bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral 5-ASA Versus Prednisone in Short Term Treatment of Crohn's Disease: A Multicentre Controlled Trial
Authors: Martin F , Sutherland L , Beck IT , Anderson AH , Williams CN , Saibel F , Barrowman J , Lemire S
Published: April 2016

A multicencre randomized controlled trial was designed to compare the efficacy and safety of Eudragit-L coated oral 5-aminosalicylic acid (5-ASA) (Salofalk; lnterfalk) 3 g per day to a 'standard' oral prednisone therapeutic regimen in a 12 week treatment period of uncomplicated attacks of Crohn's ileitis and ileocolitis. Fifty patients with active Crohn's disease (Crohn's disease activity index [CDAI] 200 to 450) were randomized to receive either four 250 mg Eudragit-L-100 coated 5-ASA tablets three times a day for 12 weeks or oral prednisone ( 4 mg tablets) at a sustained 40 mg per day for two weeks followed by a 4 mg/day weekly dose reduction for the 10 subsequent weeks. Efficacy was determined by changes in the calculated CDAI and, as a novel assessment, the McMaster University quality of life index at two, four, six, eight, 10 and 12 weeks. Standard blood and urine values were obtained and physician's assessment completed at each two week visit. Clinical remission was obtained in 12 of 26 patients (46%) in the prednisone group and in nine of 19 (47%) in the 5-ASA group. Treatment failure was observed in three patients in each group. All other patients improved during the treatment period. Patients on prednisone reduced their CDAI scores significantly more rapidly during the first four weeks, but the reduction and maintenance of CDAI scores were similar in both groups for the remainder of the study period. In patients with ileocolitis, prednisone was significantly better than 5-ASA. Quality of life assessment parallelled the changes in CDAI, and appear a valid index. The two therapeutic regimens appear safe and did not disclose any unexpected adverse events or side effects. No significant biological abnormalities were detected in either treatment group. In conclusion, in this small trial, it was found that Salofalk at a dose of 3 g per day appears effective treatment for active Crohn's disease, and it is proposed chat higher doses may be beneficial in more extensive disease (ileocolitis) and during the first four weeks of treatment.
On the Pathogenesis of the Irritable Bowel Syndrome: The Irritable Bowel or the Irritable Patient?
Authors: Collins Stephen M
Published: April 2016

The traditional perspective of irritable bowel syndrome (IBS) as a behavioural problem has tended to downplay the role of gastrointestinal dysfunction. Contrary to predictions based on the traditional philosophy, a recent study has shown that IBS patients have increased pain tolerance compared to healthy subjects. This profile of pain tolerance is similar to that seen in chronic organic disease of the gut (eg, Crohn's disease), raising the possibility that IBS patients may experience pain resulting from gastrointestinal dysfunction. The recent finding of increased airway responsiveness to inhaled methacholine in certain IBS patients provides an objective and quantifiable measurement of tissue dysfunction in that syndrome, and focuses attention on possible mechanisms underlying the altered responsiveness of hollow organs in patients with IBS; these mechanisms are discussed.
Therapeutic Options in the Treatment and Prevention of Nonsteroidal Anti-Inflammatory Drug-Induced Ulceration
Authors: Champion Malcolm C
Published: April 2016

This article reviews the current status of H2receptor antagonists, omeprazole, sucralfate and misoprostol as therapeutic options for the prophylaxis and treatment of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal ulceration. The efficacy of the Hz receptor antagonists appears to be restricted to prophylaxis and treatment of NSAID-induced duodenal ulcer disease. Omeprazole may have a place in the future treatment of NSAID-induced gastric ulcers. However, more studies are necessary to examine this drug's efficacy in both the prophylaxis and treatment of NSAID-induced ulceration. Sucralface improves symptoms, but does not appear to have any effect on improving gastric mucosal damage when compared to placebo. It may, however, be useful in the treatment of NSAID-induced duodenal ulcers. Misoprostol is effective in both the prophylaxis and treatment of NSAID-induced gastric ulcers; however, its exact role in the prophylaxis and treatment of NSAlD-induced duodenal ulcers remains to be defined.
Maintaining Remission in Distal Ulcerative Colitis and Ulcerative Proctitis
Authors: Miner PB , Biddle WL
Published: April 2016

Maintenance of remission is an important consideration in the medical care of patients with ulcerative colitis. The relapse rate is high when medications are discontinued. Many types of medications have been investigated for potential efficacy of maintaining remission. This paper reviews the literature on maintenance therapy for both distal and universal ulcerative colitis. Sulphasalazine is the drug of choice since il is effective and relatively low m cost. 5-aminosalicylic acid (5-ASA) derivatives, both oral and rectal forms, are also effective. Other medications such as metronidazole, cromolyn sodium and prednisone have nor been shown to be effective maintenance therapy. Strategies for maintenance are outlined and include possible regimens with 5-ASA enemas. While 1 g of 5-ASA is effective, the long term relapse rate is similar co that seen with sulphasalazine. Patients capered co 1 g 5-ASA enemas have a good chance of maintaining remission if the colitis does not flare within the first few months, because most colites will flare up early on. Other possible regimens include intermittent enemas, eg, every other night or every third night. Patients in remission can be safely maintained in remission with sulphasalazine or one of its 5-ASA derivatives.
Hemochromatosis and Yersiniosis
Authors: Adams Paul C , Gregor James
Published: April 2016

Two patients with documented hemochromatosis and systemic infection with Yersinia enterocolitica are described. The first patient presented with Y enterocolitica septicemia and an infected hip prosthesis which led to the diagnosis of hemochromatosis. The second patient was previously treated for Y enterocolitica with antibiotics but did not recover fully until aggressive phlebotomy therapy was started. The simultaneous occurrence of these two uncommon diseases is related to the ability of the yersinia organism to thrive in the presence of large amounts of iron. The association between iron overload and susceptibility to yersinia infection is reviewed within the context of these two cases.
Treatment of Inflammatory Bowel Disease in Children
Authors: Gall D Grant
Published: April 2016

As no curative therapy exists, supportive measures play an important role in the management of patients with inflammatory bowel disease (IBO). Aminosalicylic acid (ASA) compounds and corticosteroids remain the mainstay of medical therapy. Aminosalicylates are recommended for therapy of mild to moderate active ulcerative colitis and for the maintenance of remission in ulcerative colitis. The role of 5-ASA preparations in Crohn's disease is less clear. In granulomatous colitis, 5-ASA therapy is recommended. With the development of new delivery systems, the role for 5-ASA in the treatment of small bowel Crohn's disease is under investigation. Prednisone remains the drug of choice in severe ulcerative colitis and active Crohn's disease. The role of immunosuppressive drugs in pediatric patients is unclear. Nutritional therapy has been an important advance in the treatment of children with Crohn's disease, especially those with growth failure. Nutritional therapy can consist of combined total parenteral and enteral nutrition or enteral nutrition alone. An initial period of total parenteral nutrition followed by a six to eight week course of enteral therapy with a semisynthetic diet has been shown to be effective in the management of patients with severe active disease and growth failure.
Screening by Colonoscopy - Has the Time Arrived?
Authors: Hunt Richard H
Published: April 2016

Colorectal cancer mortality may be reduced by several screening strategies - mathematical modelling suggests that mortality may be reduced by one-third in patients over the age of 40 years who undergo annual fecal occult blood testing. Similar modelling suggests that either colonoscopy or barium enema may reduce mortality by up to 85%. This paper reviews the evidence for different screening approaches for colorectal cancer, and identifies high risk groups in whom full colonoscopy has been studied. These studies include patients with first degree relatives with colorectal cancer, family cancer syndrome, prior breast, uterine or ovarian lesions, and follow-up for prior adenomatous polyps or cancer. The role of colonoscopy in the surveillance of patients with chronic total ulcerative colitis for dysplasia is also reviewed. The implications for patient management and possible clinical strategies are discussed.
Lifestyle Issues: What Do I Tell My Patients? Smoking and Diet
Authors: Benoni C
Published: April 2016

During the past decade, smoking has been recognized as a risk factor in inflammatory bowel disease (IBD). Smoking is associated with Crohn's disease, and nonsmoking with ulcerative colitis. The biological rationale behind these findings is not known. Because of the negative effects of smoking, advice to patients with IBD cannot differ from advice given to any patient. In families with IBD, young healthy members should be advised never to start smoking. In Crohn's disease, a fat-reduced diet will be necessary when bile salt metabolism is disturbed. Prospective trials with unrefined carbohydrate fibre-rich diets or low-residue diets versus normal diets show no difference in the clinical course of Crohn's disease. Thus the patient should have a well balanced diet with unrestricted fibre intake, supplemented in case of malabsorption with vitamins and minerals. Diet counselling itself has proved beneficial, probably because of optimization of nutritional status. In ulcerative colitis, patients may be lactose intolerant without lactase deficiency. Low dietary fibre intake doses does not seem to be of importance. The ulcerative colitis patient should be advised to eat a normal to high fibre diet. Recent studies have suggested a possible beneficial effect of dietary supplementation with fish oil.
Natural Killer Cell and Large Granular Lymphocyte Deficiency in the Gut of Children with Inflammatory Bowel Disease
Authors: Hadziselimovic F , Emmons LR , Schaub U
Published: April 2016

The occurrence of natural killer cells and large granular lymphocytes (LGL) within the epithelium of colonic mucosa in children with inflammatory bowel disease (IBD) was compared to normal controls. Their numbers and localization within the epithelium from various regions of the colon were analyzed with immunohistochemical techniques using fluorescent, light and electron microscopy. The average number of natural killer cells and LGL in normal controls was 3.0±1.l per mn2. In contrast, there were no natural killer cells in the gut epithelium of children with IBD, irrespective of disease activity, whether the biopsy specimens were obtained from involved or uninvolved inflammatory regions of the gut, or the treatment status of the patients. However, the number of natural killer cells was normal in patients in remission with left-sided colitis. The lack of natural killer cells and LGL in the gut epithelium in children with IBD may be indicative of a possible genetic predisposition. The authors also present a new therapeutic strategy consisting of low dose interferon-alpha-2a that is efficacious in ameliorating ulcerative col iris and Crohn's disease and concomitantly increasing the number of natural killer cells and LGL in the gut.
The Efficacy of Umbelliferone, Arbutin, and N-Acetylcysteine to Prevent Microbial Colonization and Biofilm Development on Urinary Catheter Surface: Results from a Preliminary Study
Authors: Cai Tommaso , Gallelli Luca , Meacci Francesca , Brugnolli Anna , Prosperi Letizia , Roberta Stefani , Eccher Cristina , Mazzoli Sandra , Lanzafame Paolo , Caciagli Patrizio , Malossini Gianni , Bartoletti Riccardo
Published: April 2016

We evaluated, in a preliminary study, the efficacy of umbelliferone, arbutin, and N-acetylcysteine to inhibit biofilm formation on urinary catheter. We used 20 urinary catheters: 5 catheters were incubated withEnterococcus faecalis(control group); 5 catheters were incubated withE. faecalisin presence of umbelliferone (150 mg), arbutin (60 mg), and N-acetylcysteine (150 mg) (group 1); 5 catheters were incubated withE. faecalisin presence of umbelliferone (150 mg), arbutin (60 mg), and N-acetylcysteine (400 mg) (group 2); and 5 catheters were incubated withE. faecalisin presence of umbelliferone (300 mg), arbutin (60 mg), and N-acetylcysteine (150 mg) (group 3). After 72 hours, planktonic microbial growth and microorganisms on catheter surface were assessed. In the control group, we found a planktonic load of ≥105 CFU/mL in the inoculation medium and retrieved 3.69 × 106 CFU/cm from the sessile cells adherent to the catheter surface. A significantly lower amount in planktonic (p<0.001) and sessile (p=0.004) bacterial load was found in group 3, showing <100 CFU/mL and 0.12 × 106 CFU/cm in the incubation medium and on the catheter surface, respectively. In groups 1 and 2, 1.67 × 106 CFU/cm and 1.77 × 106 CFU/cm were found on catheter surface. Our results document that umbelliferone, arbutin, and N-acetylcysteine are able to reduceE. faecalisbiofilm development on the surface of urinary catheters.
Exploring the Barriers of Home Care Services in Iran: A Qualitative Study
Authors: Heydari Heshmatolah , Shahsavari Hooman , Hazini Abdolrahim , Nasrabadi Alireza Nikbakht
Published: April 2016

With increasing chronic diseases, the use of home care is rising in the world. Home care in Iran has many challenges and to improve that, we should identify the challenges and barriers of home care. The aim of this study was to identify and explore the barriers of home care in Iran. This is a qualitative study with content analysis approach that was conducted in Iran in 2015. Fourteen key informants comprising health policymakers, faculty members, nurses, and physicians as well as patients and families engaged in home care purposefully participated in this study. Data was obtained using face-to-face semistructured interviews. A focus group discussion was also used to complete the findings. Graneheim and Lundman’s approach was used for analysis of data and Lincoln and Guba’s criteria were used to confirm the trustworthiness of study’s findings. The data were divided into three main categories and eight subcategories. Main categories included treatment-based approach in the healthcare system, cultural dimensions, and the lack of adequate infrastructure. A position for home care in the healthcare system, considering cultural dimensions in Iranian society and providing an appropriate infrastructure, can be beneficial to improve the situation of home care services in Iran.
Study of Tribological Behavior of Silicon Carbide Based Aluminum Metal Matrix Composites under Dry and Lubricated Environment
Authors: Singh Kalyan Kumar , Singh Saurabh , Shrivastava Anil Kumar
Published: April 2016

Friction and wear behavior of silicon carbide based aluminum metal matrix composite and aluminum matrix alloy have been studied for sliding speeds of 3.14 m/s and 3.77 m/s and load range from 10 N to 30 N under dry and lubricated environment, respectively. The experiments were performed on pin on disk tribometer (Make: DUCOM). The composite was fabricated by stir casting process and has several challenges like inferior bonds and interfacial reaction products which will deteriorate the mechanical and tribological properties. Therefore, addition of reactive metal like magnesium (Mg) should be done which will lead to reduced solidification shrinkage, lower tendency towards hot tearing, and faster process cycles. Results have revealed that the developed composites have lower coefficient of friction and wear rates when compared with aluminum matrix alloy under dry and lubricated environment. Experimental results show that under dry condition coefficient of friction of both the matrix alloy and the composite decreases with increase in load, whereas it increases with increase in sliding speeds; on the other hand wear rates of both aluminum matrix alloy and the composites increase with increase in load as well as with sliding speeds. FESEM of worn surfaces are also used to understand the wear mechanisms.
Improving Genetic Algorithm with Fine-Tuned Crossover and Scaled Architecture
Authors: Shrestha Ajay , Mahmood Ausif
Published: April 2016

Genetic Algorithm (GA) is a metaheuristic used in solving combinatorial optimization problems. Inspired by evolutionary biology, GA uses selection, crossover, and mutation operators to efficiently traverse the solution search space. This paper proposes nature inspired fine-tuning to the crossover operator using the untapped idea of Mitochondrial DNA (mtDNA). mtDNA is a small subset of the overall DNA. It differentiates itself by inheriting entirely from the female, while the rest of the DNA is inherited equally from both parents. This unique characteristic of mtDNA can be an effective mechanism to identify members with similar genes and restrict crossover between them. It can reduce the rate of dilution of diversity and result in delayed convergence. In addition, we scale the well-known Island Model, where instances of GA are run independently and population members exchanged periodically, to a Continental Model. In this model, multiple web services are executed with each web service running an island model. We applied the concept of mtDNA in solving Traveling Salesman Problem and to train Neural Network for function approximation. Our implementation tests show that leveraging these new concepts of mtDNA and Continental Model results in relative improvement of the optimization quality of GA.
Identification of a LargeSLC25A13Deletion via Sophisticated Molecular Analyses Using Peripheral Blood Lymphocytes in an Infant with Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD): A Clinical and Molecular Study
Authors: Zheng Qi-Qi , Zhang Zhan-Hui , Zeng Han-Shi , Lin Wei-Xia , Yang Heng-Wen , Yin Zhi-Nan , Song Yuan-Zong
Published: April 2016

Background.Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a Mendelian disorder arising from biallelicSLC25A13mutations, andSLC25A13genetic analysis was indispensable for its definite diagnosis. However, conventionalSLC25A13analysis could not detect all mutations, especially obscure large insertions/deletions. This paper aimed to explore the obscureSLC25A13mutation in an NICCD infant.Methods.Genomic DNA was extracted to screen for 4 high-frequencySLC25A13mutations, and then all 18 exons and their flanking sequences were analyzed by Sanger sequencing. Subsequently, cDNA cloning, SNP analyses, and semiquantitative PCR were performed to identify the obscure mutation.Results.A maternally inherited mutation IVS16ins3kb was screened out, and then cDNA cloning unveiled paternally inherited alternative splicing variants (ASVs) featuring exon 5 skipping. Ultimately, a large deletion c.329-1687_c.468+3865del5692bp, which has never been described in any other references, was identified via intensive study on the genomic DNA around exon 5 ofSLC25A13gene.Conclusions.An NICCD patient was definitely diagnosed as a compound heterozygote of IVS16ins3kb and c.329-1687_c.468+3865del5692bp. The large deletion enriched theSLC25A13mutation spectrum, and its identification supported the concept that cDNA cloning analysis, along with other molecular tools such as semiquantitative PCR, could provide valuable clues, facilitating the identification of obscureSLC25A13deletions.
Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1α
Authors: Wen Dan , Zou Yan-Fang , Gao Yao-Hui , Zhao Qian , Xie Yin-Yin , Shen Ping-Yan , Xu Yao-Wen , Xu Jing , Chen Yong-Xi , Feng Xiao-Bei , Shi Hao , Zhang Wen
Published: April 2016

In this study, rat models of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1α). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1α. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1αduring hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1αcan regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1α.
Study on Impedance Characteristics of Aircraft Cables
Authors: Li Weilin , Liu Wenjie , Zhang Xiaobin , Gao Zhaohui , Xie Meng , Wang Hongxia
Published: April 2016

Voltage decrease and power loss in distribution lines of aircraft electric power system are harmful to the normal operation of electrical equipment and may even threaten the safety of aircraft. This study investigates how the gap distance (the distance between aircraft cables and aircraft skin) and voltage frequency (variable frequency power supply will be adopted for next generation aircraft) will affect the impedance of aircraft cables. To be more precise, the forming mechanism of cable resistance and inductance is illustrated in detail and their changing trends with frequency and gap distance are analyzed with the help of electromagnetic theoretical analysis. An aircraft cable simulation model is built with Maxwell 2D and the simulation results are consistent with the conclusions drawn from the theoretical analysis. The changing trends of the four core parameters of interest are analyzed: resistance, inductance, reactance, and impedance. The research results can be used as reference for the applications in Variable Speed Variable Frequency (VSVF) aircraft electric power system.
The Diagnostic Value of Alpha-1-Antitrypsin Phenotype in Patients with Granulomatosis with Polyangiitis
Authors: Pervakova M. Y. , Emanuel V. L. , Titova O. N. , Lapin S. V. , Mazurov V. I. , Belyaeva I. B. , Chudinov A. L. , Blinova T. V. , Surkova E. A.
Published: April 2016

The deficiency of alpha-1 protease inhibitor, or alpha-1-antitrypsin (A1AT), predisposes to chronic lung diseases and extrapulmonary pathology. Besides classical manifestations, such as pulmonary emphysema and liver disease, alpha-1-antitrypsin deficiency (A1ATD) is also known to be associated with granulomatosis with polyangiitis (GPA or Wegener’s granulomatosis). The aim of our study was to evaluate the frequency of allelic isoforms of A1AT and their clinical significance among GPA patients. Detailed clinical information, including Birmingham Vasculitis Activity Score (BVAS), incidence of lung involvement, anti-proteinase 3 (PR3) antibodies concentrations, and other laboratory data were collected in 38 GPA patients. We also studied serum samples obtained from 46 healthy donors. In all collected samples A1AT phenotyping by isoelectrofocusing (IEF) and turbidimetric A1AT measurement were performed. Abnormal A1AT variants were found in 18.4% (7/38) of cases: 1 ZZ, 4 MZ, 2 MF, and only 1 MZ in control group (2%). The mean A1AT concentration in samples with atypical A1AT phenotypes was significantly lower (P=0.0038) than in normal A1AT phenotype. We found that patients with abnormal A1AT phenotypes had significantly higher vasculitis activity (BVAS) as well as anti-PR3 antibodies concentration. We conclude that A1AT deficiency should be considered in all patients with GPA.
Associations of Trauma Severity with Mean Platelet Volume and Levels of Systemic Inflammatory Markers (IL1β, IL6, TNFα, and CRP)
Authors: Alper Baris , Erdogan Baris , Erdogan Mehmet Özgür , Bozan Korkut , Can Murat
Published: April 2016

We investigated the associations of injury severity scores (ISSs) with the mean platelet volume, the serum levels of two interleukins (IL1βand IL6), and the serum levels of tumour necrosis factor-α(TNFα) and C-reactive protein (CRP). We sought to identify biochemical parameters that could be used as components of a new biochemical parameter-based ISS system. The levels of CRP, TNFα, IL1β, and IL6 differed significantly (allpvalues < 0.05) between severely injured patients and controls. The mean platelet volume (MPV) did not correlate with the ISSs (p> 0.05). The TNFαand IL6 levels were useful for determining the severity of injury, and the CRP level was elevated in all trauma patients but did not correlate with the ISS. The IL1βlevel was higher in the study group but did not increase as the ISS increased. IL6 and TNFαlevels were higher in the study group and increased as the ISS increased. We found no significant difference between the trauma group and healthy individuals in terms of MPV values. IL6 and TNFαlevels can be used to assess trauma severity. However, neither the MPV nor the CRP or IL1βlevel is useful for this purpose.
RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis
Authors: Brünker Peter , Wartha Katharina , Friess Thomas , Grau-Richards Sandra , Waldhauer Inja , Koller Claudia Ferrara , Weiser Barbara , Majety Meher , Runza Valeria , Niu Huifeng , Packman Kathryn , Feng Ningping , Daouti Sherif , Hosse Ralf J. , Mössner Ekkehard , Weber Thomas G. , Herting Frank , Scheuer Werner , Sade Hadassah , Shao Cuiying , Liu Bin , Wang Peng , Xu Gary , Vega-Harring Suzana , Klein Christian , Bosslet Klaus , Umaña Pablo
Published: April 2016

Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor-targeted induction of apoptosis, we engineered a bispecific antibody (BsAb), which simultaneously targets fibroblast-activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyperclustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells. Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP dependent, was independent of FcR cross-linking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono- and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis. Mol Cancer Ther; 15(5); 946–57. ©2016 AACR.
Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies
Authors: Azuara Daniel , Santos Cristina , Lopez-Doriga Adriana , Grasselli Julieta , Nadal Marga , Sanjuan Xavier , Marin Fátima , Vidal Joana , Montal Robert , Moreno Victor , Bellosillo Beatriz , Argiles Guillem , Elez Elena , Dienstmann Rodrigo , Montagut Clara , Tabernero Josep , Capellá Gabriel , Salazar Ramon
Published: April 2016

The clinical significance of low-frequent RAS pathway–mutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots, including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E), was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared with conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1% to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8%. An inverse correlation between the fraction of mutated alleles and radiologic response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel, including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy. Mol Cancer Ther; 15(5); 1106–12. ©2016 AACR.
Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization
Authors: Newick Kheng , O'Brien Shaun , Sun Jing , Kapoor Veena , Maceyko Steven , Lo Albert , Puré Ellen , Moon Edmund , Albelda Steven M.
Published: April 2016

Antitumor treatments based on the infusion of T cells expressing chimeric antigen receptors (CAR T cells) are still relatively ineffective for solid tumors, due to the presence of immunosuppressive mediators [such as prostaglandin E2 (PGE2) and adenosine] and poor T-cell trafficking. PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T-cell receptor (TCR) activation. This inhibition process requires PKA to localize to the immune synapse via binding to the membrane protein ezrin. We generated CAR T cells that expressed a small peptide called the “regulatory subunit I anchoring disruptor” (RIAD) that inhibits the association of PKA with ezrin, thus blunting the negative effects of PKA on TCR activation. After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, released more cytokines, and showed enhanced killing of tumor cells compared with CAR T cells. When injected into tumor-bearing mice, the antitumor efficacy of murine and human CAR-RIAD T cells was enhanced compared with that of CAR T cells, due to resistance to tumor-induced hypofunction and increased T-cell infiltration of established tumors. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells did in response to the chemokine CXCL10 and also had better adhesion to various matrices. Thus, the intracellular addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy, therefore, shows potential clinical application for treating solid tumors. Cancer Immunol Res; 4(6); 541–51. ©2016 AACR.
Postoperative Treatment of Pain after Hip Fracture in Elderly Patients with Dementia
Authors: Jensen-Dahm Christina , Palm Henrik , Gasse Christiane , Dahl Jørgen B. , Waldemar Gunhild
Published: April 2016

Background/Aims: Prior studies have shown that patients with dementia are at risk of receiving insufficient treatment for pain after a hip fracture. We therefore hypothesized that elderly hip fracture patients with dementia received less postoperative pain treatment than those without dementia. Method: All patients (age ≥65 years) who had been operated on for a hip fracture in the Copenhagen University Hospital region in 2009 were included. Data about analgesic use for the first 72 h after surgery were acquired from the hospitals' electronic medication system and linked with information about dementia, comorbidity, and prior drug use. Results: A total of 1,507 patients were included, of which 296 (19.6%) suffered from dementia. Both groups were equally likely to receive paracetamol and opioids. Patients with dementia received lower doses of oral morphine equivalents during the first [dementia vs. no dementia: 29.0 (26.4-31.8) vs. 34.7 (33.1-36.4) mg, p = 0.001] and second [27.8 (25.4-30.5) vs. 31.2 (29.9-32.4) mg, p = 0.019] but not on the third postoperative day (p = 0.10). Conclusion: The lower doses of opioids may reflect uncertainty about how to treat pain patients with dementia. Further guidance is needed, as inadequate treatment of pain may have adverse consequences.
Einstellung von hausärztlichen Patientinnen und Patienten zu schul- und komplementärmedizinischen Verfahren - ein Stimmungsbild
Authors: Henzen Silke , Scheiwiler Patrick , Sibalic Vladimir
Published: April 2016

Hintergrund: Komplementärmedizinische Medikamente erfreuen sich gemäss Literaturangaben einer grossen Beliebtheit im freien Arzneimittelmarkt. Eine Analyse der Patientenmeinungen in schulmedizinischen Praxen bezüglich des Einsatzes von Phytotherapie und Homöopathie bei der Behandlung von häufigen somatischen Erkrankungen unterschiedlichen Schweregrades sowie der Depression fehlt. Methoden: 203 Patienten (108 Frauen, 95 Männer) in fünf Ostschweizer Allgemeinmedizinpraxen gaben auf einer Skala von 1 bis 10 eine persönliche Einschätzung zur Wirksamkeit und zum Nebenwirkungspotenzial von Medikamenten aus der Schulmedizin, der Phytotherapie und der Homöopathie ab. Zudem wurde gefragt, welcher Therapieform der Vorzug gegeben wird. Die zu behandelnden Erkrankungen waren Herzinfarkt, funktionelle Magen-Darm-Störungen und Depression. Die Resultate wurden nach Geschlecht, Alter, Begleiterkrankungen und Schulbildung ausgewertet. Ergebnisse: 74% der Befragten erwarten, dass in der hausärztlichen Sprechstunde auch komplementärmedizinische Methoden angeboten werden. Die Schulmedizin wird bei Herzinfarkt und Depression favorisiert. Die Phytotherapie oder eine Kombination wird zur Behandlung des unruhigen Magen-Darm-Trakts bevorzugt. Frauen und unter 40- Jährige bevorzugen eher die Komplementärmedizin. Die Wirksamkeit und Nebenwirkungsrate der Phytotherapie und Homöopathie wird gleichgesetzt. Die Schulbildung beeinflusst die Beurteilung gering. Schlussfolgerung: In den letzten 10 Jahren hat sich die Patienteneinstellung kaum verändert, trotz neuer wissenschaftlicher Erkenntnisse. Die positiven Resultate der wissenschaftlichen Forschung in der Komplementärmedizin sollten an die Patienten weitergegeben werden. Dies ist eine Aufgabe der Ärztinnen und Ärzte.
Actantialité et modalité dans Les Contemplations de Victor Hugo: les effets passionnels.
Authors: Biglari Amir
Published: April 2016

Fundamentado na teoria semiótica das paixões, este artigo procura esclarecer os efeitos passionais suscitados pelas relações actanciais e modais na obra Les Contemplations, de Victor Hugo. Para tanto, focaliza especificamente o desespero do locutor, sob o duplo ponto de vista dos actantes (posicionais e transformacionais) e das modalidades (simples e complexas) aí textualizados. Também são examinados os atores e seus papéis temáticos, os simulacros passionais e o sintagma do desespero. Ao avaliar assim a discursivização de um aspecto passional em V. Hugo, desejamos contribuir, em alguma medida, para um melhor conhecimento da paixão do desespero, não apenas na obra do escritor francês, mas considerada em sua generalidade. Esperamos, além disso, que este exercício analítico possa pôr à prova o valor heurístico da teoria semiótica utilizada.
Fraseologias de gênero em resumos científicos de Linguística, Engenharia de Materiais e Ciências Econômicas
Authors: Kilian Cristiane Krause , Loguercio Sandra Dias
Published: April 2016

Neste trabalho, apresentamos um estudo sobre as fraseologias empregadas em resumos de artigos científicos em português nas áreas de Linguística, Engenharia de Materiais e Economia. Investigamos as fraseologias utilizadas que não estão vinculadas a uma temática específica, mas que são típicas do gênero científico, as quais denominamos fraseologias de gênero. Dois tipos de procedimentos são utilizados: uma análise das partes essenciais da macroestrutura, que são identificadas com funções; e o uso de processamento automático da linguagem. A partir das palavras metacientíficas mais frequentes nos corpora, buscamos as combinatórias recorrentes, estas são então agrupadas em torno da função informativa que desempenham no texto. As fraseologias selecionadas não se configuram como expressões fixas, mas apresentam uma estabilidade relativa, e são, em sua maioria, comuns às três áreas estudadas. Os resultados encontrados apontam para certas diferenças em relação aos modos de dizer de cada área, o que deve ser levado em conta na produção dos textos e na elaboração de material didático destinado ao desenvolvimento de habilidades e competências de leitura e produção textual no contexto acadêmico.
Conceptualização metafórica da anatomia em português: artérias, veias e nervos
Authors: Malaszkiewicz Paula Fernanda , Vandaele Sylvie , Reuillard Patrícia Chittoni Ramos
Published: April 2016

A partir dos anos 1980, a metáfora passou a ser estudada do ponto de vista conceptual, sendo reconhecida na linguagem científica. Pode-se apreender a conceptualização metafórica de uma área especializada através da identificação dos índices de conceptualização metafórica. No campo da tradução, o conhecimento dos índices e do modo de conceptualização é fundamental, pois estão ligados à fraseologia do domínio. Este artigo tem como objetivo mostrar os resultados de uma pesquisa que buscou identificar e descrever os índices de conceptualização metafórica utilizados em Anatomia na descrição do posicionamento das artérias, das veias e dos nervos em língua portuguesa, continuando um estudo já realizado em língua inglesa e francesa. Após terem sido identificados, os índices foram distribuídos em categorias de representação fictícia e nos modos de conceptualização identificados.
Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy
Authors: He Ben , Zhao Yi-Chao , Gao Ling-Chen , Ying Xiao-Ying , Xu Long-Wei , Su Yuan-Yuan , Ji Qing-Qi , Lin Nan , Pu Jun
Published: April 2016

Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain- and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor β–activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy.
Computational Creation and Morphing of Multilevel Rhythms by Control of Evenness
Authors: Milne Andrew J. , Dean Roger T.
Published: April 2016

We present an algorithm, instantiated in a freeware application called MeanTimes, that permits the parameterized production and transformation of a hierarchy of well-formed rhythms. Each “higher” rhythmic level fills in the gaps of all “lower” levels, and up to six such levels can be simultaneously sounded. MeanTimes has a slider enabling continuous variation of the ratios of the intervals between the beats (onsets) of the lowest level. This consequently changes—in a straightforward manner—the evenness of this level; it also changes—in a more complex, but still highly patterned manner—the evennesses of all higher levels. This specific parameter, and others used in MeanTimes, are novel: We describe their mathematical formulation, demonstrate their utility for generating rhythms, and show how they differ from those typically used for pitch-based scales. Some of the compositional possibilities continue the tradition of Cowell and Nancarrow, proceeding further into metahuman performance, and have perceptual and cognitive implications that deserve further attention.
Chaotic Writing as a Literary Element in the Story of Ahaz in 2 Chronicles 28
Authors: Amar Itzhak
Published: April 2016

This article subjects the account of Ahaz in 2 Chronicles to a synchronic literary analysis in light of the Vorlage in Kings in order to demonstrate that the “chaotic writing” that marks it forms part of the effect the Chronicler is attempting to create. By displacing and interpolating verses, he thereby paints a picture of Ahaz as a vile sinner who transgresses by nature rather than a rational tactician. This impression is heightened by the placement of the account of the Judahites’ capture and return at the centre of the narrative. The logical, coherent, sequential nature of this unit—constructed on the basis of a complication, crisis, falling action, and resolution—contrasts sharply with the rough-edged, broken pericopae on either side of it. It thus accentuates the chaos and confusion of the narrative as a whole.
WHY THE GOOD? APPEARANCE, REALITY AND THE DESIRE FOR THE GOOD IN REPUBLIC, VI, 504B-506D
Authors: MURR DIMITRI EL
Published: April 2016

What arguments does Plato offer to explain the pre-eminence he confers to the idea of the Good in Republic, 6? Considering in detail the short but key section of the Republic (504b-506d) that precedes the analogy between the Good and the Sun, this paper argues that it is what Plato claims to be the universal recognition that the Good exists independently of any opinion that makes it so important for human thought. Nothing less than the concept that can make everything else intelligible, as the sun makes everything in the sensible world visible.
IL PROBLEMA DELLE IDEE DI ARTEFATTO IN PLATONE
Authors: FORCIGNANÒ FILIPPO
Published: April 2016

It is widely believed that Plato promoted a version of the "one over many" argument such that there would be Forms of all things. Among these Forms are also included those of artefacts. Aristotle denies, however, that Plato would accept such Forms. The ancient Platonic tradition is unusually unanimous in denying the existence of Forms of artefacts. This paper supports three main points: (a) through a careful examination of some Platonic texts (in particular Resp. 596a) it is possible to assert that he has never encouraged a version of the "one over many" that justifies the existence of Forms of all things; (b) the reductio ad unum defended by Plato can not be considered identical to Aristotle’s version of "one over many" argument; (c) there are some good textual and speculative reasons to deny the existence of Forms of artefacta. It is finally discussed a recent proposal by David Sedley, according to which Plato, in his mature works, accepted only Form of what has opposed properties and of artefacts (but not of natural things).
VEGLIE A CONFRONTO IL SIGNIFICATO DI "ESSERE SVEGLI" IN ERACLITO E DEMOCRITO
Authors: PIERGIACOMI ENRICO
Published: April 2016

The paper compares Heraclitus’ and Democritus’ opinions on the notion of wakefulness. Its aim is threefold. First of all, it aims to demonstrate that the fragments of both philosophers distinguish between two kinds of wakefulness: physical wakefulness, i.e. the bodily state which all men are in when they are not asleep, and "intellectual" waking, conceived as a form of superior rational consciousness which human bings do not normally possess. The second aim of the paper is to prove that Heraclitus and Democritus share the idea that "intellectual" wakefulness has notable existential and ethical implications. For example, it divides humanity into two classes: the class of wise men, who have the right understanding of reality, and that of fools, who live their entire lives like dull sleepwalkers. The third and final aim consists instead in illutraing the main differences between the two Presocratic philosophers, as well as highlighting some important connections between the doctrine of waking and their ontology, epistemology and political thought.
Review of the Lispe caesia-group (Diptera: Muscidae) from Palaearctic and
adjacent regions, with redescriptions and one new synonymy
Authors: ZHANG DONG , GE YING-QIANG , LI XIN-YU , LIU XIAN-HUI , ZHANG MING , WANG RONG-RONG
Published: April 2016

Species of Lispe caesia-group from Palaearctic and adjacent regions are reviewed. Diagnostic characters of this group are updated. One new synonymy is established: L. frontalis Zielke, 1972, syn. nov. for L. leucocephala Loew, 1856. Key to males of ten species (with two subspecies) from Palaearctic, Oriental and Ethiopian regions is given. Nine species (with two subspecies) are photographed. Six species and one subspecies are redescribed. More detailed ultrastructural or external characters for male swollen hind tarsi and the wing interference patterns are also provided.
Redescription of the genus Wachsiella (Hemiptera: Heteroptera: Largidae: Physopeltinae) with description of male and comments on its tribal placement
Authors: STEHLÍK Jaroslav L. , HEMALA Vladimír , KMENT Petr
Published: April 2016

A detailed redescription (including first description of the male sex) of the genus Wachsiella Schmidt, 1931 (Hemiptera: Heteroptera: Largidae: Physopeltinae) and its single species, Wachsiella horsti Schmidt, 1931, is provided. The systematic placement of the genus is discussed and it is placed in the tribe Physopeltini. Wachsiella horsti is a species endemic to south Sulawesi (Indonesia), known only from specimens collected in 1895–1896 and has never been reported since.