bluuebunny/crossref_metadata_2025 huggingface dataset:
AP‐1‐Targeted Anti‐Inflammatory Activities of the Nanostructured, Self‐Assembling S5 Peptide
Authors: Yang Woo Seok , Son Young-Jin , Kim Mi-Yeon , Kim Soochan , Kim Jong-Hoon , Cho Jae Youl
Published: May 2015

Peptide‐based therapeutics have received increasing attention in medical research. However, the local delivery of such therapeutics poses unique challenges. Self‐assembling peptides that use decorated nanofibers are one approach by which these therapeutics may be delivered. We previously found that the self‐assembling K5 peptide affects the anti‐inflammatory response. The aim of the present study was to investigate another self‐assembling peptide, S5. Unlike the K5 peptide which has a positive charge, the S5 peptide has a free hydroxyl (‐OH) group. We first examined whether the S5 peptide regulates the inflammatory response in primary cells and found that the S5 peptide reduced the production of prostaglandin E2 (PGE2) and tumor necrosis factor (TNF)‐α in lipopolysaccharide‐ (LPS‐) treated bone marrow‐derived macrophages. Moreover, the S5 peptide significantly downregulated cyclooxygenase- (COX-) 2, TNF-α, and interleukin- (IL-) 1β expression by blocking the nuclear translocation of c‐Jun. Consistent with this finding, the S5 peptide diminished the activation of inflammatory signaling enzymes related to p38. The S5 peptide also inhibited the formation of the p38/c‐Jun signaling complex in RAW264.7 cells. Similarly, p38 and MKK3/6 were inhibited by the S5 peptide in LPS‐activated peritoneal macrophages. Taken together, these results strongly suggest that the S5 peptide could exert anti‐inflammatory effects by inhibiting the c‐Jun/p38 signaling pathway.
Association of Plasma Adiponectin and Oxidized Low-Density Lipoprotein with Carotid Intima-Media Thickness in Diabetic Nephropathy
Authors: Tavridou Anna , Georgoulidou Anastasia , Roumeliotis Athanasios , Roumeliotis Stefanos , Giannakopoulou Efstathia , Papanas Nikolaos , Passadakis Ploumis , Manolopoulos Vangelis G. , Vargemezis Vassilis
Published: May 2015

Aims. We sought to determine the association between levels of adiponectin and oxidized low-density lipoprotein (ox-LDL) in patients with diabetic nephropathy as well as their effect on carotid intima-media thickness (cIMT).Methods. Adiponectin and ox-LDL were determined in 25 diabetic patients without nephropathy and 94 patients at different stages of diabetic nephropathy including subjects on hemodialysis. cIMT was measured using real-time B-mode ultrasonography.Results. Plasma adiponectin levels increased significantly with severity of diabetic nephropathy (P=0.002), on the contrary to ox-LDL which decreased with disease severity (P<0.001). cIMT was significantly higher at late stages of diabetic nephropathy compared with early stages (P=0.022). Adiponectin was a significant negative predictor of ox-LDL levels (β=-5.45,P=0.023), independently of confounding factors. There was no significant correlation between cIMT and adiponectin or ox-LDL either in the total sample population or according to disease staging. Cluster analysis showed that patients with the highest cIMT values, highest levels of adiponectin, and lowest levels of ox-LDL were included in one cluster and all assigned to stage 5 of diabetic nephropathy.Conclusions. There was no significant association between adiponectin or ox-LDL and cIMT and, therefore, other factors affecting this surrogate marker of cardiovascular disease in diabetic nephropathy should be sought.
Chimney-Graft as a Bail-Out Procedure for Endovascular Treatment of an Inflammatory Juxtarenal Abdominal Aortic Aneurysm
Authors: Fratesi Francesca , Handa Ashok , Uberoi Raman , Sideso Ediri
Published: May 2015

Inflammatory and juxtarenal Abdominal Aortic Aneurysm (j-iAAA) represents a technical challenge for open repair (OR) due to the peculiar anatomy, extensive perianeurysmal fibrosis, and dense adhesion to the surrounding tissues. A 68-year-old man with an 11 cm asymptomatic j-iAAA was successfully treated with elective EVAR and chimney-graft (ch-EVAR) without postprocedural complications. Target vessel patency and normal renal function are present at 24-month follow-up. The treatment of j-iAAA can be technically challenging. ch-EVAR is a feasible and safe bail-out method for elective j-iAAA with challenging anatomy.
Deformation of a Circular Elastic Tube between Two Parallel Bars: Quasi-Analytical Geometrical Ring Models
Authors: Van Hirtum A.
Published: May 2015

Several engineering problems are confronted with elastic tubes. In the current work, homothetic quasi-analytical geometrical ring models, ellipse, stadium, and peanut, are formulated allowing a computationally low cost ring shape estimation as a function of a single parameter, that is, the pinching degree. The dynamics of main geometrical parameters due to the model choice is discussed. Next, the ring models are applied to each cross section of a circular elastic tube compressed between two parallel bars for pinching efforts between 40% and 95%. The characteristic error yields less than 4% of the tubes diameter when the stadium model was used.
Storage Effect on Phenols and on the Antioxidant Activity of Extracts fromAnemopsis californicaand Inhibition of Elastase Enzyme
Authors: Del-Toro-Sánchez Carmen Lizette , Gutiérrez-Lomelí Melesio , Lugo-Cervantes Eugenia , Zurita Florentina , Robles-García Miguel Angel , Ruiz-Cruz Saul , Aguilar Jose Antonio , Morales-Del Rio Juan Alfredo , Guerrero-Medina Pedro Javier
Published: May 2015

The amount of total phenols and flavonoids and the antioxidant activity of leaf, stem, and rhizome methanolic extracts from a commonly consumedAnemopsis californicaunder different storage conditions were investigated. Storage conditions were at 50, 25, 4, and −20°C, protected or not from light, during 180 days. The inhibition of the elastase enzyme was also evaluated. The results demonstrated that leaf, stem, and rhizome methanolic extracts ofAnemopsis californicamaintain approximately up to 97 and 95% stability in phenolic content and antioxidant activity, respectively, when stored during 60 days at −20°C in the dark. Additionally, these extracts, principally from leaf and rhizome, showed an elastase inhibitory effect by 75 and 71.8%, respectively. Therefore, this study provides the basis for further research on the anti-inflammatory activity. On the other hand,Anemopsis californicacould comprise a good alternative of use as antioxidant in foods.
Combination of Triple Therapy and Chronic PPI Use May Decrease Risk of Colonic Adenomatous Polyps inHelicobacter pyloriInfection
Authors: Zuniga Rina , Bautista Josef , Sapra Katherine , Westerfield Keith , Williams Susan , Sy Alexander M.
Published: May 2015

Aim. The aim of the paper is to determine association betweenH. pyloriand colonic adenomatous polyps and to explore whether treatment or chronic PPI use can mitigate this risk.Methods. This case-control study included 943 patients who hadH. pyloritesting and underwent colonoscopy. Presence of polyps was the outcome of interest, whereas age, sex, race,H. pyloriinfection, triple therapy, and chronic PPI use were independent variables. Multivariate regression analysis was used to calculate odds ratios at 95% confidence intervals. This study was approved by the New York Medical College Institutional Review Board.Results.H. pyloriwas associated with increased odds of colonic adenomatous polyps (adjusted OR 1.43, 95% CI 1.04–1.77), with stronger association among patients older than 50 (OR 1.65, 95% CI 1.18–2.33). Triple therapy (OR 0.69, 95% CI 0.44–1.07) or chronic PPI use (OR 0.69, 95% CI 0.43–1.09) decreased odds of polyp formation. Analysis revealed a statistically significant reduction in patients who received both triple therapy and chronic PPI, lowering the odds by 60% (adjusted OR 0.43, 95% CI 0.27–0.67).Conclusion. There is increased risk of colonic adenomatous polyps amongH. pylori-infected patients. Triple therapy or chronic PPI use may mitigate this risk, with further reduction when these two interventions are combined.
A Rare Reason for Pelvic Pain in Pregnancy: Infectious Sacroiliitis
Authors: Cekmez Yasemin , Göçmen Ahmet , Arslan Oğuz , Şanlıkan Fatih , Bağcı Türkmen Simge
Published: May 2015

Introduction. Although the incidence of pregnancy-associated sacroiliitis is low, it is associated with significant morbidity and mortality. Timely diagnosis of the disease is confusing due to its nonspecific clinical features.Case. A 28-year-old woman at 34 weeks of gestation with severe pain in her right buttock radiating down the backside of the right thigh was admitted to our hospital. White blood cell (WBC) count and C-reactive protein (CRP) were elevated. The pelvic magnetic resonance imaging (MRI) scan revealed right sacroiliitis.Conclusion. Infectious sacroiliitis should be considered as a differential diagnosis even in low-risk women who present with debilitating pelvic pain in pregnancy and medical treatment should not be delayed.
On(k,kn-k2-2k-1)-Choosability ofn-Vertex Graphs
Authors: Charoenpanitseri Wongsakorn
Published: May 2015

A(k,t)-list assignmentLof a graphGis a mapping which assigns a set of sizekto each vertexvofGand|⋃v∈V(G)‍L(v)|=t. A graphGis(k,t)-choosable ifGhas a proper coloringfsuch thatf(v)∈L(v)for each(k,t)-list assignmentL. In 2011, Charoenpanitseri et al. gave a characterization of(k,t)-choosability ofn-vertex graphs whent≥kn-k2-2k+1and left open problems whent≤kn-k2-2k. Recently, Ruksasakchai and Nakprasit obtain the results whent=kn-k2-2k. In this paper, we extend the results to caset=kn-k2-2k-1.
A Rare Complication of Extracorporeal Shock Wave Lithotripsy: Intrarenal Hematoma Mimicking Pelvis Renalis Tumor
Authors: Akbulut Fatih , Kucuktopcu Onur , Ucpinar Burak , Savun Metin , Ozgor Faruk , Sonmezay Erkan , Simsek Abdulmuttalip , Gurbuz Gokhan
Published: May 2015

Extracorporeal shock wave lithotripsy (SWL) is a very commonly used treatment modality for appropriate sized stones. Even though it is a noninvasive treatment technique, major complications may occur following SWL sessions. Herein, we report a 17-year-old male patient, who received 2 sessions of SWL treatment for his left kidney stone, 4 months before his admission. Imaging methods showed an enhanced left renal pelvis mass with contrast-enhanced computerized tomography (CT) and this finding raised a suspicion of pelvis renalis tumor. Diagnostic ureterorenoscopy was planned for the patient and operation revealed a left intrarenal hematoma, which was drained percutaneously during the same operation. Careful history should be taken from patients with renal pelvis masses and intrarenal hematoma formation should be kept in mind, especially if the patient has a previous SWL history.
Solid-Phase Extraction of Pesticides by Using Bioinspired Peptide Receptors
Authors: Lanzone Valentina , Sergi Manuel , Mascini Marcello , Scarpone Rossana , Della Pelle Flavio , Del Carlo Michele , Scortichini Giampiero , Compagnone Dario
Published: May 2015

A virtual development of hexapeptide receptors bioinspired by the acetylcholinesterase enzyme active site is proposed. A semicombinatorial approach was applied to generate a virtual hexapeptides library with different affinity properties towards organophosphate and carbamate pesticides. The virtual screening process was addressed to obtain peptides able to separate pesticide subclasses in the experimental work. Three hexapeptides, two generated by molecular modeling and one having a scrambled sequence, were used as selective sorbent materials for pesticides in preanalytical solid-phase extraction (SPE) method. Selective adsorption and cross-reactivity were tested directly on a mix of four pesticides (carbaryl, chlorpyrifos-ethyl, malathion, and thiabendazole) having different structures and physico-chemical properties, at a total concentration of 120 ppb (each pesticide at concentration of 30 ppb). The results were compared to traditional sorbent material such as C-18 and strata-X. Data showed that only one of the hexapeptides virtually designed had significant differences in competitive absorption between aliphatic pesticide malathion, fungicide thiabendazole chosen as negative control, and aromatic pesticides. These results partially supported the simulated strategy.
An Open-Label Trial of Memantine for Cognitive Impairment in Patients with Posttraumatic Stress Disorder
Authors: Ramaswamy Sriram , Madabushi Jayakrishna , Hunziker John , Bhatia Subhash C. , Petty Frederick
Published: May 2015

Background. Studies using standard neuropsychological instruments have demonstrated memory deficits in patients with PTSD. We evaluated the efficacy and safety of the N-methyl-D-aspartate antagonist memantine in veterans with PTSD and cognitive impairment.Methods. Twenty-six veterans with PTSD and cognitive impairment received 16 weeks of memantine in an open-label fashion. Cognition was assessed using the Spatial Span, Logical Memory I, and Letter-Number Sequencing subtests of the Wechsler Memory Scale III and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RBANS measures attention, language, visuospatial skills, and immediate and delayed memories. The Clinician Administered PTSD Scale (CAPS), Hamilton Depression Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and Sheehan Disability Scale (SDS) were secondary outcome measures.Results. There was a significant improvement in RBANS, both total and subscale scores (P<0.05), over time. There was a reduction in total CAPS scores, avoidance/numbing symptoms (CAPS-C) and hyperarousal symptoms (CAPS-D), HAM-D, Q-LES-Q, and SDS scores. However, there was no reduction in reexperiencing (CAPS-B) and HAM-A scores. Memantine was well tolerated.Conclusions.Memantine improved cognitive symptoms, PTSD symptoms, and mood in veterans with PTSD. Randomized double-blind studies are needed to validate these preliminary observations.
A Survival Association Study of 102 Polymorphisms Previously Associated with Survival Outcomes in Colorectal Cancer
Authors: Savas Sevtap , Xu Jingxiong , Werdyani Salem , Shestopaloff Konstantin , Dicks Elizabeth , Green Jane , Parfrey Patrick , Green Roger , Xu Wei
Published: May 2015

Several published studies identified associations of a number of polymorphisms with a variety of survival outcomes in colorectal cancer. In this study, we aimed to explore 102 previously reported common genetic polymorphisms and their associations with overall survival (OS) and disease-free survival (DFS) in a colorectal cancer patient cohort from Newfoundlandn=505. Genotypes were obtained using a genomewide SNP genotyping platform. For each polymorphism, the best possible genetic model was estimated for both overall survival and disease-free survival using a previously published approach. These SNPs were then analyzed under their genetic models by Cox regression method. Correction for multiple comparisons was performed by the False Discovery Rate (FDR) method. Univariate analysis results showed thatRRM1-rs12806698,IFNGR1-rs1327474,DDX20-rs197412, andPTGS2-rs5275 polymorphisms were nominally associated with OS or DFSp<0.01. In stage-adjusted analysis, the nominal associations ofDDX20-rs197412,PTGS2-rs5275, andHSPA5-rs391957 with DFS were detected. However, after FDR correction none of these polymorphisms remained significantly associated with the survival outcomes. We conclude that polymorphisms investigated in this study are not associated with OS or DFS in our colorectal cancer patient cohort.
An Adaptive Procedure for Task Scheduling Optimization in Mobile Cloud Computing
Authors: Phuoc Hung Pham , Huh Eui-Nam
Published: May 2015

Nowadays, mobile cloud computing (MCC) has emerged as a new paradigm which enables offloading computation-intensive, resource-consuming tasks up to a powerful computing platform in cloud, leaving only simple jobs to the capacity-limited thin client devices such as smartphones, tablets, Apple’s iWatch, and Google Glass. However, it still faces many challenges due to inherent problems of thin clients, especially the slow processing and low network connectivity. So far, a number of research studies have been carried out, trying to eliminate these problems, yet few have been found efficient. In this paper, we present an enhanced architecture, taking advantage of collaboration of thin clients and conventional desktop or laptop computers, known as thick clients, particularly aiming at improving cloud access. Additionally, we introduce an innovative genetic approach for task scheduling such that the processing time is minimized, while considering network contention and cloud cost. Our simulation shows that the proposed approach is more cost-effective and achieves better performance compared with others.
Testicular Metabolic Reprogramming in Neonatal Streptozotocin-Induced Type 2 Diabetic Rats Impairs Glycolytic Flux and Promotes Glycogen Synthesis
Authors: Rato L. , Alves M. G. , Dias T. R. , Cavaco J. E. , Oliveira Pedro F.
Published: May 2015

Defects in testicular metabolism are directly implicated with male infertility, but most of the mechanisms associated with type 2 diabetes- (T2DM) induced male infertility remain unknown. We aimed to evaluate the effects of T2DM on testicular glucose metabolism by using a neonatal-streptozotocin- (n-STZ) T2DM animal model. Plasma and testicular hormonal levels were evaluated using specific kits. mRNA and protein expression levels were assessed by real-time PCR and Western Blot, respectively. Testicular metabolic profile was assessed by1H-NMR spectroscopy. T2DM rats showed increased glycemic levels, impaired glucose tolerance and hyperinsulinemia. Both testicular and serum testosterone levels were decreased, whereas those of 17β-estradiol were not altered. Testicular glycolytic flux was not favored in testicles of T2DM rats, since, despite the increased expression of both glucose transporters 1 and 3 and the enzyme phosphofructokinase 1, lactate dehydrogenase activity was severely decreased contributing to lower testicular lactate content. However, T2DM enhanced testicular glycogen accumulation, by modulating the availability of the precursors for its synthesis. T2DM also affected the reproductive sperm parameters. Taken together these results indicate that T2DM is able to reprogram testicular metabolism by enhancing alternative metabolic pathways, particularly glycogen synthesis, and such alterations are associated with impaired sperm parameters.
The Role of Microvesicles Derived from Mesenchymal Stem Cells in Lung Diseases
Authors: Chen Jie , Li Chonghui , Chen Liangan
Published: May 2015

Microvesicles (MVs) are membrane vesicles that are released by many types of cells and have recently been considered important mediators of cell-to-cell communication. MVs serve as a vehicle to transfer proteins and messenger RNA and microRNA (miRNA) to distant cells, which alters the gene expression, proliferation, and differentiation of the recipient cells. Several studies have demonstrated that mesenchymal stem cells (MSCs) have the capacity to reverse acute and chronic lung injury in different experimental models through paracrine mechanisms. This paracrine action may be partially accounted for by MVs that are derived from MSCs. MSC-derived MVs may confer a stem cell-like phenotype to injured cells with the consequent activation of self-regenerative programmers. In this review, we summarize the characteristics and biological activities of MSC-derived MVs, and we describe their potential in novel therapeutic approaches in regenerative medicine to repair damaged tissues. Additionally, we provide an overview of studies that have assessed the role of MSC-derived MVs in lung diseases, including the mechanisms that may account for their therapeutic potential. Finally, we discuss the clinical use of MSC-derived MVs with several suggestions for enhancing their therapeutic efficiency.
Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma
Authors: Barth Matthew J. , Mavis Cory , Czuczman Myron S. , Hernandez-Ilizaliturri Francisco J.
Published: May 2015

Purpose: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma considered to be incurable with current treatments, including first-line rituximab in combination with multiagent chemotherapy and for those eligible, high-dose chemotherapy and stem cell support or rituximab maintenance. On the other hand, achieving a complete remission by high-sensitive flow cytometry is associated with prolonged duration of remission, stressing the need to develop and/or incorporate novel agents into the management of MCL. To this end, we examined the activity of ofatumumab, an anti-CD20 monoclonal antibody with distinct binding and immunologic properties compared to rituximab, in MCL preclinical models.

Experimental Design: MCL cells were labeled with 51Cr before incubation with rituximab or ofatumumab (10 μg/mL) plus human serum or effector cells. 51Cr-release was measured and the percentage of lysis was calculated. Surface CD20, CD55, and CD59 were measured by Imagestream analysis. SCID mice inoculated subcutaneously with Z138 cells were assigned to control versus four doses of ofatumumab or rituximab (10 mg/kg/dose).

Results: Ofatumumab exhibited enhanced in vitro complement-dependent cytotoxicity activity compared with rituximab in MCL cell lines, despite a high degree of in vitro resistance to rituximab associated with low CD20 levels and/or high expression of complement inhibitory proteins. Ofatumumab also delayed tumor progression and prolonged survival in a murine model of MCL.

Conclusions: Our results demonstrate that ofatumumab is more effective than rituximab in MCL preclinical models, including in the presence of rituximab resistance, and support the clinical investigation of ofatumumab in combination with standard systemic chemotherapy in MCL (NCT01527149). Clin Cancer Res; 21(19); 4391–7. ©2015 AACR.
An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
Authors: Lamhamedi-Cherradi Salah-Eddine , Menegaz Brian A. , Ramamoorthy Vandhana , Aiyer Ramani A. , Maywald Rebecca L. , Buford Adrianna S. , Doolittle Dannette K. , Culotta Kirk S. , O'Dorisio James E. , Ludwig Joseph A.
Published: May 2015

Ewing sarcoma is a transcription factor–mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279–mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma. Mol Cancer Ther; 14(7); 1591–604. ©2015 AACR.
Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer
Authors: Dienstmann Rodrigo , Patnaik Amita , Garcia-Carbonero Rocio , Cervantes Andrés , Benavent Marta , Roselló Susana , Tops Bastiaan B.J. , van der Post Rachel S. , Argilés Guillem , Skartved Niels J.Ø. , Hansen Ulla H. , Hald Rikke , Pedersen Mikkel W. , Kragh Michael , Horak Ivan D. , Braun Stephan , Van Cutsem Eric , Tolcher Anthony W. , Tabernero Josep
Published: May 2015

Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFRS492R mutation that is predictive of cetuximab resistance.

Significance: Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted. Cancer Discov; 5(6);598–609. ©2015 AACR.

See related commentary by Stintzing and Heinemann, p. 578

This article is highlighted in the In This Issue feature, p. 565
Activated Hemostatic Biomarkers in Patients with Implanted Left Ventricle Assist Devices: Are Heparin and/or Clopidogrel Justified?
Authors: Pacholewicz Jerzy , Kuliczkowski Wiktor , Kaczmarski Jacek , Zakliczyński Michał , Garbacz Marcin , Zembala Marian , Serebruany Victor
Published: May 2015

Background: Adequate anticoagulation represents a major problem for left ventricle assist device (LVAD) utilization in patients awaiting heart transplantation as well as for regeneration of the native heart. The proper management of hemostatic abnormalities during LVAD support may improve survival by reducing the incidence of hemorrhagic and/or thromboembolic complications. Case Report: A 40-year-old man with implanted pulsatile LVAD due to dilated cardiomyopathy received aspirin and warfarin. The patient underwent serial weekly monitoring of hemostatic biomarkers including international normalization ratio, prothrombin time, prothrombin activity, activated partial thromboplastin time, fibrinogen, D-dimer, platelet aggregation induced by adenosine diphosphate and arachidonic acid, platelet count, and mean platelet volume. The external pump was exchanged three times - twice because of a clot formation in the blood chamber of the pump, and once according to the standard protocol. Results: LVAD use was consistently associated with enhanced adenosine diphosphate-induced platelet aggregation independent from the timing of clot formation or external pump exchange. Among coagulation indices, increased D-dimer holds predictive value for clot formation. The fibrinogen level peaked before the first pump exchange and was twice as high than the average values. Gradual improvement in exercise capacity was observed 2 years after implantation, after which the patient underwent a controlled stress test in the stop mode of the LVAD and the device was successfully explanted. Conclusions: Serial assessment of hemostatic biomarkers may benefit and triage LVAD patients. Consistent platelet activation during long-term LVAD may justify the addition of clopidogrel, while high D-dimer and/or elevated fibrinogen may indicate adding heparin to the conventional antithrombotic regimen. Randomized evidence is needed to test such a hypothesis.
Chloride Depletion Alkalosis as a Predictor of Inhospital Mortality in Patients with Decompensated Heart Failure
Authors: Khan Nazia Naz S. , Nabeel Muhammad , Nan Bin , Ghali Jalal K.
Published: May 2015

Objectives: Chloride depletion alkalosis (CDA) is often seen as a consequence of diuresis in heart failure (HF) but its prognostic significance remains unknown. The purpose of this study was to evaluate the prognostic role of CDA in decompensated HF (DHF). Methods: A retrospective cohort analysis was performed on 674 patients who were admitted with DHF. Patients were assigned to 2 groups based on the change in serum bicarbonate (median = 3 mmol/l) after diuresis, which was calculated by computing the difference in the admission and discharge serum bicarbonate: the CDA group (a change in serum bicarbonate ≥3 mmol/l) and the non-CDA group (change in serum bicarbonate <3 mmol/l). The primary end points were inhospital mortality and the composite end point of all-cause 30-day mortality and hospital readmission for HF. Results: In a multivariable logistic regression model, the CDA group, i.e. 374 patients, had a lower inhospital mortality than the non-CDA group, i.e. 300 patients (OR 0.11, 95% CI 0.03-0.38; p = 0.0005) after adjusting for other covariates. There was no statistically significant difference in the combined end point of all-cause 30-day mortality and readmission between the 2 groups (OR 1.26, 95% CI 0.74-2.12; p = 0.39). Conclusion: The presence of CDA during hospitalization for DHF was independently associated with a better inhospital survival rate.
CTLA4 and CD28 Gene Polymorphisms with Respect to Affective Symptom Domain in Schizophrenia
Authors: Frydecka Dorota , Beszłej Jan Aleksander , Pawlak-Adamska Edyta , Misiak Błażej , Karabon Lidia , Tomkiewicz Anna , Partyka Anna , Jonkisz Anna , Szewczuk-Bogusławska Monika , Zawadzki Marcin , Kiejna Andrzej
Published: May 2015

Background: Accumulating evidence indicates that immune alterations in schizophrenia are due to genetic underpinnings. Here, we aimed at investigating whether polymorphisms in CTLA4 and CD28 genes, encoding molecules that regulate T-cell activity, influence schizophrenia symptomatology. Method: We recruited 120 schizophrenia patients and 380 healthy age- and sex-matched controls. We divided the patients into two groups: one with no co-occurrence between psychotic and affective symptoms and the second one with psychotic symptoms dominating in the clinical manifestation, although also with occasional affective disturbances in the course of illness. Results: Among the patients with co-occurring affective symptoms, there were significantly more CTLA4 c.49A>G[A] alleles (p = 0.018, odds ratio (OR) 2.03, 95% confidence interval (CI) 1.2-3.66) and more CTLA4 g.319C>T[T] alleles (p = 0.07, OR 1.93, 95% CI 0.94-4.13) in comparison to the second group. Additionally, we have shown that CD28 c.17 + 3T>C[C+] were more significantly overrepresented among patients with co-occurring psychotic and affective symptoms (p = 0.0003, OR 3.36, 95% CI 1.69-6.68) than in patients without co-occurence between these symptoms (p = 0.012, OR 1.88, 95% CI 1.15-3.10). Conclusion:CTLA4 and CD28 gene polymorphisms may not only act in immune deregulation observed in schizophrenia, but may also influence the course of the illness by modifying the susceptibility to the co-occurrence of psychotic and affective symptoms.
Physical Exercise Counteracts Genetic Susceptibility to Depression
Authors: Haslacher Helmuth , Michlmayr Matthias , Batmyagmar Delgerdalai , Perkmann Thomas , Ponocny-Seliger Elisabeth , Scheichenberger Vanessa , Pilger Alexander , Dal-Bianco Peter , Lehrner Johann , Pezawas Lukas , Wagner Oswald , Winker Robert
Published: May 2015

Background/Aims: Depression is a highly prevalent disorder in elderly individuals. A genetic variant (rs6265) of the brain-derived neurotrophic factor (BDNF) impacting on emotion processing is known to increase the risk for depression. We aim to investigate whether intensive endurance sports might attenuate this genetic susceptibility in a cohort of elderly marathon athletes. Methods: Fifty-five athletes and 58 controls were included. rs6265 of the BDNF gene was genotyped by the TaqMan method. Depressive symptoms were assessed by standardized self-rating tests (BDI = Beck Depression Inventory, GDS = Geriatric Depression Scale). Results: In multivariable analysis of BDI and GDS scores, the interaction between group (athletes vs. controls) and genotypes ([C];[C] vs. [C];[T] + [T];[T]) was found to be statistically significant (BDI: p = 0.027, GDS: p = 0.013). Among [C];[C] carriers, merely controls had an increased relative risk of 3.537 (95% CI = 1.276-9.802) of achieving a subclinical depression score ≥10 on the BDI. There was no such effect in carriers of the [T] allele. In a multivariable binary logistic regression, genetic information, group (athletes/controls), but no information on rs6265 allele carrier status presented as a significant predictor of BDI scores ≥10. Conclusion: Physical exercise positively affects BDNF effects on mood. Since 66Met BDNF secretion is impaired, this effect seems to be much stronger in [C];[C] homozygous individuals expressing the 66Val variant. This confirms that genetic susceptibility to depressive symptoms can indeed be influenced by endurance sports in elderly people.
Beta-Amyloid Plasma Levels in Adolescents with Anorexia Nervosa of the Restrictive Type
Authors: Conti Elisa , Nacinovich Renata , Bomba Monica , Raggi Maria E. , Neri Francesca , Ferrarese Carlo , Tremolizzo Lucio
Published: May 2015

Background: Reduced plasma leptin and elevated homocysteine (Hcy) are known to lead to increased β-amyloid (Aβ) production, besides being hallmarks of anorexia nervosa (AN) of the restrictive type. AN subjects display several neuropsychiatric manifestations, which may entail Aβ-mediated altered synaptic functions. The aim of this study consisted in assessing Aβ plasma levels in AN patients. Methods: A total of 24 adolescent female AN outpatients were recruited together with 12 age-comparable healthy controls. For each subject we assessed Aβ40 and leptin plasma levels, as well as APOE genotype. Hcy plasma levels were also determined in AN patients who underwent clinical characterization, including the Eating Disorder Inventory-3 (EDI-3), the Children's Depression Inventory (CDI) and the estimation of the speed of BMI loss (DPI, disease progression index). Results: Plasma Aβ40 levels were similar between patients and controls, while a marked reduction was observed for leptin (∼80%) in AN patients. Aβ40 plasma levels failed to correlate with leptin, while a linear correlation was present with Hcy (r = 0.50, p < 0.03). Examined clinical features were not related with Aβ40 plasma levels, with the only exception of the DPI (r = 0.47, p < 0.03). Conclusion: This exploratory study does not support a significant role for altered Aβ production in AN-associated dysfunctions. Further studies are required to clarify whether exceptions to this conclusion can be drawn for those patients expressing significantly elevated Hcy plasma levels or for those progressing more rapidly.
Significance of High Trough Concentration of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus Infection
Authors: Sato Yuhki , Tokimatsu Issei , Suzuki Yosuke , Itoh Hiroki , Hiramatsu Kazufumi , Kadota Jun-ichi
Published: May 2015

Background: Teicoplanin (TEIC) is a glycopeptide currently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). A plasma trough concentration (Cmin) of >20 mg/l should be used for severe infections. The aim of this study was to assess the efficacy, safety and use of Cmin >20 mg/l on day 4-6 in patients with complicated MRSA infections. Methods: Blood samples were drawn from the 41 included patients just before TEIC administration between day 4 and 6. The patients were divided into three groups (group A: >20 mg/l, group B: 10-20 mg/l and group C: <10 mg/l) based on their Cmin on day 4-6. Results: Differences in efficacy between the groups were significant, but differences in safety were not. The patients in group A required lower cumulative doses than those in either groups B or C. Conclusions: The optimal clinical efficacy and safety might be associated with TEIC Cmin on the fourth to sixth day.
Effects of Renal Denervation from the Intima and the Adventitia of Renal Arteries on Renal Sympathetic Nerve Activity in Dogs: A Comparative Study
Authors: Bai Minfu , Yang Chaokuan , Gao Chuanyu , Wang Xianpei , Liu Hongzhi , Zhang You , Liu Jun , Wu Jintao , Jian Dongdong , Zhu Lijie , Zhao Wenli , Ma Peiyao , Han Yaqi
Published: May 2015

Objectives: This study was designed to observe the efficacy and safety of renal denervation from the inside and outside of renal arteries. Methods: Fourteen beagles were randomly divided into a control group (n = 4) and treatment group (n = 10). One renal artery in every beagle of the treatment group was randomly assigned to an intimal group (10 renal arteries) which underwent percutaneous renal denervation from the inside, and another renal artery was assigned to an adventitial group (10 renal arteries) which underwent renal denervation from the outside by laparotomy. Results: Compared with the intimal group, the renal norepinephrine (NE) concentration in the adventitial group had significantly decreased (p = 0.003) at 3 months postsurgery. Renal artery HE staining showed that the perineurium from the adventitial group appeared thickened. Western blotting showed that renal tissue tyrosine hydroxylase (TH) protein expression in the adventitial group was significantly lower than that in the intimal group (p < 0.01) at 3 months postsurgery. There was a renal artery stenosis and a renal atrophy in the intimal group after 1 month of follow-up. Conclusion: The inhibitory effect on renal sympathetic nerve activity was more effective in the adventitial group than the intimal group, and renal denervation in the former group was safe.
Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams–Oliver Syndrome With Variable Cardiac Anomalies
Authors: Southgate Laura , Sukalo Maja , Karountzos Anastasios S.V. , Taylor Edward J. , Collinson Claire S. , Ruddy Deborah , Snape Katie M. , Dallapiccola Bruno , Tolmie John L. , Joss Shelagh , Brancati Francesco , Digilio Maria Cristina , Graul-Neumann Luitgard M. , Salviati Leonardo , Coerdt Wiltrud , Jacquemin Emmanuel , Wuyts Wim , Zenker Martin , Machado Rajiv D. , Trembath Richard C.
Published: May 2015

Background—

Adams–Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS.

Methods and Results—

Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating
NOTCH1
mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique
NOTCH1
mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of
NOTCH1
-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring
NOTCH1
extracellular domain mutations, we observed significant reduction of
NOTCH1
expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized
NOTCH1
missense constructs also revealed significant reduction in gene expression. Mutant
NOTCH1
expression was associated with downregulation of the Notch target genes
HEY1
and
HES1
, indicating that
NOTCH1
-related AOS arises through dysregulation of the Notch signaling pathway.

Conclusions—

These findings highlight a key role for
NOTCH1
across a range of developmental anomalies that include cardiac defects and implicate
NOTCH1
haploinsufficiency as a likely molecular mechanism for this group of disorders.
B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival
Authors: Holditch Sara J. , Schreiber Claire A. , Nini Ryan , Tonne Jason M. , Peng Kah-Whye , Geurts Aron , Jacob Howard J. , Burnett John C. , Cataliotti Alessandro , Ikeda Yasuhiro
Published: May 2015

Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production or impaired BNP release and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of this study was to create and characterize a novel model of BNP deficiency to investigate the effects of BNP absence on cardiac and renal structure, function, and survival. Genetic BNP deletion was generated in Dahl salt-sensitive rats. Compared with age-matched controls, BNP knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knockout rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at 9 months in knockout rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in BNP knockout rats. End-organ damage contributed to a significant decline in overall survival. Systemic BNP overexpression reversed the phenotype of genetic BNP deletion. Our results demonstrate the critical role of BNP defect in the development of systemic hypertension and associated end-organ damage in adulthood.
Systematic Validation of
RNF213
Coding Variants in Japanese Patients With Moyamoya Disease
Authors: Moteki Yosuke , Onda Hideaki , Kasuya Hidetoshi , Yoneyama Taku , Okada Yoshikazu , Hirota Kengo , Mukawa Maki , Nariai Tadashi , Mitani Shohei , Akagawa Hiroyuki
Published: May 2015

Background

A founder variant of

RNF
213

, p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease (
MMD
) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other

RNF
213

variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with
MMD
.

Methods and Results

To detect variants of

RNF
213

, all coding exons were sequenced in 27 Japanese
MMD
patients without p.R4810K. We also validated all previously reported variants in our case–control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population‐based controls. Forty‐six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with
MMD
. We conducted a variable threshold test using Combined Annotation‐Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum
P
=0.045).

Conclusions

Not only p.4810K but also other functional missense variants of

RNF
213

conferred susceptibility to
MMD
. Our analysis also revealed that ≈20% of Japanese
MMD
patients did not harbor susceptibility variants of

RNF
213

, indicating the presence of other susceptibility genes for
MMD
.
Effects of Parental Smoking on Exercise Systolic Blood Pressure in Adolescents
Authors: Hacke Claudia , Weisser Burkhard
Published: May 2015

Background

In adults, exercise blood pressure seems to be more closely related to cardiovascular risk than resting blood pressure; however, few data are available on the effects of familial risk factors, including smoking habits, on exercise blood pressure in adolescents.

Methods and Results

Blood pressure at rest and during exercise, parental smoking, and other familial risk factors were investigated in 532 adolescents aged 12 to 17 years (14.6±1.5 years) in the Kiel
EX
.
PRESS
. (
EX
ercise
PRESS
ure) Study. Exercise blood pressure was determined at 1.5 W/kg body weight using a standardized submaximal cycle ergometer test. Mean resting blood pressure was 113.1±12.8/57.2±7.1 mm Hg, and exercise blood pressure was 149.9±19.8/54.2±8.6 mm Hg. Parental smoking increased exercise systolic blood pressure (+4.0 mm Hg, 3.1 to 4.9;
P=
0.03) but not resting blood pressure of the subjects (adjusted for age, sex, height, body mass index percentile, fitness). Parental overweight and familial hypertension were related to both higher resting and exercise systolic blood pressure values, whereas associations with an inactive lifestyle and a low educational level of the parents were found only with adolescents' blood pressure during exercise. The cumulative effect of familial risk factors on exercise systolic blood pressure was more pronounced than on blood pressure at rest.

Conclusions

Parental smoking might be a novel risk factor for higher blood pressure, especially during exercise. In addition, systolic blood pressure during a submaximal exercise test was more closely associated with familial risk factors than was resting blood pressure, even in adolescents.
The Role of Mentoring in Adolescents’ Spiritual Formation
Authors: Chiroma Nathan Hussaini
Published: May 2015

An integrative approach that emphasises the fundamental role of mentoring is essential in adolescents’ spiritual formation. Leading adolescents into spiritual formation necessitates walking alongside them through mentoring rather than simply teaching them to cope with pressures. There is a tremendous hunger among the adolescents of today for spiritual guides and mentors that will come alongside them in their journey of spiritual formation. Much has been written about mentoring; however, this article focuses on the use of mentoring in fostering adolescents’ spiritual formation, drawing on recent research. This article shows how youth workers can and should embrace mentoring in order to facilitate adolescents’ spiritual formation.
Two new species of the genus Vosmaeropsis Dendy, 1892 (Porifera, Calcarea), with comments on the distribution of V. sericata (Ridley, 1881) along the Southwestern Atlantic Ocean
Authors: CAVALCANTI FERNANDA F. , BASTOS NILMA , LANNA EMILIO
Published: May 2015

Two new species of the genus Vosmaeropsis are described: V. recruta sp. nov. and V. complanatispinifera sp. nov., both from the Brazilian coast. These species possess arrow-shaped large diactines in their skeletons, which are being described for the first time in Vosmaeropsis. In addition, the latter species presents another remarkable character: the apical actines of its atrial tetractines is flattened and provided with spines. Vosmaeropsis complanastispinifera sp. nov. is being proposed based on the re-analysis of specimens that in the past were assigned to V. sericata. Thus, with the reallocation of these specimens to the newly described species, the current distribution range of V. sericata does not include the Brazilian northeastern coast. Vosmaeropsis now comprises 23 species. Most of them present an endemic pattern of distribution, but the genus is widely distributed in tropical and temperate regions around the world.