bluuebunny/crossref_metadata_2025 huggingface dataset:
Volumetric Modulated Arc Therapy for Spine Radiosurgery: Superior Treatment Planning and Delivery Compared to Static Beam Intensity Modulated Radiotherapy
Authors: Zach Leor , Tsvang Lev , Alezra Dror , Ben Ayun Maoz , Harel Ran
Published: January 2016

Purpose. Spine stereotactic radiosurgery (SRS) delivers an accurate and efficient high radiation dose to vertebral metastases in 1–5 fractions. We aimed to compare volumetric modulated arc therapy (VMAT) to static beam intensity modulated radiotherapy (IMRT) for spine SRS.Methods and Materials. Ten spine lesions of previously treated SRS patients were planned retrospectively using both IMRT and VMAT with a prescribed dose of 16 Gy to 100% of the planning target volume (PTV). The plans were compared for conformity, homogeneity, treatment delivery time, and safety (spinal cord dose).Results. All evaluated parameters favored the VMAT plan over the IMRT plans.Dminin the IMRT was significantly lower than in the VMAT plan (7.65 Gy/10.88 Gy,p<0.001), the Dice Similarity Coefficient (DSC) was found to be significantly better for the VMAT plans compared to the IMRT plans (0.77/0.58, resp.,p  value<0.01), and an almost 50% reduction in the net treatment time was calculated for the VMAT compared to the IMRT plans (6.73 min/12.96 min,p<0.001).Conclusions. In our report, VMAT provides better conformity, homogeneity, and safety profile. The shorter treatment time is a major advantage and not only provides convenience to the painful patient but also contributes to the precision of this high dose radiation therapy.
Numerical Research on Flow Characteristics around a Hydraulic Turbine Runner at Small Opening of Cylindrical Valve
Authors: Mo Zhenwei , Xiao Juliang , Wang Gang
Published: January 2016

We use the continuity equation and the Reynolds averaged Navier-Stokes equations to study the flow-pattern characteristics around a turbine runner for the small-opening cylindrical valve of a hydraulic turbine. For closure, we adopt the renormalization-groupk-εtwo-equation turbulence model and use the computational fluid dynamics (CFD) software FLUENT to numerically simulate the three-dimensional unsteady turbulent flow through the entire passage of the hydraulic turbine. The results show that a low-pressure zone develops around the runner blades when the cylindrical valve is closed in a small opening; cavitation occurs at the blades, and a vortex appears at the outlet of the runner. As the cylindrical valve is gradually closed, the flow velocity over the runner area increases, and the pressure gradient becomes more significant as the discharge decreases. In addition, the fluid flow velocity is relatively high between the lower end of the cylindrical valve and the base, so that a high-velocity jet is easily induced. The calculation and analysis provide a theoretical basis for improving the performance of cylindrical-valve operating systems.
Activation of Melanocortin Receptors MC1and MC5Attenuates Retinal Damage in Experimental Diabetic Retinopathy
Authors: Rossi S. , Maisto R. , Gesualdo C. , Trotta M. C. , Ferraraccio F. , Kaneva M. K. , Getting S. J. , Surace E. , Testa F. , Simonelli F. , Grieco P. , Merlino F. , Perretti M. , D’Amico M. , Di Filippo C.
Published: January 2016

We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12–16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors,Mc1randMc5r. The intravitreal injection (5 μL) of the selective MC1small molecule agonist BMS-470539 (33 μmol) and the MC5peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1α, IL-1β, IL-6, MIP-1α, MIP-2α, MIP-3α, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5and MC1antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4agonist/antagonists resulted to be inactive with respect to all parameters under assessment.
Rescaled Local Interaction Simulation Approach for Shear Wave Propagation Modelling in Magnetic Resonance Elastography
Authors: Hashemiyan Z. , Packo P. , Staszewski W. J. , Uhl T.
Published: January 2016

Properties of soft biological tissues are increasingly used in medical diagnosis to detect various abnormalities, for example, in liver fibrosis or breast tumors. It is well known that mechanical stiffness of human organs can be obtained from organ responses to shear stress waves through Magnetic Resonance Elastography. The Local Interaction Simulation Approach is proposed for effective modelling of shear wave propagation in soft tissues. The results are validated using experimental data from Magnetic Resonance Elastography. These results show the potential of the method for shear wave propagation modelling in soft tissues. The major advantage of the proposed approach is a significant reduction of computational effort.
Time-Series Mapping of PM10Concentration Using Multi-Gaussian Space-Time Kriging: A Case Study in the Seoul Metropolitan Area, Korea
Authors: Park No-Wook
Published: January 2016

This paper presents space-time kriging within a multi-Gaussian framework for time-series mapping of particulate matter less than 10 μm in aerodynamic diameter (PM10) concentration. To account for the spatiotemporal autocorrelation structures of monitoring data and to model the uncertainties attached to the prediction, conventional multi-Gaussian kriging is extended to the space-time domain. Multi-Gaussian space-time kriging presented in this paper is based on decomposition of the PM10concentrations into deterministic trend and stochastic residual components. The deterministic trend component is modelled and regionalized using the temporal elementary functions. For the residual component which is the main target for space-time kriging, spatiotemporal autocorrelation information is modeled and used for space-time mapping of the residual. The conditional cumulative distribution functions (ccdfs) are constructed by using the trend and residual components and space-time kriging variance. Then, the PM10concentration estimate and conditional variance are empirically obtained from the ccdfs at all locations in the study area. A case study using the monthly PM10concentrations from 2007 to 2011 in the Seoul metropolitan area, Korea, illustrates the applicability of the presented method. The presented method generated time-series PM10concentration mapping results as well as supporting information for interpretations, and led to better prediction performance, compared to conventional spatial kriging.
Characterization of Enhancing MS Lesions by Dynamic Texture Parameter Analysis of Dynamic Susceptibility Perfusion Imaging
Authors: Verma Rajeev K. , Slotboom Johannes , Locher Cäcilia , Heldner Mirjam R. , Weisstanner Christian , Abela Eugenio , Kellner-Weldon Frauke , Zbinden Martin , Kamm Christian P. , Wiest Roland
Published: January 2016

Purpose. The purpose of this study was to investigate statistical differences with MR perfusion imaging features that reflect the dynamics of Gadolinium-uptake in MS lesions using dynamic texture parameter analysis (DTPA).Methods. We investigated 51 MS lesions (25 enhancing, 26 nonenhancing lesions) of 12 patients. Enhancing lesions (n=25) were prestratified into enhancing lesions with increased permeability (EL+;n=11) and enhancing lesions with subtle permeability (EL−;n=14). Histogram-based feature maps were computed from the raw DSC-image time series and the corresponding texture parameters were analyzed during the inflow, outflow, and reperfusion time intervals.Results. Significant differences (p<0.05) were found between EL+ and EL− and between EL+ and nonenhancing inactive lesions (NEL). Main effects between EL+ versus EL− and EL+ versus NEL were observed during reperfusion (mainly in mean and standard deviation (SD): EL+ versus EL− and EL+ versus NEL), while EL− and NEL differed only in their SD during outflow.Conclusion. DTPA allows grading enhancing MS lesions according to their perfusion characteristics. Texture parameters of EL− were similar to NEL, while EL+ differed significantly from EL− and NEL. Dynamic texture analysis may thus be further investigated as noninvasive endogenous marker of lesion formation and restoration.
Design, Fabrication, and Efficiency Study of a Novel Solar Thermal Water Heating System: Towards Sustainable Development
Authors: Khan M. Z. H. , Al-Mamun M. R. , Sikdar S. , Halder P. K. , Hasan M. R.
Published: January 2016

This paper investigated a novel loop-heat-pipe based solar thermal heat-pump system for small scale hot water production for household purposes. The effective use of solar energy is hindered by the intermittent nature of its availability, limiting its use and effectiveness in domestic and industrial applications especially in water heating. The easiest and the most used method is the conversion of solar energy into thermal energy. We developed a prototype solar water heating system for experimental test. We reported the investigation of solar thermal conversion efficiency in different seasons which is 29.24% in summer, 14.75% in winter, and 15.53% in rainy season. This paper also discusses the DC heater for backup system and the current by using thermoelectric generator which are 3.20 V in summer, 2.120 V in winter, and 1.843 V in rainy season. This solar water heating system is mostly suited for its ease of operation and simple maintenance. It is expected that such novel solar thermal technology would further contribute to the development of the renewable energy (solar) driven heating/hot water service and therefore lead to significant environmental benefits.
Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated ΔNp73 Inhibition and p73 Activation
Authors: Prabhu Varun V. , Hong Bo , Allen Joshua E. , Zhang Shengliang , Lulla Amriti R. , Dicker David T. , El-Deiry Wafik S.
Published: January 2016

Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo. Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro. Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N-terminally truncated isoform ΔNp73 in Aldefluor(+) cells. Accordingly, p73 knockdown or ΔNp73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and ΔNp73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53-reporter activation, ΔNp73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73-activating therapeutics to target CRCSCs. Cancer Res; 76(7); 1989–99. ©2016 AACR.
Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer
Authors: Espelin Christopher W. , Leonard Shannon C. , Geretti Elena , Wickham Thomas J. , Hendriks Bart S.
Published: January 2016

Trastuzumab is the standard of care for HER2-positive breast cancer patients, markedly improving disease-free and overall survival. Combined with chemotherapy, it enhances patient outcomes, but cardiotoxicity due to the trastuzumab treatment poses a serious adverse effect. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its delivery to HER2-overexpressing tumor cells while limiting exposure to nontarget tissues, including the heart. In this study, we evaluated the feasibility and preclinical activity of combining MM-302 with trastuzumab. MM-302 and trastuzumab target different domains of the HER2 receptor and thus could simultaneously bind HER2-overexpressing tumor cells in vitro and in vivo. Furthermore, trastuzumab did not disrupt the mechanism of action of MM-302 in delivering doxorubicin to the n0ucleus and inducing DNA damage. Reciprocally, MM-302 did not interfere with the ability of trastuzumab to block prosurvival p-Akt signaling. Interestingly, coadministration of the two agents acutely increased the deposition of MM-302 in human xenograft tumors and subsequently increased the expression of the DNA damage marker p-p53. Finally, the combination of MM-302 and trastuzumab induced synergistic antitumor activity in HER2-overexpressing xenograft models of breast and gastric cancer. Collectively, our findings highlight a novel combination therapy that efficiently targets HER2-overexpressing cells through multiple mechanisms and support the ongoing investigation of combined MM-302/trastuzumab therapy for HER2-positive metastatic breast cancer in a randomized phase II clinical trial. Cancer Res; 76(6); 1517–27. ©2016 AACR.
Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress
Authors: Tohme Samer , Yazdani Hamza O. , Al-Khafaji Ahmed B. , Chidi Alexis P. , Loughran Patricia , Mowen Kerri , Wang Yanming , Simmons Richard L. , Huang Hai , Tsung Allan
Published: January 2016

Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil–derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse. Cancer Res; 76(6); 1367–80. ©2016 AACR.
Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth
Authors: Liu Liu , Zhao Xiaoping , Zhao Li , Li Jiajin , Yang Hao , Zhu Zongping , Liu Jianjun , Huang Gang
Published: January 2016

Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity. Furthermore, PRMT5-induced methylation prevented phosphorylation of SREBP1a on S430 by GSK3β, leading to its disassociation from Fbw7 (FBXW7) and its evasion from degradation through the ubiquitin–proteasome pathway. Consequently, methylation-stabilized SREBP1a increased de novo lipogenesis and accelerated the growth of cancer cells in vivo and in vitro. Clinically, R321 symmetric dimethylation status was associated with malignant progression of human hepatocellular carcinoma, where it served as an independent risk factor of poor prognosis. By showing how PRMT5-induced methylation of SREBP1a triggers hyperactivation of lipid biosynthesis, a key event in tumorigenesis, our findings suggest a new generalized strategy to selectively attack tumor metabolism. Cancer Res; 76(5); 1260–72. ©2016 AACR.
Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages
Authors: Zhao Jun-Long , Huang Fei , He Fei , Gao Chun-Chen , Liang Shi-Qian , Ma Peng-Fei , Dong Guang-Ying , Han Hua , Qin Hong-Yan
Published: January 2016

Tumor-associated macrophages (TAM) contribute greatly to hallmarks of cancer. Notch blockade was shown to arrest TAM differentiation, but the precise role and underlying mechanisms require elucidation. In this study, we employed a transgenic mouse model in which the Notch1 intracellular domain (NIC) is activated conditionally to define the effects of active Notch1 signaling in macrophages. NIC overexpression had no effect on TAM differentiation, but it abrogated TAM function, leading to repressed growth of transplanted tumors. Macrophage miRNA profiling identified a novel downstream mediator of Notch signaling, miR-125a, which was upregulated through an RBP-J–binding site at the first intronic enhancer of the host gene Spaca6A. miR-125a functioned downstream of Notch signaling to reciprocally influence polarization of M1 and M2 macrophages by regulating factor inhibiting hypoxia inducible factor-1α and IRF4, respectively. Notably, macrophages transfected with miR-125a mimetics increased phagocytic activity and repressed tumor growth by remodeling the immune microenvironment. We also identified a positive feedback loop for miR-125a expression mediated by RYBP and YY1. Taken together, our results showed that Notch signaling not only supported the differentiation of TAM but also antagonized their protumorigenic function through miR-125a. Targeting this miRNA may reprogram macrophages in the tumor microenvironment and restore their antitumor potential. Cancer Res; 76(6); 1403–15. ©2016 AACR.
MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4
Authors: Lemos Clara , Hardt Markus S. , Juneja Manisha , Voss Cynthia , Förster Susann , Jerchow Boris , Haider Wolfram , Bläker Hendrik , Stein Ulrike
Published: January 2016

Purpose: We have previously identified the gene MACC1 as a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Here, we report for the first time the generation of transgenic mouse models for MACC1.

Experimental Design: We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with ApcMin mice (vil-MACC1/ApcMin).

Results: vil-MACC1/ApcMin mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large tumors (≥3-mm diameter; P = 0.0024). A detailed histopathologic analysis of these lesions demonstrated that the tumors from the vil-MACC1/ApcMin mice had a more invasive phenotype and, consequently, showed a significantly reduced survival time than ApcMin mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/ApcMin mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors compared with ApcMin controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r = 0.7005 and r = 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively).

Conclusions: We provide proof of principle that MACC1-induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression. Clin Cancer Res; 22(11); 2812–24. ©2016 AACR.
Focusing on Core Patient-Reported Outcomes in Cancer Clinical Trials: Symptomatic Adverse Events, Physical Function, and Disease-Related Symptoms
Authors: Kluetz Paul G. , Slagle Ashley , Papadopoulos Elektra J. , Johnson Laura Lee , Donoghue Martha , Kwitkowski Virginia E. , Chen Wen-Hung , Sridhara Rajeshwari , Farrell Ann T. , Keegan Patricia , Kim Geoffrey , Pazdur Richard
Published: January 2016

Cancer clinical trials have relied on overall survival and measures of tumor growth or reduction to assess the efficacy of a drug. However, benefits are often accompanied by significant symptomatic toxicities. The degree to which a therapy improves disease symptoms and introduces symptomatic toxicity affects how patients function in their daily lives. These concepts are important contributors to health-related quality of life (HRQOL). In this article, we discuss patient-reported outcome (PRO) assessment in cancer trials and challenges relying solely on static multi-item HRQOL instruments. We propose focusing on three separate measures of well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms, which are key contributors to the effect of a therapy on HRQOL. Separate measures of these three concepts may facilitate the incorporation of emerging contemporary instruments that can tailor the PRO assessment strategy to different trial contexts. Irrespective of the PRO measures used, continued improvement in trial design and conduct is crucial to decrease missing data and optimize the quality of PRO information. International stakeholder collaboration and continued research into optimal practices for PRO and other clinical outcome assessments are necessary to advance a common framework for generating and reporting rigorous patient-centered data from cancer clinical trials. Clin Cancer Res; 22(7); 1553–8. ©2016 AACR.
No Effect of Rapamycin on Cardiac Adhesion Formation: A Drug-Loaded Bioresorbable Polylactone Patch in a Porcine Cardiac Surgical Model
Authors: Qazi Saddiq , Kjaergaard Benedict , Yang Fei , Shen Hong , Wang Shenguo , Zhang Navee , Vyberg Mogens , Wøyen Arne , Andreasen Jan Jesper
Published: January 2016

Background: The fusing of the epicardium and sternum due to adhesion is a common problem during repeated cardiac surgery and carries with it an increased risk of bleeding. The use of barriers and patches has been tested to prevent the formation of adhesions, but the very presence of a patch can provoke adhesion formation. The objective of this study was, therefore, to investigate both biodegradable and bioresorbable polylactone patches [(polycaprolactone-poly(ethylene oxide)-polycaprolactone tri-block copolymer (PCE)]. The patches were also tested with a controlled release of rapamycin, which prevents cell migration and extracellular matrix deposition. The clinical effectiveness of rapamycin in pericardial patches has not previously been examined. Materials and Methods: Three groups of 6 female Danish Landrace pigs underwent sternotomy and abrasion of the epicardium, before being randomized to either group 1 - the control group (with no patch), group 2 - PCE patch implanted between the sternum and epicardium, or group 3 - PCE patch and slow-release 1.6-mg rapamycin. After a median time period of 26 days, the pigs were euthanized and their hearts removed en bloc with the sternum, for macroscopic, histological and pathological examination. Results: Upon macroscopic examination, a significantly lower degree of adhesion in group 2, as compared to group 1 (p < 0.05), was found. Histological analysis of the tissues showed significantly more fibrosis, inflammation and foreign body granulomas (p < 0.05) in both group 2 and group 3, when compared to group 1. Conclusion: A PCE patch following sternotomy in animal subjects reduces postoperative macroscopic adhesions without reducing microscopic fibrosis or inflammation. Loading the patch with rapamycin was found not to increase the antifibrotic effect.
Cerebral β-Amyloid Angiopathy Is Associated with Earlier Dementia Onset in Alzheimer's Disease
Authors: Vidoni Eric D. , Yeh Hung-Wen , Morris Jill K. , Newell Kathy L. , Alqahtani Abdulfattah , Burns Nicole C. , Burns Jeffrey M. , Billinger Sandra A.
Published: January 2016

Background: Cerebral β-amyloid angiopathy (CAA) occurs when β-amyloid (Aβ) is deposited in the vascular media and adventitia. It is a common pathology in the brains of older individuals and has been linked to cognitive decline, but relatively little is known about the influence that CAA has on the clinical manifestation of Alzheimer's disease (AD). The aim of this retrospective analysis was to quantify the effect that CAA had on the manifestation of initial AD-related cognitive change and subsequent progression of dementia. Methods: We analyzed neuropathological data from the National Alzheimer's Coordinating Center's data set, performing parametric analyses to assess differences in age of progression to moderate-stage dementia. Results: We found that individuals with both CAA burden and Aβ neuritic plaque burden at death had the greatest risk of earlier conversion to very mild and moderate-stage dementia, but not necessarily faster progression. Conclusions: Our results suggest that CAA contributes to changes in early AD pathogenesis. This supports the idea that vascular change and neuritic plaque deposition are not just parallel processes but reflect additive pathological cascades that influence the course of clinical AD manifestation. Further inquiry into the role of CAA and its contribution to early cognitive change in AD is suggested.
Myelin Sheath Injury in Kaolin-Induced Hydrocephalus: A Light and Electron Microscopy Study
Authors: Ayannuga Olugbenga A. , Shokunbi M. Temitayo , Naicker T.A.
Published: January 2016

Background: In hydrocephalus, the impairment of cognitive and motor functions is thought to be partly due to injury to the myelin sheath of axons in the central nervous system. The exact nature of this injury is not completely understood. Methods: We induced hydrocephalus in 3-week-old rats with an intracisternal injection of kaolin suspension (0.04 ml of 200 mg/ml) and examined paraffin and ultrathin sections of the subcortical white matter from coronal slices of the cerebrum obtained at the level of the optic chiasm after sacrifice at weekly intervals for 4 weeks. Results: Over time, there was a progression of injury to the myelin sheath consisting of attenuation, lamella separation and accumulation of myelin debris, focal degeneration, and the appearance of casts and loops. Conclusion: The results suggest that myelin injury in kaolin-induced hydrocephalus progresses with the duration and severity of ventriculomegaly.
Neonatal Vaccination: Challenges and Intervention Strategies
Authors: Morris Matthew C. , Surendran Naveen
Published: January 2016

Background: While vaccines have been tremendously successful in reducing the incidence of serious infectious diseases, newborns remain particularly vulnerable in the first few months of their life to life-threatening infections. A number of challenges exist to neonatal vaccination. However, recent advances in the understanding of neonatal immunology offer insights to overcome many of those challenges. Objective: This review will present an overview of the features of neonatal immunity which make vaccination difficult, survey the mechanisms of action of available vaccine adjuvants with respect to the unique features of neonatal immunity, and propose a possible mechanism contributing to the inability of neonates to generate protective immune responses to vaccines. Methods: We surveyed recent published findings on the challenges to neonatal vaccination and possible intervention strategies including the use of novel vaccine adjuvants to develop efficacious neonatal vaccines. Results: Challenges in the vaccination of neonates include interference from maternal antibody and excessive skewing towards Th2 immunity, which can be counteracted by the use of proper adjuvants. Conclusion: Synergistic stimulation of multiple Toll-like receptors by incorporating well-defined agonist-adjuvant combinations to vaccines is a promising strategy to ensure a protective vaccine response in neonates.
Evaluation of the Antiulcer Activity of the Leaves of Azadirachta indica: An Experimental Study
Authors: Bhajoni Pranjit Santonu , Meshram Girish Gulab , Lahkar Mangala
Published: January 2016

Background:Azadirachta indica, an evergreen tree, is used by several folkloric practitioners to treat peptic ulcers in India. The present study was carried out to evaluate the antiulcer activity of the aqueous extract (AE) of the leaves of A. indica in Wistar rats. Methods: Gastric ulcerations were induced by pyloric ligation, aspirin, and cold restraint stress. AE was used in doses of 150, 300, and 600 mg/kg body weight per os. Distilled water served as the control and ranitidine 20 mg/kg body weight intraperitoneal as the reference standard. The ulcer index (UI) and percentage inhibition (PI) values were determined in each model. The volume of gastric contents, free acidity, total acidity, and pH were measured in the pyloric ligation-induced ulcer model. Results: AE showed a dose-dependent and significant (p < 0.05) decrease in the UI and an increase in the PI in all models employed compared to the control group. AE caused a dose-dependent decline in the gastric content volume, free acidity, and total acidity. Conclusion: The leaves of A. indica possess significant antiulcer activity and act via multiple mechanisms.
Alopecia Areata Progression Index, a Scoring System for Evaluating Overall Hair Loss Activity in Alopecia Areata Patients with Pigmented Hair: A Development and Reliability Assessment
Authors: Jang Yong Hyun , Moon Sun Young , Lee Weon Ju , Lee Seok-Jong , Lee Won Kee , Park Byung Cheol , Kim Hyojin , Kim Do Won
Published: January 2016

Background: No scoring systems to evaluate overall hair loss activity in alopecia areata (AA) have been established. Objective: We sought to develop a measurement tool (Alopecia Areata Progression Index, AAPI) for the evaluation of overall hair loss activity in AA patients with pigmented hair. Methods: The scalp surface area was divided into 4 quadrants. In each quadrant, hair loss activity was scored on the basis of the percentage of alopecic area, clinical findings associated with hair loss. The AAPI was measured in 17 patients with different severities of AA. Results: Interobserver and intraobserver reliabilities were assessed by 4 investigators. A significant correlation of the total AAPI was found among the 4 investigators. In addition, intraobserver reliability was excellent, and interobserver reliability was statistically reliable. Conclusion: The AAPI seems to represent a system capable of truly quantifying overall hair loss activity in AA patients with different severity, demonstrating trustworthy interobserver and intraobserver reliability.
Phospholipid Composition in Synthetic Surfactants Is Important for Tidal Volumes and Alveolar Stability in Surfactant-Treated Preterm Newborn Rabbits
Authors: Calkovska Andrea , Linderholm Bim , Haegerstrand-Björkman Marie , Pioselli Barbara , Pelizzi Nicola , Johansson Jan , Curstedt Tore
Published: January 2016

Background: The development of synthetic surfactants for the treatment of lung pulmonary diseases has been going on for many years. Objectives: To investigate the effects of phospholipid mixtures combined with SP-B and SP-C analogues on lung functions in an animal model of respiratory distress syndrome. Methods: Natural and synthetic phospholipid mixtures with/without SP-B and/or SP-C analogues were instilled in ventilated premature newborn rabbits. Lung functions were evaluated. Results: Treatment with Curosurf® or phospholipids from Curosurf combined with SP-B and SP-C analogues gave similar results. Treatment with phospholipids from adult rabbit lungs or liver combined with dipalmitoylphosphatidylcholine (DPPC) and palmitoyloleoylphosphatidylglycerol (POPG) gave tidal volumes (VT) well above physiological levels, but alveolar stability at end-expiration was only achieved when these phospholipids were combined with analogues of SP-B and SP-C. Treatment with egg yolk-PC mixed with DPPC with and without POPG gave small VT, but after addition of both analogues VT was only somewhat lower and lung gas volumes (LGV) similar to those obtained with Curosurf. Substitution of egg yolk-PC (≥99% PC) with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and combining them with DPPC, POPG and 2% each of the SP-B and SP-C analogue gave a completely synthetic surfactant with similar effects on VT and LGV as Curosurf. Conclusions: Phospholipid composition is important for VT while the SP-B and SP-C analogues increase alveolar stability at end-expiration. Synthetic surfactant consisting of unsaturated and saturated phosphatidylcholines, POPG and the analogues of SP-B and SP-C has similar activity as Curosurf regarding VT and LGV in an animal model using preterm newborn rabbits ventilated without positive end-expiratory pressure.
A Case of Myxofibrosarcoma in an Unusual Thoracic Location
Authors: Gopalratnam Kavitha , Rodriguez Jose A. , Woodson Kevin A. , Folman Robert
Published: January 2016

Myxofibrosarcoma is a soft tissue neoplasm composed of malignant fibroblasts with a myxoid matrix. It is commonly found in patients during their 6th through 8th decades of life with a slight male predominance. Myxofibrosarcomas are classified as low- to high-grade tumors that are differentiated by hypercellularity, variation of mitotic activity and degree of necrosis. The most common sites are the extremities (77%) and trunk (12%), with the retroperitoneum and mediastinum being very rare. In this case report, we describe a patient presenting with myxofibrosarcoma of the mediastinum, a rare site for the development of myxofibrosarcoma. This case of primary mediastinal myxofibrosarcoma appears to be only the second described in the English-language literature.
Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis
Authors: Boyd John H. , Fjell Christopher D. , Russell James A. , Sirounis Demetrios , Cirstea Mihai S. , Walley Keith R.
Published: January 2016

Purpose: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. Methods: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. Results: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). Conclusions: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock.
Type 1 Diabetes Duration Decreases Pulmonary Diffusing Capacity during Exercise
Authors: Lee Michelle J. , Coast J. Richard , Hempleman Steven C. , Baldi J. Christopher
Published: January 2016

Background: Diabetes damages peripheral tissues; however, its effects on the lung are less known. Lung diffusing capacity (DLCO) is influenced by alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (VC), both of which are reduced in adults with type 1 diabetes (T1D). Objective: We sought to determine if diabetes duration affects DLCO, DM, VC, and cardiac output (Q). Methods: 24 T1D patients (10.7-52.8 years) and 24 non-diabetic controls were recruited and had DLCO, DM, VC, and Q measured at rest and during exercise (40, 70 and 90% VO2max). Results: When stratified into two groups based on age (young, <20.6 years old), there were no significant differences in DLCO, DM, VC, or Q (all of which were normalized to body surface area [BSA]) in the young group or in the old group. When stratified by diabetes duration (short duration, 0.33-8.9 years vs. long duration, 9.6-28 years), the T1D patients in the long duration group had lower DLCO/BSA and DM/BSA compared to the controls (p < 0.05). There were no differences in any of the variables in the short duration group. Conclusions: This study has shown that duration of diabetes is associated with decrements in diffusing capacity and its components.
Birth Weight Could Influence Bone Mineral Contents of 10- to 18-Year-Old Korean Adolescents: Results from the Korea National Health and Nutrition Examination Survey (KNHANES) 2010
Authors: Cho Won Kyoung , Ahn Moonbae , Jeon Yeon Jin , Jung In Ah , Han Kyungdo , Kim Shin Hee , Cho Kyoung Soon , Park So Hyun , Jung Min Ho , Suh Byung-Kyu
Published: January 2016

Background: We investigate the relationship between birth weight (BW) and bone mineral content (BMC) in Korean adolescents. Methods: Data were obtained from the Korea National Health and Nutrition Examination Survey conducted in 2010. Baseline characteristics were compared according to age- and sex-specific BMC quartiles of total body less head (TBLH), lumbar spine (LS) and femur neck (FN) in 10- to 18-year-old adolescents (male = 474, female = 394). Results: BW showed a positive correlation with current weight-SDS (p = 0.006 in males, p = 0.008 in females). BW according to TBLH-BMC quartile groups (p for trend <0.003 in males, <0.0001 in females), LS-BMC quartile groups (p for trend <0.034 in males) and FN-BMC quartile groups (p for trend <0.008 in males, <0.020 in females) showed significant differences. The odds ratio (OR) of being in the highest BMC quartile, per 1-kg increase in BW, was significantly increased in TBLH-BMC (OR = 2.14 in males, OR = 3.26 in >16-year-old adolescents) and FN-BMC (OR = 2.62 in males, OR = 3.06 in >16-year-old adolescents) after adjusting for age, height, smoking, drinking, metabolic equivalent of task, and gestational age. Conclusion: BW might be one of the determinant factors of BMC in Korean adolescents.
Screening Algorithm for BK Virus-Associated Nephropathy Using Sequential Testing of Urinary Cytology: A Probabilistic Model Analysis
Authors: Ma Maggie K.M. , Leung Anskar Y.H. , Lo Kin Yee , Lio Weng In , Chan Hoi Wong , Wong Ivy , Hau Anthony K.C. , Tam Chun Hay , Wong Andrew K.M. , Kuok Un I , Chau Ka Foon , Fung Samuel K.S. , Kwan Tsz Hoi , Wong Sunny S.H. , Tang Sydney C.W.
Published: January 2016

Background: Incorporating urinary cytology in BK virus (BKV) screening algorithm potentially reduces the screening cost for BK viral nephropathy. We aimed to evaluate the test performances and screening cost of sequential 2-stage screening consisting of urine cytology followed by BKV serum quantitative polymerase chain reaction (PCR). Methods: Ninety-five kidney transplant recipients who had BKV serum quantitative PCR/urine cytology tested and verified with histopathology (the reference gold standard) were included. A probabilistic model was constructed to evaluate the test performance and screening cost of 2-stage screening, and was compared with screening with urine cytology or serum viral load alone. Results: At a viral load threshold of ≥104 copies/ml, the sensitivity and specificity of quantitative PCR alone were 83% (95% CI 69-96) and 91% (95% CI 83-97), respectively. The sensitivity and specificity of urine cytology alone were 91% (95% CI 79-100) and 74% (95% CI 60-91), respectively. Sequential 2-stage screening resulted in loss in sensitivity but a net gain in specificity (viral load threshold ≥104 copies/ml - sensitivity, 75% (95% CI 60-91); specificity, 98% (95% CI 95-99)). Two-stage screening also had superior positive predictive value and is cost effective when BKV-associated nephropathy prevalence is below 94%. Conclusions: Our study had demonstrated a favorable test performance and cost efficiency of 2-stage BKV screening.
A Prospective Study of Ripple Mapping in Atrial Tachycardias
Authors: Luther Vishal , Linton Nick W.F. , Koa-Wing Michael , Lim Phang Boon , Jamil-Copley Shahnaz , Qureshi Norman , Ng Fu Siong , Hayat Sajad , Whinnett Zachary , Davies D. Wyn , Peters Nicholas S. , Kanagaratnam Prapa
Published: January 2016

Background—

Post ablation atrial tachycardias are characterized by low-voltage signals that challenge current mapping methods. Ripple mapping (RM) displays every electrogram deflection as a bar moving from the cardiac surface, resulting in the impression of propagating wavefronts when a series of bars move consecutively. RM displays fractionated signals in their entirety thereby helping to identify propagating activation in low-voltage areas from nonconducting tissue. We prospectively used RM to study tachycardia activation in the previously ablated left atrium.

Methods and Results—

Patients referred for atrial tachycardia ablation underwent dense electroanatomic point collection using CARTO3v4. RM was played over a bipolar voltage map and used to determine the voltage “activation threshold” that differentiated functional low voltage from nonconducting areas for each map. Ablation was guided by RM, but operators could perform entrainment or review the isochronal activation map for diagnostic uncertainty. Twenty patients were studied. Median RM determined activation threshold was 0.3 mV (0.19–0.33), with nonconducting tissue covering 33±9% of the mapped surface. All tachycardias crossed an isthmus (median, 0.52 mV, 13 mm) bordered by nonconducting tissue (70%) or had a breakout source (median, 0.35 mV) moving away from nonconducting tissue (30%). In reentrant circuits (14/20) the path length was measured (87–202 mm), with 9 of 14 also supporting a bystander circuit (path lengths, 147–234 mm). In breakout tachycardias, splitting of wavefronts resulted in 2 to 4 incomplete circuits. RM-guided ablation interrupted the tachycardia in 19 of 20 cases with the first ablation set.

Conclusions—

RM helps to define activation through low-voltage regions and aids ablation of atrial tachycardias.
Quantifying the 3 Biases That Lead to Unintentional Overestimation of the Blood Pressure–Lowering Effect of Renal Denervation
Authors: Howard James P. , Shun-Shin Matthew J. , Hartley Adam , Bhatt Deepak L. , Krum Henry , Francis Darrel P.
Published: January 2016

Background—

Studies of renal denervation report disparate results. Meta-analysis by trial design may allow quantitative estimation of sources and magnitude of biases in denervation studies.

Methods and Results—

One hundred forty nonrandomized, 6 randomized open-label, and 2 randomized blinded studies were analyzed for 2 outcomes: (1) blood pressure changes for nonrandomized, open-label randomized, and blinded studies; and (2) quantification of 3 biases potentially contributing to apparent antihypertensive effects: (a) regression to the mean, (b) asymmetrical data handling, and (c) true blood pressure drops caused by something other than the tested therapy (confounding). Nonrandomized studies and open-label randomized trials reported large reductions in office blood pressure of 23.6 mm Hg (95% confidence interval [CI], 22.0 to 25.3) and 29.1 mm Hg (95% CI, 25.2 to 33.1 mm Hg), respectively. They reported smaller reductions in ambulatory blood pressures (11.2 mm Hg; 95% CI, 10.0 to 12.4). The blinded trials found no significant reduction in blood pressure (2.9 mm Hg; 95% CI, −0.4 to 6.3). Analyses of these data indicate the magnitude of the 3 potential sources of bias to be regression to the mean, −1.01 mm Hg (95% CI, 4.24 to −6.27); asymmetrical data handling, −10.8 mm Hg (95% CI, −8.77 to −12.87); and confounding, −8.3 mm Hg (95% CI, −4.73 to −11.83).

Conclusions—

Increasingly bias-resistant trial designs report effect sizes of decreasing magnitude. This disparity may be caused by asymmetrical data handling and confounding (eg, increased drug adherence). If these differences are caused by trial design and not by some other differences in patients or procedures, which happen to match the trial design, then randomization alone is not enough: blinding is also needed. This has broad implications across trials of medications and devices.