bluuebunny/crossref_metadata_2025 huggingface dataset:
Marker-Assisted Gene Pyramiding and the Reliability of Using SNP Markers Located in the Recombination Suppressed Regions of Sunflower (Helianthus annuus L.)
Authors: Qi Lili , Ma Guojia
Published: December 2019

Rust caused by the fungus Puccinia helianthi and downy mildew (DM) caused by the obligate pathogen Plasmopara halstedii are two of the most globally important sunflower diseases. Resistance to rust and DM is controlled by race-specific single dominant genes. The present study aimed at pyramiding rust resistance genes combined with a DM resistance gene, using molecular markers. Four rust resistant lines, HA-R3 (carrying the R4 gene), HA-R2 (R5), HA-R8 (R15), and RHA 397 (R13b), were each crossed with a common line, RHA 464, carrying a rust gene R12 and a DM gene PlArg. An additional cross was made between HA-R8 and RHA 397. Co-dominant simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers linked to the target genes were used to discriminate between homozygotes and heterozygotes in F2 populations. Five pyramids with different combinations of rust resistance genes were selected in the homozygous condition through marker-assisted selection, and three of them were combined with a DM resistance gene PlArg: R4/R12/PlArg, R5/R12/PlArg, R13b/R12/PlArg, R15/R12, and R13b/R15. The pyramiding lines with the stacking of two rust and one DM genes were resistant to all known races of North American sunflower rust and all known races of the pathogen causing DM, potentially providing multiple and durable resistance to both rust and DM. A cluster of 12 SNP markers spanning a region of 34.5 Mb on chromosome 1, which co-segregate with PlArg, were tested in four populations. Use of those markers, located in a recombination suppressed region in marker selection, is discussed.
Cell-Free DNA Methylation: The New Frontiers of Pancreatic Cancer Biomarkers’ Discovery
Authors: Brancaccio Mariarita , Natale Francesco , Falco Geppino , Angrisano Tiziana
Published: December 2019

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancer types world-wide. Its high mortality is related to the difficulty in the diagnosis, which often occurs when the disease is already advanced. As of today, no early diagnostic tests are available, while only a limited number of prognostic tests have reached clinical practice. The main reason is the lack of reliable biomarkers that are able to capture the early development or the progression of the disease. Hence, the discovery of biomarkers for early diagnosis or prognosis of PDAC remains, de facto, an unmet need. An increasing number of studies has shown that cell-free DNA (cfDNA) methylation analysis represents a promising non-invasive approach for the discovery of biomarkers with diagnostic or prognostic potential. In particular, cfDNA methylation could be utilized for the identification of disease-specific signatures in pre-neoplastic lesions or chronic pancreatitis (CP), representing a sensitive and non-invasive method of early diagnosis of PDAC. In this review, we will discuss the advantages and pitfalls of cfDNA methylation studies. Further, we will present the current advances in the discovery of pancreatic cancer biomarkers with early diagnostic or prognostic potential, focusing on pancreas-specific (e.g., CUX2 or REG1A) or abnormal (e.g., ADAMTS1 or BNC1) cfDNA methylation signatures in high risk pre-neoplastic conditions and PDAC.
Effects of Physical Self-Concept, Emotional Isolation, and Family Functioning on Attitudes towards Physical Education in Adolescents: Structural Equation Analysis
Authors: Padial-Ruz Rosario , Pérez-Turpin José Antonio , Cepero-González Mar , Zurita-Ortega Félix
Published: December 2019

(1) Background: The present research seeks to define and contrast an explanatory model of physical self-concept, emotional isolation, attitude towards physical education, and family functioning, and analyse the existing associations between these variables. (2) Methods: The sample was made up of 2388 adolescents (43.39% male and 56.61% female), with ages of 11–17 years (M = 13.85; SD = 1.26) from Spain. Self-concept (AF-5), Isolation (UCLA), Attitude towards Physical Education (CAEF), and Family Functioning (APGAR) were analyzed. (3) Results: Good fit was obtained for all evaluation indices included in the structural equation model, which was significantly adjusted (χ2 = 233,023; DF = 14; p < 0.001; comparative fit index (CFI) = 0.913; normalized fit index (NFI) = 0.917; incremental fit index (IFI) = 0.906; root mean square error of approximation (RMSEA) = 0.072). (4) Conclusions: Attitudes towards physical activity were found to be positive when isolation levels were low and where adequate self-concept existed, specifically in students reporting high family functioning.
Canyoning Accidents in Austria from 2005 to 2018
Authors: Ströhle Mathias , Beeretz Ina , Rugg Christopher , Woyke Simon , Rauch Simon , Paal Peter
Published: December 2019

Canyoning has become a popular recreational sport. Nevertheless, little is known about injuries or diseases associated with canyoning. The aim of this study was to examine accident causes, injury patterns, out-of-hospital and in-hospital treatment and outcomes. For this purpose, national out-of-hospital data from the Austrian Alpine Safety Board and regional in-hospital data from Innsbruck Medical University Hospital were analysed for the period from November 1, 2005 to October 31, 2018. Nationally, 471 persons were involved in such accidents; 162 (34.4%) were severely injured, nine of whom died. Jumping (n = 110, 23.4%), rappelling (n = 51, 10.8%), sliding (n = 41, 8.7%) and stumbling (n = 26, 5.5%) were the most common causes of canyoning accidents. A large proportion of injuries were documented for the lower extremities (n = 133, 47.5%), followed by the upper extremities (n = 65, 23.2%) and the spine (n = 44, 15.7%). Death was mainly caused by drowning. Overall mortality was 1.9% (n = 9), and the absolute risk was 0.02 deaths per 1000 hrs of canyoning. Many uninjured persons required evacuation (n = 116, 24.6%), which resulted in a substantial expense and workload for emergency medical services. Increased safety precautions are required to reduce accidents while jumping and rappelling and fatalities caused by drowning.
Feasibility, Safety and Efficacy of a Virtual Reality Exergame System to Supplement Upper Extremity Rehabilitation Post-Stroke: A Pilot Randomized Clinical Trial and Proof of Principle
Authors: Norouzi-Gheidari Nahid , Hernandez Alejandro , Archambault Philippe S. , Higgins Johanne , Poissant Lise , Kairy Dahlia
Published: December 2019

(1) Background: Increasing the amount of therapy time has been shown to improve motor function in stroke survivors. However, it is often not possible to increase the amount of therapy time provided in the current one-on-one therapy models. Rehabilitation-based virtual reality exergame systems, such as Jintronix, can be offered to stroke survivors as an adjunct to traditional therapy. The goal of this study was to examine the safety and feasibility of providing additional therapy using an exergame system and assess its preliminary clinical efficacy. (2) Methods: Stroke survivors receiving outpatient rehabilitation services participated in this pilot randomized control trial in which the intervention group received 4 weeks of exergaming sessions in addition to traditional therapy sessions. (3) Results: Nine subjects in the intervention and nine subjects in the control group completed the study. The intervention group had at least two extra sessions per week, with an average duration of 44 min per session and no serious adverse events (falls, dizziness, or pain). The efficacy measures showed statistically meaningful improvements in the activities of daily living measures (i.e., MAL-QOM (motor activity log-quality of movement) and both mobility and physical domains of the SIS (stroke impact scale) with mean difference of 1.0%, 5.5%, and 6.7% between the intervention and control group, respectively) at post-intervention. (4) Conclusion: Using virtual reality exergaming technology as an adjunct to traditional therapy is feasible and safe in post-stroke rehabilitation and may be beneficial to upper extremity functional recovery.
The Effects of a Forest Therapy Programme on Mental Hospital Patients with Affective and Psychotic Disorders
Authors: Bielinis Ernest , Jaroszewska Aneta , Łukowski Adrian , Takayama Norimasa
Published: December 2019

The positive effect of forest bathing on the mental health and wellbeing of those suffering from post-traumatic stress disorder or experiencing stress has been proven. It is not known, however, how ‘forest therapy’ affects the mental health of people who are treated in a psychiatric hospital for affective or psychotic disorders. Potentially, forest therapy could bring many benefits to these people. To test the potential effectiveness of this therapy, a quasi-experiment was carried out in a psychiatric hospital in Olsztyn (north Poland). In the summer and autumn of 2018, the patients of the psychiatric hospital in Olsztyn participated in forest therapy interventions. The proposed forest therapy consisted of participating in one hour and forty-five minutes walks under the supervision of a therapist. Subjects filled out the Profile of Mood States Questionnaire (POMS) and the State Trait Anxiety Inventory (STAI-S) before and after the study. In the case of a group of patients with affective disorders, forest therapy had a positive effect on nearly all POMS scale subscales, with the exception of the ‘anger–hostility’ subscale, which did not change its values significantly after the intervention. In these patients, the greatest impacts were noted in the subscales ‘confusion’ and ‘depression–dejection’; the level of anxiety measured with the STAI-S scale also significantly decreased. In the case of patients with psychotic disorders, the values of the ‘confusion’ and ‘vigour’ subscales and the STAI-S scale exhibited the greatest changes. These changes were positive for the health of patients. Regarding the ‘fatigue’ subscale, no significant changes were observed in patients with psychotic disorders. The observed changes in psychological indicators in psychiatric hospital patients with both kinds of disorders indicate that the intervention of forest therapy can positively affect their mental health. The changes observed in psychological indicators were related to the characteristics of the given disorder.
Does Neuraxial Anesthesia as General Anesthesia Damage DNA? A Pilot Study in Patients Undergoing Orthopedic Traumatological Surgery
Authors: Kucharova Monika , Astapenko David , Zubanova Veronika , Koscakova Maria , Stetina Rudolf , Zadak Zdenek , Hronek Miloslav
Published: December 2019

The human organism is exposed daily to many endogenous and exogenous substances that are the source of oxidative damage. Oxidative damage is one of the most frequent types of cell component damage, leading to oxidation of lipids, proteins, and the DNA molecule. The predominance of these damaging processes may later be responsible for human diseases such as cancer, neurodegenerative disease, or heart failure. Anesthetics undoubtedly belong to the group of substances harming DNA integrity. The goal of this pilot study is to evaluate the range of DNA damage by general and neuraxial spinal anesthesia in two groups of patients undergoing orthopedic traumatological surgery. Each group contained 20 patients, and blood samples were collected before and after anesthesia; the degree of DNA damage was evaluated by the comet assay method. Our results suggest that general anesthesia can cause statistically significant damage to the DNA of patients, whereas neuraxial anesthesia has no negative influence.
The Mitochondrial Small Heat Shock Protein HSP22 from Pea is a Thermosoluble Chaperone Prone to Co-Precipitate with Unfolding Client Proteins
Authors: Avelange-Macherel Marie-Hélène , Rolland Aurélia , Hinault Marie-Pierre , Tolleter Dimitri , Macherel David
Published: December 2019

The small heat shock proteins (sHSPs) are molecular chaperones that share an alpha-crystallin domain but display a high diversity of sequence, expression, and localization. They are especially prominent in plants, populating most cellular compartments. In pea, mitochondrial HSP22 is induced by heat or oxidative stress in leaves but also strongly accumulates during seed development. The molecular function of HSP22 was addressed by studying the effect of temperature on its structural properties and chaperone effects using a recombinant or native protein. Overexpression of HSP22 significantly increased bacterial thermotolerance. The secondary structure of the recombinant protein was not affected by temperature in contrast with its quaternary structure. The purified protein formed large polydisperse oligomers that dissociated upon heating (42 °C) into smaller species (mainly monomers). The recombinant protein appeared thermosoluble but precipitated with thermosensitive proteins upon heat stress in assays either with single protein clients or within complex extracts. As shown by in vitro protection assays, HSP22 at high molar ratio could partly prevent the heat aggregation of rhodanese but not of malate dehydrogenase. HSP22 appears as a holdase that could possibly prevent the aggregation of some proteins while co-precipitating with others to facilitate their subsequent refolding by disaggregases or clearance by proteases.
Functional Analysis of preA in Aeromonas veronii TH0426 Reveals a Key Role in the Regulation of Virulence and Resistance to Oxidative Stress
Authors: Yang Bintong , Song Haichao , An Dingjie , Zhang Dongxing , Raza Sayed Haidar Abbas , Wang Guiqin , Shan Xiaofeng , Qian Aidong , Kang Yuanhuan , Wang Chunfeng
Published: December 2019

Aeromonas veronii is one of the main pathogens causing freshwater fish sepsis and ulcer syndrome. This bacterium has caused serious economic losses in the aquaculture industry worldwide, and it has become an important zoonotic and aquatic agent. However, little is known about the molecular mechanism of pathogenesis of A. veronii. In this study, we first constructed an unmarked mutant strain (ΔpreA) by generating an in-frame deletion of the preA gene, which encodes a periplasmic binding protein, to investigate its role in A. veronii TH0426. Our results showed that the motility and biofilm formation ability of ΔpreA were similar to those of the wild-type strain. However, the adhesion and invasion ability in epithelioma papulosum cyprini (EPC) cells were significantly enhanced (2.0-fold). Furthermore, the median lethal dose (LD50) of ΔpreA was 7.6-fold higher than that of the wild-type strain, which illustrates that the virulence of the mutant was significantly enhanced. This finding is also supported by the cytotoxicity test results, which showed that the toxicity of ΔpreA to EPC cells was enhanced 1.3-fold relative to the wild type. Conversely, tolerance test results showed that oxidative stress resistance of ΔpreA decreased 5.9-fold compared to with the wild-type strain. The results suggest that preA may negatively regulate the virulence of A. veronii TH0426 through the regulation of resistance to oxidative stress. These insights will help to further elucidate the function of preA and understand the pathogenesis of A. veronii.
Modification of Luffa Sponge for Enrichment of Phosphopeptides
Authors: Dai Lili , Sun Zhe , Zhou Ping
Published: December 2019

The enrichment technique is crucial to the comprehensive analysis of protein phosphorylation. In this work, a facile, green and efficient synthetic method was set up for quaternization of luffa sponge. The resultant luffa sponge showed strong anion-exchange characteristics and a high adsorption ability for phosphate ions. Along with the unique physical properties, e.g., tenacity and porous texture, quaternized luffa sponge was demonstrated to be a well-suited solid-phase extraction (SPE) material. The quaternized luffa sponge-based SPE method was simple, cost-effective and convenient in operation, and was successfully applied to the capture of phosphopeptides from protein digests. The enrichment approach exhibited exceptionally high selectivity, sensitivity and strong anti-interference ability. Four phosphopeptides were still detected by using the digest mixture of β-casein and bovine serum albumin with a molar ratio of 1:100. 21 phosphopeptides were identified from the tryptic digest of non-fat milk.
Host- and Microbiota-Derived Extracellular Vesicles, Immune Function, and Disease Development
Authors: Macia Laurence , Nanan Ralph , Hosseini-Beheshti Elham , Grau Georges E.
Published: December 2019

Extracellular vesicles (EVs) are blebs of either plasma membrane or intracellular membranes carrying a cargo of proteins, nucleic acids, and lipids. EVs are produced by eukaryotic cells both under physiological and pathological conditions. Genetic and environmental factors (diet, stress, etc.) affecting EV cargo, regulating EV release, and consequences on immunity will be covered. EVs are found in virtually all body fluids such as plasma, saliva, amniotic fluid, and breast milk, suggesting key roles in immune development and function at different life stages from in utero to aging. These will be reviewed here. Under pathological conditions, plasma EV levels are increased and exacerbate immune activation and inflammatory reaction. Sources of EV, cells targeted, and consequences on immune function and disease development will be discussed. Both pathogenic and commensal bacteria release EV, which are classified as outer membrane vesicles when released by Gram-negative bacteria or as membrane vesicles when released by Gram-positive bacteria. Bacteria derived EVs can affect host immunity with pathogenic bacteria derived EVs having pro-inflammatory effects of host immune cells while probiotic derived EVs mostly shape the immune response towards tolerance.
The Inhibitory Effects of Gold Nanoparticles on VEGF-A-Induced Cell Migration in Choroid-Retina Endothelial Cells
Authors: Chan Chi-Ming , Hsiao Chien-Yu , Li Hsin-Ju , Fang Jia-You , Chang Der-Chen , Hung Chi-Feng
Published: December 2019

Background: Vascular endothelial growth factor (VEGF) is upregulated by hypoxia and is a crucial stimulator for choroidal neovascularization (CNV) in age-related macular degeneration and pathologic myopia, as well as retinal neovascularization in proliferative diabetic retinopathy. Retinal and choroidal endothelial cells play key roles in the development of retinal and CNV, and subsequent fibrosis. At present, the effects of gold nanoparticles (AuNPs) on the VEGF-induced choroid-retina endothelial (RF/6A) cells are still unknown. In our study, we investigated the effects of AuNPs on RF/6A cell viabilities and cell adhesion to fibronectin, a major ECM protein of fibrovascular membrane. Furthermore, the inhibitory effects of AuNPs on RF/6A cell migration induced by VEGF and its signaling were studied. Methods: The cell viability assay was used to determine the viability of cells treated with AuNPs. The migration of RF/6A cells was assessed by the Transwell migration assay. The cell adhesion to fibronectin was examined by an adhesion assay. The VEGF-induced signaling pathways were determined by western blotting. Results: The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay revealed no cytotoxicity of AuNPs on RF/6A cells. AuNPs inhibited VEGF-induced RF/6A cell migration in a concentration-dependent manner but showed no significant effects on RF/6A cell adhesion to fibronectin. Inhibitory effects of AuNPs on VEGF-induced Akt/eNOS were found. Conclusions: These results suggest that AuNPs are an effective inhibitor of VEGF-induced RF/6A cell migration through the Akt/eNOS pathways, but they have no effects on their cell viabilities and cell adhesion to fibronectin.
Design and Implementation of a Multi-Disaster Risk Assessment Database System in South Korea
Authors: Chai Su-Seong , Suh Dongjun
Published: December 2019

To cope with natural disasters and their impact, various types of risk assessment tools have been developed to assess hazards from a scientific point of view as well as the socioeconomic impacts of a hazardous event. Because most of the assessment tools have been developed using local and regional characteristics, there are limitations when applying special cases consisting of various disaster-related datasets in Korea. In this paper, we collected open data scattered among various institutions and guaranteed data interoperability through a standardization process considering various formats. In addition, this study presents a scalable design method and implementation of a database system which can be easily employed in Korean loss estimation due to natural hazards. The proposed database system will be of great help in predicting the disaster scale and degree of damage, in supporting decision-making to minimize damage, and could serve as a data platform of disaster risk reduction and prevention.
Online Plasma Diagnostics in the Remote Spectroscopy Laboratory for Practical Training and Experimental Research
Authors: Zimin Alexander , Shumov Andrey , Troynov Vladislav , Zemtsov Ivan
Published: December 2019

This paper deals with an integrated Internet-based education laboratory that allows both practical lab sessions and full-blown research projects to be carried out using state-of-the-art experimental facilities. The setup of a system that controls lab equipment via a global computer network is described, and a distributed hardware and software control facility supporting remote lab operations is considered in terms of its structural arrangement and component interaction. We present a computer-aided dispatch-and-information system that allows students to generate their own experiment scenarios, conduct experiments remotely, and store/process experimental results from their personal cabinets. We also discuss the peculiarities of developing a computerized system to support plasma spectroscopy hands-on education and research. Further emphasis is given to the laboratory modernization, regarding both hardware and result processing software.
Application of an Ecosystem Methodology Based on Legal Language Processing for the Transformation of Court Decisions and Legal Opinions into Open Data
Authors: Garofalakis John , Plessas Konstantinos , Plessas Athanasios , Spiliopoulou Panoraia
Published: December 2019

Regulation of modern societies requires the generation of large sets of heterogeneous legal documents: bills, acts, decrees, administrative decisions, court decisions, legal opinions, circulars, etc. More and more legal publishing bodies publish these documents online, although usually in formats that are not machine-readable and without following Open Data principles. Until an open by default generation and publication process is employed, ex-post transformation of legal documents into Legal Open Data is required. Since manual transformation is a time-consuming and costly process, automated methods need to be applied. While some research efforts toward the automation of the transformation process exist, the alignment of such approaches with proposed Open Data methodologies in order to promote data exploitation is still an open issue. In this paper, we present a methodology aligned to the Open Data ecosystem approach for the automated transformation of Greek court decisions and legal opinions into Legal Open Data that builds on legal language processing methods and tools. We show that this approach produces Legal Open Data of satisfying quality while highly reducing the need for manual intervention.
Determining Effects of Winter Weather Conditions on Adult Amblyomma americanum (Acari: Ixodidae) Survival in Connecticut and Maine, USA
Authors: Linske Megan , Williams Scott , Stafford Kirby , Lubelczyk Charles , Henderson Elizabeth , Welch Margret , Teel Peter
Published: December 2019

The lone star tick (Amblyomma americanum L.) is native to the United States, with its primary range encompassing the Southeast and portions of the Midwest. It is an aggressive ectoparasite that actively seeks out hosts through detection of carbon dioxide and vibrations and can transfer ehrlichiosis-causing bacteria as well as a carbohydrate that causes alpha-gal syndrome (red meat allergy) in humans. It has become of increasing concern as its range has recently expanded into coastal regions of the Northeast. Historically, harsh northeastern winter weather conditions made these areas inhospitable for A. americanum survival, but a warming climate coupled with increased host availability seem to have facilitated their range expansion. We developed a study to observe the effects of weather conditions on adult A. americanum overwintering survival. The study was conducted over three years in Connecticut and Maine. Ground-level conditions were manipulated to determine the effects of differing combinations of natural insulative barriers (leaf litter and snow accumulation) on adult A. americanum survival. We determined that there was a significant difference in survival between the two states, between years in Maine, and between sexes within Connecticut. However, presence or absence of snow and/or leaf litter had no impact on survival. Overall, we found a positive correlation between mean hourly temperature and adult survival in Maine, where temperatures were consistently below freezing. The results of this study can be included in an adaptive, predictive analytic model to accommodate the expected fluctuations and range expansion of A. americanum that will most likely accompany an increase in temperatures throughout the Northeast.
Interspecific Hybridization between the Two Sympatric Termite Reticulitermes Species under Laboratory Conditions
Authors: Wu Jia , Xu Huan , Hassan Ali , Huang Qiuying
Published: December 2019

Closely related species have similar reproductive behaviors and recognition systems, which contribute to interspecific interactions. However, few studies have explored interspecific reproduction choice and mating in termites. We investigated whether hybridization between two sympatric termites, Reticulitermes flaviceps and R. chinensis, occurs under laboratory conditions. We found that frequencies of acceptance were significantly higher than those of agonism between interspecific partners. There were no significant differences in frequencies of tandem and mating behaviors between intraspecific and interspecific partners. However, the allogrooming frequencies of interspecific partners were significantly higher than intraspecific partners. There were no significant differences in the duration of tandem, allogrooming, or mating behavior at each time between conspecific partners and heterospecfic partners. Genotyping analyses further showed that both intraspecific and interspecific mating were able to produce offspring. We conclude that interspecific hybridization does occur between two termite Reticulitermes species under laboratory conditions.
Lipophilicity of Bacteriochlorin-Based Photosensitizers as a Determinant for PDT Optimization through the Modulation of the Inflammatory Mediators
Authors: Pucelik Barbara , Arnaut Luis G. , Dąbrowski Janusz M.
Published: December 2019

Photodynamic therapy (PDT) augments the host antitumor immune response, but the role of the PDT effect on the tumor microenvironment in dependence on the type of photosensitizer and/or therapeutic protocols has not been clearly elucidated. We employed three bacteriochlorins (F2BOH, F2BMet and Cl2BHep) of different polarity that absorb near-infrared light (NIR) and generated a large amount of reactive oxygen species (ROS) to compare the PDT efficacy after various drug-to-light intervals: 15 min. (V-PDT), 3h (E-PDT) and 72h (C-PDT). We also performed the analysis of the molecular mechanisms of PDT crucial for the generation of the long-lasting antitumor immune response. PDT-induced damage affected the integrity of the host tissue and developed acute (protocol-dependent) local inflammation, which in turn led to the infiltration of neutrophils and macrophages. In order to further confirm this hypothesis, a number of proteins in the plasma of PDT-treated mice were identified. Among a wide range of cytokines (IL-6, IL-10, IL-13, IL-15, TNF-α, GM-CSF), chemokines (KC, MCP-1, MIP1α, MIP1β, MIP2) and growth factors (VEGF) released after PDT, an important role was assigned to IL-6. PDT protocols optimized for studied bacteriochlorins led to a significant increase in the survival rate of BALB/c mice bearing CT26 tumors, but each photosensitizer (PS) was more or less potent, depending on the applied DLI (15 min, 3 h or 72 h). Hydrophilic (F2BOH) and amphiphilic (F2BMet) PSs were equally effective in V-PDT (>80 cure rate). F2BMet was the most efficient in E-PDT (DLI = 3h), leading to a cure of 65 % of the animals. Finally, the most powerful PS in the C-PDT (DLI = 72 h) regimen turned out to be the most hydrophobic compound (Cl2BHep), allowing 100 % of treated animals to be cured at a light dose of only 45 J/cm2.
HCMV Infection in a Mesenchymal Stem Cell Niche: Differential Impact on the Development of NK Cells versus ILC3
Authors: Ising Ricarda , Weinhold Sandra , Bennstein Sabrina Bianca , Zimmermann Albert , Degistirici Özer , Kögler Gesine , Meisel Roland , Hengel Hartmut , Timm Jörg , Uhrberg Markus
Published: December 2019

Human cytomegalovirus (HCMV) is highly prevalent in most populations worldwide and has a major influence on shaping the human immune system. Natural killer (NK) cells are important antiviral effectors that adapt to HCMV infection by expansion of virus-specific effector/memory cells. The impact of HCMV infection on the development of NK cells and innate lymphoid cells (ILC) in general is less well understood. In this context, we have recently established a novel in vitro platform to study human NK cell development in a stem cell niche based on human bone marrow-derived mesenchymal stem cells (MSC). Here, the system was modified by infecting MSC with HCMV to study the influence of virus infection on NK/ILC development. We show that cord blood-derived hematopoietic progenitor cells are successfully differentiated into mature CD56+CD94+NKG2A+ NK cells on HCMV-infected MSC with significant higher anti-viral cytokine production compared to NK cells developing on non-infected MSC. Furthermore, the generation of ILC3, characterized by expression of the signature transcription factor RAR-related orphan receptor gamma (RORγt) and the production of IL-22, was strongly impaired by HCMV infection. These observations are clinically relevant, given that ILC3 are associated with protection from graft-versus-host disease (GvHD) following stem cell transplantation and HCMV reactivation in turn is associated with increased incidence of GvHD.
Effects of Encircled Abdominal Compression Device in Colonoscopy: A Meta-Analysis
Authors: Nishizawa Toshihiro , Suzuki Hidekazu , Higuchi Hajime , Ebinuma Hirotoshi , Toyoshima Osamu
Published: December 2019

Background and Aim: The efficacy of encircling abdominal compression devices in colonoscopies is inconsistent. We performed a meta-analysis of randomized controlled trials (RCTs) in which encircling abdominal compression devices were compared with control in colonoscopies. Methods: We systematically searched RCTs published in the Cochrane Library, PubMed, and the Igaku-Chuo-Zasshi database. The data from the eligible RCTs were combined using the random-effects model. The weighted mean differences (WMDs), pooled odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Results: Five RCTs were included in this meta-analysis. Compared to the control group, encircling abdominal compression devices significantly reduced the caecal intubation time (WMD: −1.31, 95% CI: −2.40 to −0.23, p = 0.02). Compared to the control group, encircling abdominal compression devices significantly decreased the frequency of postural change (OR 0.30, 95% CI: 0.22 to 0.41, p < 0.00001). Compared to the control group, the use of encircling abdominal compression devices significantly reduced the need for abdominal compression (OR: 0.35, 95% CI: 0.17 to 0.70, p = 0.003). Conclusions: Encircling abdominal compression devices in colonoscopies was found to reduce the caecal intubation time and the frequency of abdominal compression.
NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology
Authors: Rodriguez-Gil Jorge L. , Watkins-Chow Dawn E. , Baxter Laura L. , Yokoyama Tadafumi , Zerfas Patricia M. , Starost Matthew F. , Gahl William A. , Malicdan May Christine V. , Porter Forbes D. , Platt Frances M. , Pavan William J.
Published: December 2019

The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1em1Pav, and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1em1Pav/em1Pav mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1em1Pav/em1Pav mice. The phenotypic severity of the Npc1em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients.
Changes in Opioid Prescribing Behaviors among Family Physicians Who Participated in a Weekly Tele-Mentoring Program
Authors: Díaz Santana , Zhao Jane , Cronin Shawna , Jaglal Susan , Bombardier Claire , Furlan Andrea D.
Published: December 2019

A weekly tele-mentoring program was implemented in Ontario to help address the growing opioid crisis through teaching and mentoring family physicians on the management of chronic pain and opioid prescribing. This study assessed opioid prescribing behaviours among family physicians who attended the tele-mentoring program compared to two groups of Ontario family physicians who did not attend the program. We conducted a retrospective cohort study with two control groups: a matched cohort, and a random sample of 3000 family physicians in Ontario. Each physician was followed from one year before the program, which is the index date, and one year after. We examined the number and proportion of patients on any opioid, on high dose opioids, and the average daily morphine equivalent doses prescribed to each patient. We included 24 physicians who participated in the program (2760 patients), 96 matched physicians (11,117 patients) and 3000 random family doctors (374,174 patients). We found that, at baseline, the tele-mentoring group had similar number of patients on any opioid, but more patients on high dose opioids than both control groups. There was no change in the number of patients on any opioid before and after the index date, but there was a significant reduction in high-dose opioid prescriptions in the extension for community healthcare outcomes (ECHO) group, compared to a non-significant increase in the matched cohort, and a non-significant reduction in the Ontario group during the same comparable periods. Participation in the program was associated with a greater reduction in high-dose opioid prescribing.
The Relationship between Sleep Bruxism Intensity and Renalase Concentration—An Enzyme Involved in Hypertension Development
Authors: Martynowicz Helena , Wieckiewicz Mieszko , Poreba Rafal , Wojakowska Anna , Smardz Joanna , Januszewska Lidia , Markiewicz-Gorka Iwona , Mazur Grzegorz , Pawlas Krystyna , Gac Pawel
Published: December 2019

Background and objectives: Renalase, a novel amine oxidase, is involved in the development of hypertension. Sleep bruxism (SB) is a sleep-related behavior characterized by rhythmic or non-rhythmic activity of the masticatory muscles, which leads to the mechanical wear of teeth, pain in the masticatory muscles, and disturbed sleep. Recent studies indicate that SB plays a role in increased blood pressure. Therefore, this study aimed to determine the relationship between sleep bruxism intensity and renalase concentration, which may help in the future to elucidate the pathogenesis of hypertension and other cardiovascular disorders. Material and methods: SB was evaluated in 87 adult patients using single-night diagnostic polysomnography with video and audio recordings, and the episodes of bruxism were scored according to the standards of the American Academy of Sleep Medicine. The levels of serum renalase were measured in the patients using enzyme-linked immunosorbent assay kits. Results: SB (Bruxism Episode Index (BEI) ≥2) was diagnosed in 54% (n = 47) of the studied population, and the mean concentration of renalase was found to be decreased in the hypertensive group compared with the normotensive group (133.33 ± 160.71 vs 219.23 ± 220.58, p = 0.047). In addition, a linear negative correlation was observed between the renalase concentration and the body mass index (BMI) in the SB group (r = 0.38, p < 0.05) but not in controls. Thus, higher BEI and higher BMI were identified as factors independently associated with the lower concentration of renalase, but only in the group of patients which had a blood renalase concentration of >212.5 ng/mL. Conclusion: There exists an association between renalase concentration and SB intensity, and further studies are needed to clarify the role of renalase in the pathogenesis of hypertension and other cardiovascular disorders.
Use of DIAGNOdent and VistaProof in diagnostic of Pre-Cavitated Caries Lesions—A Systematic Review and Meta-Analysis
Authors: Iranzo-Cortés José Enrique , Montiel-Company José María , Almerich-Torres Teresa , Bellot-Arcís Carlos , Almerich-Silla José Manuel
Published: December 2019

Objective: To analyse the published evidence of the validity of DIAGNDOdent and VistaProof in diagnosing carious depths in pre-cavitated lesions. Material and methods: A systematic review was carried out after identifying a total of 184 articles, including 27 concerning the qualitative review and a subsequent meta-analysis. The quality of the studies was evaluated by using the QUADAS-2 tool. Results: For DIAGNOdent, the sensitivity value was 0.77, the specificity value was 0.75 and AUC was 0.81 for the global meta-analyses. In relation to subgroups, the values estimated 0.85, 0.76 and 0.86, respectively, for the in vivo group and 0.71, 0.75 and 0.83 for the in vitro group. For VistaProof, sensitivity was 0.81, specificity 0.75 and AUC had a value of 0.80 in the global meta-analysis. For the subgroups, these were considered at 0.75, 0.81 and 0.89, respectively, for the in vivo group and 0.91, 0.74 and 0.76 for the in vitro group. Neither case presented publication bias when analysing the funnel plot, the classic fail-safe number and Egger’s intercept. Conclusion: Both VistaProof and DIAGNOdent are valid as they offer a moderate to high diagnostic effectiveness for dentine depth in pre-cavitated lesions.
Plagiocephaly after Neonatal Developmental Dysplasia of the Hip at School Age
Authors: Valkama A Marita , Aarnivala Henri I , Sato Koshi , Harila Virpi , Heikkinen Tuomo , Pirttiniemi Pertti
Published: December 2019

Developmental dysplasia of the hip (DDH) may require early abduction treatment with infants sleeping on their back for the first few months of life. As sleeping on back is known to cause deformational plagiocephaly, we assessed school age children treated for dislocation or subluxation of the hip-joint in infancy. Plagiocephaly was analyzed by using cephalic index (CI) and oblique cranial length ratio (OCLR) as anthropometric measurements from 2D digital vertex view photographs. Six of the 58 (10.3%) DDH children and only one of the 62 (1.6%) control children had plagiocephaly (p = 0.041). Furthermore, cross bite was found in 14 (24.1%) of the DDH children and in 7 (10.3%) of the control children. Developmental dysplasia of the hip in infancy was associated with cranial asymmetries and malocclusions at school age. Preventive measures should be implemented.
Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components
Authors: Turner Richard Myles , Pirmohamed Munir
Published: December 2019

Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.
Bionic Upper Limb Reconstruction: A Valuable Alternative in Global Brachial Plexus Avulsion Injuries—A Case Series
Authors: Hruby Laura A. , Gstoettner Clemens , Sturma Agnes , Salminger Stefan , Mayer Johannes A. , Aszmann Oskar C.
Published: December 2019

Global brachial plexopathies including multiple nerve root avulsions may result in complete upper limb paralysis despite surgical treatment. Bionic reconstruction, which includes the elective amputation of the functionless hand and its replacement with a mechatronic device, has been described for the transradial level. Here, we present for the first time that patients with global brachial plexus avulsion injuries and lack of biological shoulder and elbow function benefit from above-elbow amputation and prosthetic rehabilitation. Between 2012 and 2017, forty-five patients with global brachial plexus injuries approached our centre, of which nineteen (42.2%) were treated with bionic reconstruction. While fourteen patients were amputated at the transradial level, the entire upper limb was replaced with a prosthetic arm in a total of five patients. Global upper extremity function before and after bionic arm substitution was assessed using two objective hand function tests, the action research arm test (ARAT), and the Southampton hand assessment procedure (SHAP). Other outcome measures included the DASH questionnaire, VAS to assess deafferentation pain and the SF-36 health survey to evaluate changes in quality of life. Using a hybrid prosthetic arm mean ARAT scores improved from 0.6 ± 1.3 to 11.0 ± 6.7 (p = 0.042) and mean SHAP scores increased from 4.0 ± 3.7 to 13.8 ± 9.2 (p = 0.058). After prosthetic arm replacement mean DASH scores improved from 52.5 ± 9.4 to 31.2 ± 9.8 (p = 0.003). Deafferentation pain decreased from mean VAS 8.5 ± 1.0 to 6.7 ± 2.1 (p = 0.055), while the physical and mental component summary scale as part of the SF-36 health survey improved from 32.9 ± 6.4 to 40.4 ± 9.4 (p = 0.058) and 43.6 ± 8.9 to 57.3 ± 5.5 (p = 0.021), respectively. Bionic reconstruction can restore simple but robust arm and hand function in longstanding brachial plexus patients with lack of treatment alternatives.
Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor
Authors: Alejo Alí , Sánchez Carolina , Amu Sylvie , Fallon Padraic G. , Alcamí Antonio
Published: December 2019

The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein. A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model.
Stronger Correlations between Neurophysiological and Peripheral Disease Biomarkers Predict Better Prognosis in Two Severe Diseases
Authors: Gidron Yori , De Couck Marijke , Reynders Tatjana , Marechal Raphael , Engelborghs Sebastiaan , D’hooghe Marie
Published: December 2019

‘Mind–body’ debates assume that better brain–body associations are healthy. This study examined whether degree of associations between a neurophysiological vagal nerve index and peripheral disease biomarkers predict prognosis in pancreatic cancer (PC) and multiple sclerosis (MS). Sample 1 included 272 patients with advanced PC. Sample 2 included 118 patients with MS. We measured the vagal nerve index heart rate variability (HRV) derived from electrocardiograms. We examined associations between HRV and patients’ peripheral disease biomarkers: CA19-9 in PC and neurofilament light chain (NFL) in MS. Associations between HRV and each biomarker were examined separately in patients who survived or died (PC), and in those with and without relapse during 12 months (MS). In PC, HRV was significantly inversely related to the tumor marker CA19-9 in patients who later survived (r = −0.44, p < 0.05) but not in those who died (r = 0.10, NS). In MS, HRV was significantly and inversely related to NFL only in those who did not relapse (r = −0.25, p < 0.05), but not in those who relapsed (r = −0.05, NS). The degree of association between a neurophysiological vagal marker and peripheral disease biomarkers has prognostic value in two distinct diseases.