bluuebunny/crossref_metadata_2025 huggingface dataset:
3rd Highlights of Algorithms (HALG 2018)
Authors: Czumaj Artur , Krauthgamer Robert
Published: October 2018

The 3rd edition of the Highlights of Algorithms (HALG) conference took place in Amsterdam, June 46, 2018. In this report, the chairs of the Steering Committee and the Program Committee discuss the role, format and impact of the conference until now, and describe their goals and motivation for the future.
Tolerance and Innate Immunity Shape the Development of Postpartum Uterine Disease and the Impact of Endometritis in Dairy Cattle
Authors: Sheldon I. Martin , Cronin James G. , Bromfield John J.
Published: October 2018

Bacteria are ubiquitous in the bovine uterus after parturition, but 50 years ago, cows tolerated these bacteria and few animals developed uterine disease. Now, up to 40% of dairy cattle develop postpartum uterine disease. Uterine disease causes infertility by compromising the function of not only the endometrium but also the ovary. Animals defend themselves against pathogens using tolerance and resistance mechanisms. Tolerance is the ability to limit the disease severity induced by a given pathogen burden. Resistance is the ability to limit the pathogen burden and is usually the function of immunity. Endometrial cells contribute to tolerance and have roles in innate immunity and the inflammatory response to pathogens. However, failures in endometrial tolerance and the character of the inflammatory response shape postpartum uterine disease. We propose that uterine health is more dependent on the ability of the endometrium to tolerate pathogens than the ability to resist invading bacteria.
Pathology and Pathogenesis of Chagas Heart Disease
Authors: Bonney Kevin M. , Luthringer Daniel J. , Kim Stacey A. , Garg Nisha J. , Engman David M.
Published: October 2018

Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host–parasite equation. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection—Chagas heart disease—and concludes with a discussion of key unanswered questions and a view to the future.
Differential Privacy and Federal Data Releases
Authors: Reiter Jerome P.
Published: October 2018

Federal statistics agencies strive to release data products that are informative for many purposes, yet also protect the privacy and confidentiality of data subjects’ identities and sensitive attributes. This article reviews the role that differential privacy, a disclosure risk criterion developed in the cryptography community, can and does play in federal data releases. The article describes potential benefits and limitations of using differential privacy for federal data, reviews current federal data products that satisfy differential privacy, and outlines research needed for adoption of differential privacy to become widespread among federal agencies.
3D Face Recognition based on Local Conformal Parameterization and Iso-Geodesic Stripes Analysis
Authors: Lv Chenlei , Zhao Junli
Published: October 2018

3D face recognition is an important topic in the field of pattern recognition and computer graphic. We propose a novel approach for 3D face recognition using local conformal parameterization and iso-geodesic stripes. In our framework, the 3D facial surface is considered as a Riemannian 2-manifold. The surface is mapped into the 2D circle parameter domain using local conformal parameterization. In the parameter domain, the geometric features are extracted from the iso-geodesic stripes. Combining the relative position measure, Chain 2D Weighted Walkthroughs (C2DWW), the 3D face matching results can be obtained. The geometric features from iso-geodesic stripes in parameter domain are robust in terms of head poses, facial expressions, and some occlusions. In the experiments, our method achieves a high recognition accuracy of 3D facial data from the Texas3D and Bosphorus3D face database.
The First Harmonic of Radial Pulse as an Early Predictor of Silent Coronary Artery Disease and Adverse Cardiac Events in Type 2 Diabetic Patients
Authors: Chang Chi-Wei , Liao Kuo-meng , Chang Yi-Ting , Wang Sheng-Hung , Chen Ying-chun , Wang Gin-Chung
Published: October 2018

Background. It has been reported that harmonics of radial pulse is related to coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). It is still unclear whether or not the first harmonics of the radial pulse spectrum is an early independent predictor of silent coronary artery disease (SCAD) and adverse cardiac events (ACE). Objectives. To measure the risk of SCAD in patients with T2DM and also to survey whether or not an increment of the first harmonic (C1) of the radial pulse increases ACE. Methods. 1968 asymptomatic individuals with T2DM underwent radial pulse wave measurement. First harmonic of the radial pressure wave, C1, was calculated. Next, the new occurrence of ACE and the new symptoms and signs of coronary artery disease were recorded. The follow-up period lasted for 14.7 ± 3.5 months. Results. Out of 1968 asymptomatic individuals with T2DM, ACE was detected in 239 (12%) of them during the follow-up period. The logrank test demonstrated that the cumulative incidence of ACE in patients with C1 above 0.96 was greater than that in those patients with C1 below 0.89 (P<0.01). By comparing the data of patients with C1 smaller than the first quartile and the patients with C1 greater than the third quartile, the hazard ratios were listed as follows: ACE (hazard ratio, 2.29; 95% CI, 1.55–3.37), heart failure (hazard ratio, 2.22; 95% CI, 1.21–4.09), myocardial infarction (hazard ratio, 2.44; 95% CI, 1.51–3.93), left ventricular dysfunction (Hazard ratio, 2.01; 95% CI, 0.86–4.70), and new symptoms and signs for coronary artery disease (hazard ratio, 2.03; 95% CI, 1.45–2.84). As C1 increased, the risk for composite ACE (P<0.001 for trend) and for coronary disease (P<0.001 for trend) also increased. The hazard ratio and trend for cardiovascular-cause mortality were not significant. Conclusions. This study showed that C1 of the radial pulse wave is correlated with cardiovascular events. Survival analysis showed that C1 value is an independent predictor of ACE and SCAD in asymptomatic patients with T2DM. Thus, screening for the first harmonic of the radial pulse may improve the risk stratification of cardiac events and SCAD in asymptomatic patients although they had no history of coronary artery disease or angina-related symptom.
Localization of Energy-Momentum for a Black Hole Spacetime Geometry with Constant Topological Euler Density
Authors: Radinschi Irina , Grammenos Theophanes , Rahaman Farook , Spanou Andromahi , Cazacu Marius Mihai , Chattopadhyay Surajit , Pasqua Antonio
Published: October 2018

The evaluation of the energy-momentum distribution for a new four-dimensional, spherically symmetric, static and charged black hole spacetime geometry with constant nonzero topological Euler density is performed by using the energy-momentum complexes of Einstein and Møller. This black hole solution was recently developed in the context of the coupled Einstein–nonlinear electrodynamics of the Born-Infeld type. The energy is found to depend on the mass M and the charge q of the black hole, the cosmological constant Λ, and the radial coordinate r, while in both prescriptions all the momenta vanish. Some limiting and particular cases are analyzed and discussed, illustrating the rather extraordinary character of the spacetime geometry considered.
DiarrheagenicEscherichia coliAssociated with Acute Gastroenteritis in Children from Soriano, Uruguay
Authors: Peirano Vivian , Bianco María Noel , Navarro Armando , Schelotto Felipe , Varela Gustavo
Published: October 2018

Introduction. Acute diarrheal disease still deserves worldwide attention due to its high morbidity and mortality, especially in developing countries. While etiologic determination is not mandatory for management of all individual cases, it is needed for generating useful epidemiologic knowledge. DiarrheagenicEscherichia coli(DEC) are relevant enteropathogens, and their investigation requires specific procedures to which resources and training should be dedicated in reference laboratories.Methodology. Following the hypothesis that enteric pathogens affecting children in towns located in the interior of Uruguay may be different from those found in Montevideo, we conducted a diagnostic survey on acute diarrheal disease in 83 children under 5 years of age from populations in the south of the country.Results. DEC pathotypes were the only bacterial pathogens found in diarrheal feces (20.48%), followed by rotavirus (14.45%) and enteric adenovirus (4.81%). Atypical EPEC (aEPEC) was the most frequent DEC pathotype identified, and unexpectedly, it was associated with bloody diarrheal cases. These patients were of concern and provided with early consultation, as were children who presented with vomiting, which occurred most frequently in rotavirus infections. aEPEC serotypes were diverse and different from those previously reported in Montevideo children within the same age group and different from serotypes identified in regional and international studies. Enteroinvasive (EIEC) O96 : H19, associated with large outbreaks in Europe, was also isolated from two patients. Antibiotic susceptibility of pathogenic bacteria identified in this study was higher than that observed in previous national studies, which had been mainly carried out in children from Montevideo.Conclusion. The reduced number of detected species, the marked prevalence of aEPEC, the scarce resistance traits, and the diverse range of serotypes in the virulent DEC identified in this study confirm that differences exist between enteropathogens affecting children from interior towns of Uruguay and those circulating among children in Montevideo.
UAV-Assisted Data Dissemination in Delay-Constrained VANETs
Authors: Fan Xiying , Huang Chuanhe , Fu Bin , Wen Shaojie , Chen Xi
Published: October 2018

Due to the high mobility of vehicles, the frequent path failures caused by dynamic network topology, and a variety of obstructions, efficient data dissemination with delay constraint in vehicular ad hoc networks (VANETs) is a challenging issue. To address these problems, a novel mobile relaying technique by employing unmanned aerial vehicles (UAVs) is considered to facilitate data dissemination in vehicular environments where the communication infrastructures are not available or the network connectivity is poor. This paper studies and formulates the throughput maximization problem in UAV-assisted VANETs, which aims to achieve high throughput while guarantee the delay constraint of data flows to the vehicles in the area. To maximize the network throughput, the maximization problem tries to find an optimal delivery strategy for data dissemination by optimizing the transmission rate. To solve the problem, the knapsack problem can be reduced to the maximization problem, which is proved NP-hard. A polynomial time approximation scheme is proposed to achieve an approximate solution. Detailed theoretical analysis including time complexity and approximation ratio of the proposed algorithm is presented. Simulation results demonstrate the effectiveness of the proposed algorithm.
Manganese-Enhanced T1 Mapping in the Myocardium of Normal and Infarcted Hearts
Authors: Spath N. B. , Lilburn D. M. L. , Gray G. A. , Le Page L. M. , Papanastasiou G. , Lennen R. J. , Janiczek R. L. , Dweck M. R. , Newby D. E. , Yang P. C. , Jansen M. A. , Semple S. I.
Published: October 2018

Background. Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods. T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 μmol/kg)) or chelated (mangafodipir (22–44 μmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100–200 μmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48 h later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Masson’s trichrome (MTC). Results. Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30–43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI −14.8 to 17.1 P>0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI −9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI −10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=−0.61, P=0.022). Conclusions. MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.
Polymer Thin Film–Induced Tumor Spheroids Acquire Cancer Stem Cell–like Properties
Authors: Choi Minsuk , Yu Seung J. , Choi Yoonjung , Lee Hak R. , Lee Eunbeol , Lee Eunjung , Lee Yumi , Song Junhyuk , Son Jin G. , Lee Tae G. , Kim Jin Y. , Kang Sukmo , Baek Jieung , Lee Daeyoup , Im Sung G. , Jon Sangyong
Published: October 2018

Although cancer stem cells (CSC) are thought to be responsible for tumor recurrence and resistance to chemotherapy, CSC-related research and drug development have been hampered by the limited supply of diverse, patient-derived CSC. Here, we present a functional polymer thin film (PTF) platform that promotes conversion of cancer cells to highly tumorigenic three-dimensional (3D) spheroids without the use of biochemical or genetic manipulations. Culturing various human cancer cells on the specific PTF, poly(2,4,6,8-tetravinyl-2,4,6,8-tetramethyl cyclotetrasiloxane) (pV4D4), gave rise to numerous multicellular tumor spheroids within 24 hours with high efficiency and reproducibility. Cancer cells in the resulting spheroids showed a significant increase in the expression of CSC-associated genes and acquired increased drug resistance compared with two-dimensional monolayer-cultured controls. These spheroids also exhibited enhanced xenograft tumor-forming ability and metastatic capacity in nude mice. By enabling the generation of tumorigenic spheroids from diverse cancer cells, the surface platform described here harbors the potential to contribute to CSC-related basic research and drug development.

Significance:

A new cell culture technology enables highly tumorigenic 3D spheroids to be easily generated from various cancer cell sources in the common laboratory.
Cancer Risk and Prognosis after a Hospital Contact for an Elevated Erythrocyte Sedimentation Rate
Authors: Kornum Jette B. , Farkas Dóra K. , Sværke Claus , Severinsen Marianne T. , Thomsen Reimar W. , Sørensen Henrik T.
Published: October 2018

Background:

An elevated erythrocyte sedimentation rate (ESR) may be a marker of occult cancer.

Methods:

We linked Danish medical databases to examine cancer incidence in patients with a first-time hospital contact for elevated ESR during 1980 to 2013. We calculated standardized incidence ratios (SIR) of cancer compared with the general population, and comorbidity-adjusted HRs (aHR) versus matched population comparisons without elevated ESR. We also compared survival among patients with cancer with elevated ESR with that among patients with cancer without elevated ESR.

Results:

During median follow-up of 4.9 years, we observed 3,926 cancers among 18,540 patients with a first-time hospital contact for elevated ESR. The risk for any cancer diagnosed during the first year following the contact for elevated ESR was 8.5% [95% confidence interval (CI), 8.1%–8.9%]. The overall 1-year cancer incidence was markedly elevated [SIR 5.3 (95% CI, 5.1–5.6); aHR 5.8 (95% CI, 5.4–6.3)] and was more than 3-fold elevated for most hematologic cancers and for cancers of the peritoneum and connective tissue in the abdominal wall, kidney, and adrenal glands. After the first year, patients were at increased risk of developing especially hematologic cancers. Patients diagnosed with cancer within 1 year after a contact for elevated ESR had poorer survival compared with matched cancer comparisons [adjusted mortality rate ratio 1.2 (95% CI, 1.1–1.3)].

Conclusions:

Elevated ESR is a strong marker of undiagnosed cancer and is associated with poorer survival.

Impact:

Our findings may help clinicians in assessing absolute risk, common sites, and prognosis of cancers discovered after hospital contact with elevated ERS.
DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway
Authors: Adam Liana , San Lucas F. Anthony , Fowler Richard , Yu Yao , Wu Wenhui , Liu Yulun , Wang Huamin , Menter David , Tetzlaff Michael T. , Ensor Joe , Manyam Ganiraju , Arold Stefan T. , Huff Chad , Kopetz Scott , Scheet Paul , Overman Michael J.
Published: October 2018

Purpose:

Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.

Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays.

Results:

WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, P = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50 < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type ERBB2 model.

Conclusions:

The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.
Therapeutic Potential of Focal Adhesion Kinase Inhibition in Small Cell Lung Cancer
Authors: Aboubakar Nana Frank , Lecocq Marylène , Ladjemi Maha Zohra , Detry Bruno , Dupasquier Sébastien , Feron Olivier , Massion Pierre P. , Sibille Yves , Pilette Charles , Ocak Sebahat
Published: October 2018

Small cell lung cancer (SCLC) has a poor prognosis. Focal adhesion kinase (FAK) is a non–receptor tyrosine kinase regulating cell proliferation, survival, migration, and invasion, which is overexpressed and/or activated in several cancers, including SCLC. We wanted to determine whether FAK contributes to SCLC aggressive behavior. We first evaluated the effect of FAK small-molecule inhibitor PF-573,228 in NCI-H82, NCI-H146, NCI-H196, and NCI-H446 SCLC cell lines. PF-573,228 (0.1–5 μmol/L) inhibited FAK activity by decreasing phospho-FAK (Tyr397), without modifying total FAK expression. PF-573,228 decreased proliferation, decreased DNA synthesis, induced cell-cycle arrest in G2–M phases, and increased apoptosis in all cell lines. PF-573,228 also decreased motility in adherent cell lines. To make sure that these effects were not off-target, we then used a genetic method to inhibit FAK in NCI-H82 and NCI-H446, namely stable transduction with FAK shRNA and/or FAK-related nonkinase (FRNK), a splice variant lacking the N-terminal and kinase domains. Although FAK shRNA transduction decreased total and phospho-FAK (Tyr397) expression, it did not affect proliferation, DNA synthesis, or progression through cell cycle. However, restoration of FAK-targeting (FAT) domain (attached to focal adhesion complex where it inhibits pro-proliferative proteins such as Rac-1) by FRNK transduction inhibited proliferation, DNA synthesis, and induced apoptosis. Moreover, although FAK shRNA transduction increased active Rac1 level, FRNK reexpression in cells previously transduced with FAK shRNA decreased it. Therefore, FAK appears important in SCLC biology and targeting its kinase domain may have a therapeutic potential, while targeting its FAT domain should be avoided to prevent Rac1-mediated protumoral activity.
Binaural Perception in Single-Sided Deaf Cochlear Implant Users with Unrestricted or Restricted Acoustic Hearing in the Non-Implanted Ear
Authors: Dorbeau Camille , Galvin John , Fu Qian-Jie , Legris Elsa , Marx Mathieu , Bakhos David
Published: October 2018

Cochlear implantation (CI) can benefit patients with single-sided deafness (SSD) in terms of sound localization, speech understanding in noise, tinnitus severity, and quality of life (QoL). In previous studies, CI outcomes have been largely reported for SSD patients with normal “unrestricted” hearing in the contralateral ear. However, SSD patients may often have some degree of hearing loss in the contralateral ear (“restricted” acoustic hearing). In this study, we report results from a French clinical trial for CI in in SSD patients (NCT02204618). Localization, speech reception thresholds (SRTs) in noise, tinnitus severity, and QoL were evaluated in 18 SSD patients 1 year after CI. Data were analyzed for 2 subject groups according to the pure-tone average thresholds in the non-implanted ear: unrestricted acoustic hearing (UNRES; ≤25 dB HL; n = 10) and restricted acoustic hearing (RES; > 25 dB HL; n = 8). Across all subjects, localization was significantly better with the CI on than off (p = 0.005); there was no significant difference between subject groups (p = 0.301). When speech and noise were co-located (S0N0), there was no significant difference in SRTs with the CI on or off (p = 0.480); SRTs were significantly better for the UNRES than for the RES group (p = 0.005). When speech and noise were spatially separated (SCINNH), SRTs were significantly better with the CI on than off (p < 0.001). While SRTs were better for the UNRES than for the RES group (p = 0.024), the CI benefit was more than 50% greater for the RES group due to the restoration of high-frequency speech cues. Questionnaire data showed that tinnitus severity was significantly reduced (p = 0.045) and QoL was significantly improved after one year of experience with the CI (p < 0.001). Age at testing was significantly correlated with SRTs for the S0N0 condition; duration of deafness was correlated with SRTs for the SCINNH condition. There were relatively few correlations between behavioral and subjective measures, suggesting that both were valuable when assessing CI benefits for SSD patients. The present data suggest that indications for CI should be expanded to include unilaterally deaf patients who have normal hearing or mild-to-moderate hearing loss in the non-implanted ear.
Childhood Obesity and Impact on the Kidney
Authors: Correia-Costa Liane , Azevedo Ana , Caldas Afonso Alberto
Published: October 2018

Obesity is known to be associated with a myriad of cardiovascular and metabolic comorbidities. In children, several longitudinal studies have shown that obesity consequences start early in life and accompany the obese child into adulthood, implying a higher risk of adverse cardiovascular events. More recently, data related to the possible role of obesity in the risk of kidney disease in adults, independently of diabetes, has started to become more available. In children, the evidence is scarcer, but it has also been acknowledged that obesity acts as a risk factor for disease progression when kidney impairment already exists, thereby increasing the risk of death among children with end-stage renal disease (ESRD). Besides this, there is also evidence that otherwise healthy overweight and obese children have a significant increase in the risk of all-cause ESRD later in life. The potential mechanisms underlying this association need to be further discussed in order to allow the setting in motion of preventive strategies to halt chronic kidney disease development and progression.
The Value of Autopsy in Neonates in the 21st Century
Authors: de Sévaux Joline L.H. , Nikkels Peter G.J. , Lequin Maarten H. , Groenendaal Floris
Published: October 2018

Background: Autopsy rates in neonatal intensive care unit (NICU) patients who died are declining worldwide. Postmortem magnetic resonance imaging (MRI) is suggested as adjunct to or substitute for autopsy. Objective: The aim of this paper was to determine the additional diagnostic value of autopsy in NICU patients and whether autopsy findings were potentially detectable using postmortem MRI. Methods: From 2008 to 2015, 298 infants died during admission to our NICU. Permission for unrestricted, nonforensic autopsy was obtained in 100 (33.6%) of these 298 infants. Retrospectively, autopsy reports and medical records of NICU patients were compared. Additional autopsy findings were graded according to the Goldman system, grading the clinical relevance of additional findings. In addition, the potential detectability of these additional findings on postmortem MRI was assessed. Results: Additional findings obtained by autopsy were found in 48% of the cases, divided into major (Goldman I/II, 24%) and minor (Goldman III/IV, 24%) additional findings. Major additional findings were significantly more often found in patients with a lower gestational age, and minor additional findings in patients with a higher postnatal age at death. Of all patients with additional findings determined by autopsy, 56.3% would most likely not have been detected using postmortem MRI. Conclusions: Our results emphasize the still very important role of autopsy in the NICU setting and show that conventional autopsy could probably not be completely substituted by postmortem MRI.
Eco-Pap: The Ecological Modification of the Papanicolaou Stain for Sustainable Cervical Cancer Diagnosis
Authors: Moya-Salazar Jeel , Rojas-Zumaran Víctor
Published: October 2018

Objectives: To validate the ecological modification of the Papanicolaou stain (Eco-Pap) for the diagnosis of cervical cancer. Study Design: A prospective study was performed at the Mother and Child “San Bartolomé” Hospital, Lima, Peru. Reagent handling strategies were divided into three phases: we used (1) Harris progressive hematoxylin (for nuclear staining), (2) a polychromatic solution (a mix of EA-36/Orange G-6 to suppress the use of several alcohol baths), and (3) direct mounting (with Entellan® solution). The cellular details were analyzed by the staining quality index, an external quality control, and the Bethesda System 2014. Results: We evaluated 72,901 cervical smears stained with the Eco-Pap. The validation of the Eco-Pap against the conventional Pap stain was optimal (κ = 0.89; 95% CI: 0.87–0.92), showing a sensibility and specificity of 88.3% (95% CI: 85.1–90.0) and 98.7% (95% CI: 98–99.2), respectively. The Eco-Pap dramatically reduced the environmental pollution caused by 72 L of xylene, hydrochloric acid, and ammonia (6 L each) and mercury oxide. Conclusion: The Eco-Pap is an innovative and efficient staining method reducing the use of toxic reagents with carcinogenic potential during cervical cancer screening by exfoliative cytology.
Doxapram Treatment and Diaphragmatic Activity in Preterm Infants
Authors: de Waal Cornelia G. , Hutten Gerard J. , Kraaijenga Juliette V. , de Jongh Frans H. , van Kaam Anton H.
Published: October 2018

Background: Doxapram is a treatment option for severe apnea of prematurity (AOP). However, the effect of doxapram on the diaphragm, the main respiratory muscle, is not known. Objectives: To investigate the effect of doxapram on diaphragmatic activity measured with transcutaneous electromyography of the diaphragm (dEMG). Methods: A pilot study was conducted in a tertiary neonatal intensive care unit. Diaphragmatic activity was measured from 30 min before up to 3 h after the start of doxapram treatment. dEMG parameters were compared to baseline (5 min before doxapram treatment) and at 15, 60, 120 and 180 min after the start of doxapram infusion. Results: Eleven preterm infants were included with a mean gestational age of 25.5 ± 1.2 weeks and birth weight of 831 ± 129 g. The amplitudedEMG, peakdEMG and tonicdEMG values did not change in the 3 h after the start of doxapram infusion compared to baseline. Clinically, the number of apnea episodes in the 24 h after doxapram treatment decreased significantly. Conclusion: Doxapram infusion does not alter diaphragmatic activity measured with transcutaneous dEMG in preterm infants with AOP, indicating that its working mechanism is primarily on respiratory drive and not on respiratory muscle activity.
Anti-Erosive Effect of Solutions Containing Sodium Fluoride, Stannous Chloride, and Selected Film-Forming Polymers
Authors: Bezerra Sávio J.C. , João-Souza Samira H. , Aoki Idalina V. , Borges Alessandra B. , Hara Anderson T. , Scaramucci Taís
Published: October 2018

The aim of this study was to evaluate the anti-erosive effect of solutions containing sodium fluoride (F: 225 ppm F–), stannous chloride (Sn: 800 ppm Sn2+), and some film-forming polymers (Gantrez: Poly [methylvinylether-alt-maleic anhydride]; PGA: propylene glycol alginate; Plasdone: poly[vinylpyrrolidone]; and CMC: carboxymethylcellulose). Solutions were tested in an erosion-remineralization cycling model, using enamel and dentin specimens (n = 10, for each substrate). Distilled water was the negative control. Cycling consisted of 120 min immersion in human saliva, 5 min in 0.3% citric acid solution, and 120 min of exposure to human saliva, 4×/day, for 5 days. Treatment with solutions (pH = 4.5) was carried out 2×/day, for 2 min. Surface loss (SL) was evaluated with optical profilometry. Zeta potential of hydroxyapatite crystals was determined after treatment with the solutions. Data were statistically analyzed (α = 0.05). For enamel, all polymers showed significantly lower SL (in µm) than the control (11.09 ± 0.94), except PGA (10.15 ± 1.25). PGA significantly improved the protective effect of F (4.24 ± 0.97 vs. 5.64 ± 1.60, respectively). None of the polymers increased the protection of F+Sn (5.13 ± 0.78). For dentin, only Gantrez (11.40 ± 0.97) significantly reduced SL when compared with the negative control (12.76 ± 0.75). No polymer was able to enhance the effect of F (6.28 ± 1.90) or F+Sn (7.21 ± 1.13). All fluoridated solutions demonstrated significantly lower SL values than the control for both substrates. Treatment of hydroxyapatite nanoparticles with all solutions resulted in more negative zeta potentials than those of the control, except Plasdone, PGA, and F+Sn+PGA, the latter two presenting the opposite effect. In conclusion, Gantrez, Plasdone, and CMC exhibited an anti-erosive effect on enamel. PGA increased the protection of F. For dentin, only Gantrez reduced erosion.
Chronic Hyperkalemia in Cardiorenal Patients: Risk Factors, Diagnosis, and New Treatment Options
Authors: Di Lullo Luca , Ronco Claudio , Granata Antonio , Paoletti Ernesto , Barbera Vincenzo , Cozzolino Mario , Ravera Maura , Fusaro Maria , Bellasi Antonio
Published: October 2018

Chronic hyperkalemia (HK) is a serious medical condition that often manifests in patients with chronic kidney disease (CKD) and heart failure (HF) leading to poor outcomes and necessitating careful management by cardionephrologists. CKD, HF, diabetes, and renin-angiotensin-aldosterone system inhibitors use is known to induce HK. Current therapeutic options are not optimal, as pointed out by a large number of CKD and HF patients with HK. The following review will focus on the main risk factors for developing HK and also aims to provide a guide for a correct diagnosis and present new approaches to therapy.
Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse
Authors: Liu Anlong , Zhang Han , Qin Fenfen , Wang Qisheng , Sun Qinmei , Xie Shuwu , Wang Qian , Tang Zongxiang , Lu Zhigang
Published: October 2018

Background/Aims: Opiates are potent analgesics but their clinical use is limited by sex-associated side effects, such as drug tolerance, opioid-induced hyperalgesia and withdrawal reaction. OPRM1, as the main receptor of opioids, plays an important role in the pharmacological process of opioids in rodents and human. We have previously investigated OPRM1, the μ opioid receptor gene, which have dozens of alternatively spliced variants probably correlating with opioid-induced effects in brain regions of four inbred mouse strains and demonstrated the strain-specific expressions of these splice variants. Also, within a strain, the regional expression patterns of some of the variants were similar while others were opposite. Thus, we are aiming to seek out the relationship between sex differences and these alternatively spliced variants. Methods: The present studies follow a SYBR green quantitative PCR (qPCR) which we had used before to examine the expression of OPRM1 splice variant mRNAs in selected brain regions of male and female C57BL/6 mice. Sex-associated differences in baseline latency, opioid-induced tolerance, analgesia and addiction were examined and determined by Tail-flick test, jumps and statistical analysis. Results: The mRNA levels of opioid receptor gene splice variants in male and female mice showed significant differences among the brain regions, implying region-specific alternative splicing of the OPRM1 gene, which was consistent with our previous study. More importantly, the complete mRNA expression profiles of the OPRM1 splice variants was also gender-specific, suggesting a sexual influence on OPRM1 alternative splicing. Conclusion: In brief, we put forward that the distinctions among baseline latency, opioid-induced tolerance, analgesia and physical dependence in male and female mice might correlate with sex associated differential expressions of OPRM1 gene.
Nell-1 Enhances Osteogenic Differentiation of Pre-Osteoblasts on Titanium Surfaces via the MAPK-ERK Signaling Pathway
Authors: Shen Mei-jie , Wang Ge-ge , Wang Yu-zhen , Xie Jing , Ding Xi 
Published: October 2018

Background/Aims: This study aimed to investigate the effect of Nell-1 on the osteogenic behaviors of pre-osteoblasts on titanium (Ti) surfaces and to identify the underlying signaling pathway. Methods: Nell-1 at different concentrations was added to culture medium to stimulate MC3T3-E1 subclone 14 on Ti surfaces. A CCK-8 colorimetric assay was used to detect cell proliferation. Alkaline phosphatase activity (ALP) assay and enzyme-linked immunosorbent assay (ELISA) were used to evaluate ALP activity and the osteocalcin (OCN) secretion, respectively. Indicators of osteoblastic differentiation were assessed using real-time polymerase chain reaction analysis (RT-PCR). Western blot (WB) assay was used to analyze the expression changes of the osteogenic proteins and the mitogen-activated protein kinase (MAPK) pathway. Results: Nell-1 significantly increased the osteogenic gene and protein expression levels of ALP, OCN, Runx2, osteoprotegerin (OPG), collagen type I (Col-I), and Osterix (Osx) in pre-osteoblasts on Ti surfaces. The optimal concentration of Nell-1 was 100 ng/ ml. In addition, Nell-1 activated ERK and JNK, but not P38, in MC3T3-E1 cells on the Ti surface. Except for ALP and Col-I, the promotive effects of Nell-1 on the expression of osteogenic markers were suppressed by ERK inhibitor U0126. Conclusion: Certain concentrations of Nell-1 can promote the osteogenic differentiation of pre-osteoblasts on Ti surfaces by activating the MAPK/ERK signaling pathway.
Palmitate Induces an Anti-Inflammatory Response in Immortalized Microglial BV-2 and IMG Cell Lines that Decreases TNFα Levels in mHypoE-46 Hypothalamic Neurons in Co-Culture
Authors: Kim Stephanie M. , McIlwraith Emma K. , Chalmers Jennifer A. , Belsham Denise D.
Published: October 2018

Background and Objectives: Elevated levels of saturated fatty acids (SFA) induce a state of neuroinflammation in the hypothalamus. It has been suggested that microglia sense palmitate, a prevalent circulating SFA, and act as mediators of this inflammatory process by communicating with neurons, particularly those involved in appetite regulation. In this study, we examined the inflammatory response to palmitate in immortalized microglial cell lines, BV-2 and IMG, and the subsequent effects on inflammatory gene expression in a model of NPY/AgRP neurons, mHypoE-46. Methods: The BV-2 cells were treated with 50 µM palmitate for 4 and 24 h, and the transcriptional regulation of markers for inflammation and cellular stress was assessed using an RT2 Profiler PCR Array. Select genes were verified with qRT-PCR. The BV-2 and IMG cells were then co-cultured using 1.0-µm cell culture inserts with an immortalized hypothalamic cell line, mHypoE-46, to investigate potential intercellular communication between microglia and neurons. Results: We found that palmitate increased the mRNA levels of specific inflammatory genes, and a general anti-inflammatory profile was revealed in the microglia cells. The mRNA changes in TNFα at 4 and 24 h in BV-2 cells were abrogated with the toll-like receptor 4 (TLR4) inhibitor, TAK-242, indicating the involvement of TLR4. Co-culture of mHypoE-46 neurons with microglia pre-treated with palmitate resulted in repression of TNFα expression in the hypothalamic neurons. As palmitate significantly increased IL-13 expression in microglia, the effect of this cytokine was tested in mHypoE-46 neurons. The addition of IL-13 to neuronal cultures normalized the palmitate-mediated increase in IL-6 and AgRP expression, suggesting that microglia may protect surrounding neurons, at least in part, through the release of IL-13. Conclusions: These results suggest a potential anti-inflammatory role of microglia towards the palmitate-induced neuroinflammation, and potentially energy homeostasis, in hypothalamic neurons.
Targeted Alpha Particle Therapy for Neuroendocrine Tumours: The Next Generation of Peptide Receptor Radionuclide Therapy
Authors: Navalkissoor Shaunak , Grossman Ashley
Published: October 2018

Neuroendocrine tumours (NETs) are being seen increasingly frequently, but to date only complete surgical resection is curative. However, among the various therapeutic options, peptide receptor radionuclide therapy, linking a radioactive moiety to an octreotide derivative, has been shown to be highly efficacious and a well-tolerated therapy, improving progression-free survival and probably overall survival. Nevertheless, the current radionuclides in use are beta particle emitters with non-optimal radiobiological properties. A new generation of alpha particle-emitting radionuclides is being developed, with advantages in terms of very high energy and a short path length, which should theoretically show higher efficacy. We survey the current developments in this field, emphasising the exciting potential of this novel form of therapy for NETs.
Emergency Department Volume and Outcomes for Patients After Chest Pain Assessment
Authors: Ko Dennis T. , Dattani Neil D. , Austin Peter C. , Schull Michael J. , Ross Joseph S. , Wijeysundera Harindra C. , Tu Jack V. , Eberg Maria , Koh Maria , Krumholz Harlan M.
Published: October 2018

Background:

Chest pain is one of the most common reasons for emergency department (ED) visits in developed countries. Whether higher volume EDs have better outcomes, specifically for patients with chest pain, is unknown and pertinent.

Methods and Results:

We conducted a study using population-based data on 498 291 patients ≥40 years old, presenting to ED in Ontario, Canada from 2008 to 2014, with chest pain and were discharged after assessment. We evaluated processes of care after discharge from ED. The primary outcome was a composite of all-cause death or hospitalization for acute coronary syndrome. Hierarchical logistic regression models adjusting for potential confounding variables were used to evaluate the association of annual ED chest pain volume and outcome. We also determined if there was a volume threshold above which an increased ED volume was not associated with a lower adverse outcome. The mean age of our patients was 59 years, 46.7% were men, and 20% had diabetes mellitus. Patients discharged from higher volume EDs had higher rates of cardiologist consultations, cardiac medication use, and cardiac testing within 30 days of ED assessment. Higher ED volume was associated with significantly lower adjusted odds ratio for mortality or acute coronary syndrome (odds ratio, 0.87; 95% CI, 0.82–0.92 per each unit increase in the log of volume) at 30 days and at 1 year (odds ratio, 0.92; 95% CI, 0.88–0.92). Once the annual ED chest pain volume reached 1400 cases (95% CI, 910–1900), an increase of annual chest pain volume of 100 was associated with relative decrease in the odds of the composite outcome at 30 days of <1%.

Conclusions:

Evaluations of chest pain in EDs with higher chest pain volume had lower rates of death or hospitalizations for acute coronary syndrome. There was a volume threshold above which an increase in volume was no longer associated with reduced outcomes.
Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models
Authors: Kim Kyeongdae , Shim Dahee , Lee Jun Seong , Zaitsev Konstantin , Williams Jesse W. , Kim Ki-Wook , Jang Man-Young , Seok Jang Hyung , Yun Tae Jin , Lee Seung Hyun , Yoon Won Kee , Prat Annik , Seidah Nabil G. , Choi Jungsoon , Lee Seung-Pyo , Yoon Sang-Ho , Nam Jin Wu , Seong Je Kyung , Oh Goo Taeg , Randolph Gwendalyn J. , Artyomov Maxim N. , Cheong Cheolho , Choi Jae-Hoon
Published: October 2018

Rationale:

Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis.

Objective:

We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima.

Methods and Results:

Single-cell RNA sequencing analysis of CD45
+
leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining–based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPY
hi
SSC
hi
foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1β and many other inflammatory transcripts in atherosclerotic aorta.

Conclusions:

RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.
Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential
Authors: Skye Sarah M. , Zhu Weifei , Romano Kymberleigh A. , Guo Chun-Jun , Wang Zeneng , Jia Xun , Kirsop Jennifer , Haag Bridget , Lang Jennifer M. , DiDonato Joseph A. , Tang W.H. Wilson , Lusis Aldons J. , Rey Federico E. , Fischbach Michael A. , Hazen Stanley L.
Published: October 2018

Rationale:

Gut microbes influence cardiovascular disease and thrombosis risks through the production of trimethylamine N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA)—the precursor to TMAO—is rate limiting in the metaorganismal TMAO pathway in most humans and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the
cutC/D
(choline utilization C/D) genes in multiple human commensals.

Objective:

Direct demonstration that the gut microbial
cutC
gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported.

Methods and Results:

Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial
cutC
-dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its
cutC
gene (ie,
Clostridium sporogenes
Δ
cutC
).

Conclusions:

Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.