performance gains for multinational corporations (MNCs) with varying host-country institutional experiences in different regulatory environments. Using field studies on telecommunications regulation, executive interviews conducted in Brazil, Spain, Portugal, Canada, and the U.S., and foreign direct investment data for 96 subunit operations investing in the Brazilian telecommunications industry from 1997 to 2004, I develop an experiential-learning theoretical framework to explain the mechanisms driving MNCs’ performance in subsequent host-country institutional environments given the prior experience they acquired in 80 heterogeneous regulatory environments. I predict and find that MNCs with highly similar institutional experience compared with the target country’s institutional environment will succeed. Empirical evidence suggests that similarity, breadth, and depth of prior regulatory experience significantly prolong survival. In contrast, firms with institutional experience unrelated to the target country’s regulatory environment experience learning penalties and are six times more likely to fail. These findings suggest that variations in learning contexts affect organizations’ learning curves.
A possible analytical and clinical role of endogenous antibodies causing discrepant adrenocorticotropic hormone measurement in a case of ectopic Cushing’s syndrome
Authors: Saiegh Leonard , Odeh Majed , Chen-Konak Limor , Elias Nizar , Sheikh-Ahmad Mohammad , Reut Maria , Slobodin Gleb , Bejar Jacob , Shechner Carmela
Published: February 2014

Heterophilic antibodies are well described, but poorly appreciated interferents and is often not a recognized problem affecting most immunoassays. We report a patient presented with ectopic Cushing’s syndrome (CS), but repeated plasma adrenocorticotropic hormone (ACTH) concentrations conducted by immunoassay were inappropriately within the reference range and not elevated, most probably as a result of antibody interference. A 36-year-old woman, presented with large gastric neuroendocrine carcinoma and severe ectopic CS, while repeated plasma ACTH concentrations conducted by immunoassay were inappropriately within the reference range. As we expected ACTH concentration to be higher, we performed several tests to evaluate whether there was any assay interference causing falsely lower than expected ACTH results. We measured ACTH using a different immunoassay, assayed the sample in dilution, assayed the sample after being incubated in heterophilic antibody blocking agent tube and performed recovery studies. Tests indicated the presence of interfering compounds, most probably heterophilic antibodies. When clinicians find ACTH concentrations to be lower than expected, we recommend the laboratory investigate antibody interference.
Picking Treaties, Picking Winners
Authors: Brown Joseph M. , Urpelainen Johannes
Published: February 2014

International treaty negotiations and domestic politics are interrelated. We show that negotiators can strategically select treaties to mobilize domestic interest groups and support particular candidates for office. Interest groups will support (oppose) political parties that will ratify treaties benefiting (harming) them. By designing treaties that mobilize these “swing” groups, negotiators can affect different parties’ chances of assuming power. Our model produces specific predictions for treaty design, contingent on the preferences of negotiators, parties, and interest groups. With conservative and moderate interest groups, the results may be counterintuitive—for instance, foreign governments pushing liberal treaties on liberal incumbents they dislike, intentionally mobilizing interest groups against the treaty and in favor of conservative challengers. Highly competitive systems, particularly those where moderate interest groups’ support is in play, give treaty negotiators leeway to shape political outcomes. Powerful interest groups may exert strong influence or no influence, depending on the cost of appeasing them and whether domestic and foreign negotiators are willing to gamble the incumbent’s political future for the achievement of their policy ideals.
Effects of Causes and Causes of Effects
Authors: Smith Herbert L.
Published: February 2014

Sociology is pluralist in subject matter, theory, and method, and thus a good place to entertain ideas about causation associated with their use under the law. I focus on two themes: (1) the legal lens on causation that “considers populations in order to make statements about individuals” and (2) the importance of distinguishing between effects of causes and causes of effects.
Herodotean Realism
Authors: Schlosser Joel Alden
Published: February 2014

With the renaissance of political realism has come an insistence that the study of politics be historically located. While many political realists trace their conception of historical inquiry to Thucydides, this article shows how Herodotus can offer a more realist approach to political phenomena. Herodotus crafts a self-conscious form of historical inquiry that foregrounds the actual activity of the historian as intersubjective, reflective, and particular. Herodotus thus models a historical investigation that shows its own limits while demanding the evaluation of its readers, offering a way to address criticisms of political realism’s singular and unacknowledged historical narratives. Moreover, Herodotus’s Histories exemplify a disposition toward open inquiry among others—what Herodotus calls wonder—that can invigorate responsive curiosity as part of the project of historical understanding essential to both political realism and contemporary democracies.
Legitimacy in Realist Thought
Authors: Sleat Matt
Published: February 2014

What, if anything, can realism say about the normative conditions of political legitimacy? Must a realist political theory accept that the ability to successfully employ coercive power is equivalent to the right to rule, or can it incorporate normative criteria for legitimacy but without collapsing into a form of moralism? While several critics argue that realism fails to adequately differentiate itself from moralism or that it cannot coherently appeal to normative values so as to distinguish might from right, this article seeks to help develop a realist account of legitimacy by demonstrating how it can successfully and stably occupy this position between moralism and Realpolitik. Through this discussion, however, the article also argues that political rule necessitates the use of coercive power which is (at best) imperfectly legitimated, and that this blurs the distinction between politics and successful domination which lies at the heart of many recent accounts of political realism. In at least this sense, realism retains important and under-acknowledged affinities to Realpolitik.