bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Associated with Disparities in Appropriate Statin Therapy in an Outpatient Inner City Population
Authors: Suero-Abreu Giselle Alexandra , Karatasakis Aris , Rashid Sana , Tysarowski Maciej , Douglas Analise , Patel Richa , Siddiqui Emaad , Bhardwaj Aishwarya , Gerula Christine M. , Matassa Daniel
Published: September 2020

Lipid-lowering therapies are essential for the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). The aim of this study is to identify discrepancies between cholesterol management guidelines and current practice with a focus on statin treatment in an underserved population based in a large single urban medical center. Among 1042 reviewed records, we identified 464 statin-eligible patients. Age was 61.0 ± 10.4 years and 53.9% were female. Most patients were black (47.2%), followed by Hispanic (45.7%) and white (5.0%). In total, 82.1% of patients were prescribed a statin. An appropriate statin was not prescribed in 32.4% of statin-eligible patients who qualified based only on a 10-year ASCVD risk of ≥7.5%. After adjustment for gender and health insurance status, appropriate statin treatment was independently associated with age >55 years (OR = 4.59 (95% CI 1.09–16.66), p = 0.026), hypertension (OR = 2.38 (95% CI 1.29–4.38), p = 0.005) and chronic kidney disease (OR = 3.95 (95% CI 1.42–14.30), p = 0.017). Factors independently associated with statin undertreatment were black race (OR = 0.42 (95% CI 0.23–0.77), p = 0.005) and statin-eligibility based solely on an elevated 10-year ASCVD risk (OR = 0.14 (95% CI 0.07–0.25), p < 0.001). Hispanic patients were more likely to be on appropriate statin therapy when compared to black patients (86.8% vs. 77.2%). Statin underprescription is seen in approximately one out of five eligible patients and is independently associated with black race, younger age, fewer comorbidities and eligibility via 10-year ASCVD risk only. Hispanic patients are more likely to be on appropriate statin therapy compared to black patients.
The Role of Vesicle Trafficking Defects in the Pathogenesis of Prion and Prion-Like Disorders
Authors: Cherry Pearl , Gilch Sabine
Published: September 2020

Prion diseases are fatal and transmissible neurodegenerative diseases in which the cellular form of the prion protein ‘PrPc’, misfolds into an infectious and aggregation prone isoform termed PrPSc, which is the primary component of prions. Many neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases, such as Huntington’s disease, are considered prion-like disorders because of the common characteristics in the propagation and spreading of misfolded proteins that they share with the prion diseases. Unlike prion diseases, these are non-infectious outside experimental settings. Many vesicular trafficking impairments, which are observed in prion and prion-like disorders, favor the accumulation of the pathogenic amyloid aggregates. In addition, many of the vesicular trafficking impairments that arise in these diseases, turn out to be further aggravating factors. This review offers an insight into the currently known vesicular trafficking defects in these neurodegenerative diseases and their implications on disease progression. These findings suggest that these impaired trafficking pathways may represent similar therapeutic targets in these classes of neurodegenerative disorders.
A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43
Authors: Okada Motohiro , Fukuyama Kouji , Shiroyama Takashi , Murata Masahiko
Published: September 2020

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization’s (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.
Exosome Composition and Seminal Plasma Proteome: A Promising Source of Biomarkers of Male Infertility
Authors: Candenas Luz , Chianese Rosanna
Published: September 2020

Infertility has become a global health issue, with approximately 50% of infertility cases generated by disorders in male reproduction. Spermatozoa are conveyed towards female genital tracts in a safe surrounding provided by the seminal plasma. Interestingly, this dynamically changing medium is a rich source of proteins, essential not only for sperm transport, but also for its protection and maturation. Most of the seminal proteins are acquired by spermatozoa in transit through exosomes (epididymosomes and prostasomes). The high number of seminal proteins, the increasing knowledge of their origins and biological functions and their differential expression in the case of azoospermia, asthenozoospermia, oligozoospermia and teratozoospermia or other conditions of male infertility have allowed the identification of a wide variety of biomarker candidates and their involvement in biological pathways, thus to strongly suggest that the proteomic landscape of seminal plasma may be a potential indicator of sperm dysfunction. This review summarizes the current knowledge in seminal plasma proteomics and its potentiality as a diagnostic tool in different degrees of male infertility.
Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes
Authors: Yang Yiting , Li Ping , Zhang Zexin , Wang Zhongjian , Liu Li , Liu Xiaodong
Published: September 2020

Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.
Prognostic Significance of Stromal Periostin Expression in Non-Small Cell Lung Cancer
Authors: Ratajczak-Wielgomas Katarzyna , Kmiecik Alicja , Grzegrzołka Jedrzej , Piotrowska Aleksandra , Gomulkiewicz Agnieszka , Partynska Aleksandra , Pawelczyk Konrad , Nowinska Katarzyna , Podhorska-Okolow Marzenna , Dziegiel Piotr
Published: September 2020

Background: The microenvironment of solid tumours is significant in cancer development and progression. The aim of this study was to determine periostin (POSTN) expression by cancer-associated fibroblasts (CAFs) in non-small-cell lung cancer (NSCLC), as well as to assess associations with clinicopathological factors and prognosis. Materials and Methods: Immunohistochemical analysis of POSTN expression was performed on NSCLC (N = 700) and non-malignant lung tissue (NMLT) (N = 110) using tissue microarrays. Laser capture microdissection (LCM) for isolation of stromal and cancer cells of NSCLC was employed, and subsequently, POSTN mRNA expression was detected by real-time PCR. Immunofluorescence reaction and colocalisation analysis were performed by confocal microscopy. Results: Expression of POSTN in CAFs was significantly higher in NSCLC and in the adenocarcinoma (AC) and squamous cell carcinoma (SCC) subtypes compared to NMLT. POSTN expression in CAFs increased with clinical cancer stage, grades (G) of malignancy, and lymph node involvement in NSCLC. Higher POSTN expression in CAFs was an independent prognostic factor for overall survival (OS). LCM confirmed significantly higher POSTN mRNA expression in the stromal cells (CAFs) compared to the lung cancer cells. Conclusions: POSTN produced by CAFs might be crucial for NSCLC progression and can be an independent negative prognostic factor in NSCLC.
Beyond the Canonical Endocannabinoid System. A Screening of PPAR Ligands as FAAH Inhibitors
Authors: Brunetti Leonardo , Carrieri Antonio , Piemontese Luca , Tortorella Paolo , Loiodice Fulvio , Laghezza Antonio
Published: September 2020

In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system and PPARs has slowly but surely been accumulating over the past decade, and a multitarget approach involving these receptors and endocannabinoid degrading enzyme FAAH has been proposed for the treatment of inflammatory states, cancer, and Alzheimer’s disease. The lack of knowledge about compounds endowed with such an activity profile therefore led us to investigate a library of readily available, well-characterized PPAR agonists that we had synthesized over the years in order to find a plausible lead compound for further development. Moreover, we propose a rationalization of our results via a docking study, which sheds some light on the binding mode of these PPAR agonists to FAAH and opens the way for further research in this field.
Effects of Arbuscular Mycorrhization on Fruit Quality in Industrialized Tomato Production
Authors: Schubert Ramona , Werner Stephanie , Cirka Hillary , Rödel Philipp , Tandron Moya Yudelsy , Mock Hans-Peter , Hutter Imke , Kunze Gotthard , Hause Bettina
Published: September 2020

Industrialized tomato production faces a decrease in flavors and nutritional value due to conventional breeding. Moreover, tomato production heavily relies on nitrogen and phosphate fertilization. Phosphate uptake and improvement of fruit quality by arbuscular mycorrhizal (AM) fungi are well-studied. We addressed the question of whether commercially used tomato cultivars grown in a hydroponic system can be mycorrhizal, leading to improved fruit quality. Tomato plants inoculated with Rhizophagus irregularis were grown under different phosphate concentrations and in substrates used in industrial tomato production. Changes in fruit gene expression and metabolite levels were checked by RNAseq and metabolite determination, respectively. The tests revealed that reduction of phosphate to 80% and use of mixed substrate allow AM establishment without affecting yield. By comparing green fruits from non-mycorrhizal and mycorrhizal plants, differentially expressed genes (DEGs) were found to possibly be involved in processes regulating fruit maturation and nutrition. Red fruits from mycorrhizal plants showed a trend of higher BRIX values and increased levels of carotenoids in comparison to those from non-mycorrhizal plants. Free amino acids exhibited up to four times higher levels in red fruits due to AM, showing the potential of mycorrhization to increase the nutritional value of tomatoes in industrialized production.
Analysis of the Direct and Indirect Effects of Nanoparticle Exposure on Microglial and Neuronal Cells In Vitro
Authors: Lojk Jasna , Babič Lea , Sušjan Petra , Bregar Vladimir Boštjan , Pavlin Mojca , Hafner-Bratkovič Iva , Veranič Peter
Published: September 2020

Environmental or biomedical exposure to nanoparticles (NPs) can results in translocation and accumulation of NPs in the brain, which can lead to health-related problems. NPs have been shown to induce toxicity to neuronal cells through several direct mechanisms, but only a few studies have also explored the indirect effects of NPs, through consequences due to the exposure of neighboring cells to NPs. In this study, we analysed possible direct and indirect effects of NPs (polyacrylic acid (PAA) coated cobalt ferrite NP, TiO2 P25 and maghemite NPs) on immortalized mouse microglial cells and differentiated CAD mouse neuronal cells in monoculture (direct toxicity) or in transwell co-culture system (indirect toxicity). We showed that although the low NP concentrations (2–25 µg/mL) did not induce changes in cell viability, cytokine secretion or NF-κB activation of microglial cells, even low NP concentrations of 10 µg/mL can affect the cells and change their secretion of protein stress mediators. These can in turn influence neuronal cells in indirect exposure model. Indirect toxicity of NPs is an important and not adequately assessed mechanism of NP toxicity, since it not only affects cells on the exposure sites, but through secretion of signaling mediators, can also affect cells that do not come in direct contact with NPs.
Melanocortin Receptor 4 (MC4R) Signaling System in Nile Tilapia
Authors: Liu Tianqiang , Deng Yue , Zhang Zheng , Cao Baolong , Li Jing , Sun Caiyun , Hu Zhixing , Zhang Jiannan , Li Juan , Wang Yajun
Published: September 2020

The melanocortin receptor 4 (MC4R) signaling system consists of MC4R, MC4R ligands [melanocyte-stimulating hormone (MSH), adrenocorticotropin (ACTH), agouti-related protein (AgRP)], and melanocortin-2 receptor accessory protein 2 (MRAP2), and it has been proposed to play important roles in feeding and growth in vertebrates. However, the expression and functionality of this system have not been fully characterized in teleosts. Here, we cloned tilapia MC4R, MRAP2b, AgRPs (AgRP, AgRP2), and POMCs (POMCa1, POMCb) genes and characterized the interaction of tilapia MC4R with MRAP2b, AgRP, α-MSH, and ACTH in vitro. The results indicate the following. (1) Tilapia MC4R, MRAP2b, AgRPs, and POMCs share high amino acid identity with their mammalian counterparts. (2) Tilapia MRAP2b could interact with MC4R expressed in CHO cells, as demonstrated by Co-IP assay, and thus decrease MC4R constitutive activity and enhance its sensitivity to ACTH1-40. (3) As in mammals, AgRP can function as an inverse agonist and antagonist of MC4R, either in the presence or absence of MRAP2b. These data, together with the co-expression of MC4R, MRAP2b, AgRPs, and POMCs in tilapia hypothalamus, suggest that as in mammals, ACTH/α-MSH, AgRP, and MRAP2 can interact with MC4R to control energy balance and thus play conserved roles in the feeding and growth of teleosts.
Structural Modifications of the Quinolin-4-yloxy Core to Obtain New Staphylococcus aureus NorA Inhibitors
Authors: Cannalire Rolando , Mangiaterra Gianmarco , Felicetti Tommaso , Astolfi Andrea , Cedraro Nicholas , Massari Serena , Manfroni Giuseppe , Tabarrini Oriana , Vaiasicca Salvatore , Barreca Maria Letizia , Cecchetti Violetta , Biavasco Francesca , Sabatini Stefano
Published: September 2020

Tackling antimicrobial resistance (AMR) represents a social responsibility aimed at renewing the antimicrobial armamentarium and identifying novel therapeutical approaches. Among the possible strategies, efflux pumps inhibition offers the advantage to contrast the resistance against all drugs which can be extruded. Efflux pump inhibitors (EPIs) are molecules devoid of any antimicrobial activity, but synergizing with pumps-substrate antibiotics. Herein, we performed an in silico scaffold hopping approach starting from quinolin-4-yloxy-based Staphylococcus aureus NorA EPIs by using previously built pharmacophore models for NorA inhibition activity. Four scaffolds were identified, synthesized, and modified with appropriate substituents to obtain new compounds, that were evaluated for their ability to inhibit NorA and synergize with the fluoroquinolone ciprofloxacin against resistant S. aureus strains. The two quinoline-4-carboxamide derivatives 3a and 3b showed the best results being synergic (4-fold MIC reduction) with ciprofloxacin at concentrations as low as 3.13 and 1.56 µg/mL, respectively, which were nontoxic for human THP-1 and A549 cells. The NorA inhibition was confirmed by SA-1199B ethidium bromide efflux and checkerboard assays against the isogenic pair SA-K2378 (norA++)/SA-K1902 (norA-). These in vitro results indicate the two compounds as valuable structures for designing novel S. aureus NorA inhibitors to be used in association with fluoroquinolones.
Mesenchymal Stem Cell Secretome as an Emerging Cell-Free Alternative for Improving Wound Repair
Authors: Ahangar Parinaz , Mills Stuart J. , Cowin Allison J.
Published: September 2020

The use of mesenchymal stem cells (MSC) for the treatment of cutaneous wounds is currently of enormous interest. However, the broad translation of cell therapies into clinical use is hampered by their efficacy, safety, manufacturing and cost. MSCs release a broad repertoire of trophic factors and immunomodulatory cytokines, referred to as the MSC secretome, that has considerable potential for the treatment of cutaneous wounds as a cell-free therapy. In this review, we outline the current status of MSCs as a treatment for cutaneous wounds and introduce the potential of the MSC secretome as a cell-free alternative for wound repair. We discuss the challenges and provide insights and perspectives for the future development of the MSC secretome as well as identify its potential clinical translation into a therapeutic treatment.
In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals
Authors: Nagai Noriaki , Isaka Takumi , Deguchi Saori , Minami Misa , Yamaguchi Mizuki , Otake Hiroko , Okamoto Norio , Nakazawa Yosuke
Published: September 2020

We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50–150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5–10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.
Syndecan-4 as a Marker of Endothelial Dysfunction in Patients with Resistant Hypertension
Authors: Lipphardt Mark , Dihazi Hassan , Maas Jens-Holger , Schäfer Ann-Kathrin , Amlaz Saskia I. , Ratliff Brian B. , Koziolek Michael J. , Wallbach Manuel
Published: September 2020

(1) Background: Arterial hypertension (HTN) is one of the most relevant cardiovascular risk factors. Nowadays multiple pharmaceutical treatment options exist with novel interventional methods (e.g., baroreflex activation therapy (BAT)) as a last resort to treat patients with resistant HTN. Although pathophysiology behind resistant HTN is still not fully understood. There is evidence that selected biomarkers may be involved in the pathophysiology of HTN. (2) Methods: We investigated serum SDC4-levels in patients suffering from resistant HTN before and 6 months after BAT implantation. We collected 19 blood samples from patients with resistant HTN and blood pressure above target and measured serum SDC4-levels. (3) Results: Our results showed high serum SDC4-levels in patients with resistant HTN as compared to a healthy population. Patients with both, resistant HTN and diabetes mellitus type II, demonstrated higher serum SDC4-levels. β-blockers had lowering effects on serum SDC4-levels, whereas calcium channel blockers were associated with higher levels of serum SDC4. BAT implantation did not lead to a significant difference in serum SDC4-levels after 6 months of therapy. (4) Conclusion: Based on our results we propose SDC4 is elevated in patients suffering from resistant HTN. Thus, SDC4 might be a potential marker for endothelial dysfunction in patients with resistant hypertension.
Monomeric C-Reactive Protein Aggravates Secondary Degeneration after Intracerebral Haemorrhagic Stroke and May Function as a Sensor for Systemic Inflammation
Authors: Slevin Mark , García-Lara Elisa , Capitanescu Bogdan , Sanfeliu Coral , Zeinolabediny Yasmin , AlBaradie Raid , Olah Peter , Guo Baoqiang , Pirici Daniel , Di Napoli Mario , Popa-Wagner Aurel
Published: September 2020

Background: We previously identified increased tissue localization of monomeric C-reactive protein (mCRP) in the infarcted cortical brain tissue of patients following ischaemic stroke. Here, we investigated the relationship of mCRP expression in haemorrhagic stroke, and additionally examined the capacity of mCRP to travel to or appear at other locations within the brain that might account for later chronic neuroinflammatory or neurodegenerative effects. Methods: Immunohistochemistry was performed on Formalin-fixed, paraffin-embedded archived brain tissue blocks obtained at autopsy from stroke patients and age-matched controls. We modelled mCRP migration into the brain after haemorrhagic stroke by infusing mCRP (3.5 µg) into the hippocampus of mice and localized mCRP with histological and immunohistochemistry methods. Results: On human tissue in the early stages of haemorrhage, there was no staining of mCRP. However, with increasing post-stroke survival time, mCRP immunostaining was associated with some parenchymal brain cells, some stroke-affected neurons in the surrounding areas and the lumen of large blood vessels as well as brain capillaries. Further from the peri-haematoma region, however, mCRP was detected in the lumen of micro-vessels expressing aquaporin 4 (AQP4). In the hypothalamus, we detected clusters of neurons loaded with mCRP along with scattered lipofuscin-like deposits. In the peri-haematoma region of patients, mCRP was abundantly seen adjacent to AQP4 immunoreactivity. When we stereotactically injected mCRP into the hippocampus of mice, we also observed strong expression in distant neurones of the hypothalamus as well as cortical capillaries. Conclusions: mCRP is abundantly expressed in the brain after haemorrhagic stroke, directly impacting the pathophysiological development of the haematoma. In addition, it may have indirect effects, where the microcirculatory system appears to be able to carry it throughout the cortex as far as the hypothalamus, allowing for long-distance effects and damage through its capacity to induce inflammation and degenerate neuronal perivascular compartments.
Evaluation of an Amino Acid Mix on the Secretion of Gastrointestinal Peptides, Glucometabolic Homeostasis, and Appetite in Obese Adolescents Administered with a Fixed-Dose or ad Libitum Meal
Authors: Rigamonti Antonello E. , Tamini Sofia , Cicolini Sabrina , De Col Alessandra , Caroli Diana , Mai Stefania , Rondinelli Eugenia , Saezza Antonella , Cella Silvano G. , Sartorio Alessandro
Published: September 2020

Proteins have been demonstrated to reduce food intake in animals and humans via peripheral and central mechanisms. Supplementation of a dietetic regimen with single or mixed amino acids might represent an approach to improve the effectiveness of any body weight reduction program in obese subjects. The aim of the present study was to evaluate the effects of an amino acid mix (L-arginine + L-leucine + L-glutamine + L-tryptophan) on the secretion of some gastrointestinal peptides (i.e., ghrelin and glucagon-like peptide type 1, GLP-1), glucometabolic homeostasis (i.e., glucose, insulin, and glucagon), and appetite (hunger/satiety scored by visual analogue scale, VAS) in obese adolescents (n = 14; 10 females and 4 males; age: 16.6 ± 1.0 years; body mass index (BMI): 36.4 ± 4.6 kg/m²; fat-free mass (FFM): 54.9 ± 4.7%; fat mass (FM): 45.1 ± 4.4%) administered with a fixed-dose (lunch) or ad libitum (dinner) meal. Isocaloric maltodextrins were used as control treatment. During the lunch test, a significant increase in circulating levels of GLP-1, but not of ghrelin, was observed in the amino acid-treated group, which was congruent with significant changes in appetite, i.e., increase in satiety and decrease in hunger. A significant hyperglycemia was found in the maltodextrin-treated group during the prelunch period, without any significant changes in insulin and glucagon between the two groups. During the dinner test, there were no significant differences in appetite (hunger/satiety) and intake of calories. In conclusion, L-arginine, L-leucine, L-glutamine, and L-tryptophan, when administered to obese adolescents with a fixed-dose meal, are capable of evoking an anorexigenic response, which is, at least in part, mediated by an increase in GLP-1 released in circulation by L cells, which are capable of chemosensing specific amino acids present in the intestinal lumen. Further additional studies are requested to understand whether higher doses are necessary to inhibit ad libitum feeding.
Phosphatidylethanol for Monitoring Alcohol Use in Liver Transplant Candidates: An Observational Study
Authors: Barrio Pablo , Gual Antoni , Lligoña Anna , Teixidor Lidia , Weinmann Wolfgang , Yegles Michel , Wurst Friedrich M.
Published: September 2020

Liver transplantation remains an essential procedure for many patients suffering from alcoholic liver disease. Alcohol use monitoring remains paramount all through the stages of this complex process. Direct alcohol biomarkers, with improved specificity and sensibility, should replace traditional indirect markers. Phosphatidylethanol (PEth) has been recently tested in alcoholic liver disease patients, but more evidence is needed, especially in comparison with other direct biomarkers. We conducted an observational study among patients awaiting liver transplantation. We analyzed Peth in blood, ethylglucuronide (EtG) in hair and urine and ethylsulphate (EtS) in urine, using mass spectrometry methods. In addition, transaminases, and self-reports were analyzed. A total of 50 patients were included (84% men, mean age 59 years (SD = 6)). 18 patients (36%) screened positive for any marker. Self-reports were positive in 3 patients. EtS was the biomarker with more positive screens. It also was the most frequently exclusive biomarker, screening positive in 7 patients who were negative for all other biomarkers. PEth was positive in 5 patients, being the only positive biomarker in 2 patients. It showed a false negative in a patient admitting alcohol use the previous week and screening positive for EtG and EtS. Hair EtG was positive in 3 patients who had negative Peth, EtG. EtG did not provide any exclusive positive result.A combination of biomarkers seems to be the best option to fully ascertain abstinence in this population. Our study suggest EtS might also play a significant role.
Anxiety in Older Adolescents at the Time of COVID-19
Authors: Smirni Pietro , Lavanco Gioacchino , Smirni Daniela
Published: September 2020

Corona Virus Disease-19 (COVID-19) is a catastrophic health risk, with psychological, emotional, social, and relational implications. From the early stages of the virus spread, the elderly population was identified as the most vulnerable, and health authorities have rightly focused on this frailer population. Conversely, less attention was given to the emotional and psychological dimensions of children and adolescents. Moreover, even though they were the subjects whose lives and health were at low risk, they, nevertheless, had to face a reality full of anxiety, fears, and uncertainties. The current study investigated the state of anxiety and emotional awareness in a sample of healthy older adolescents, 84 females and 64 males, aged 17 to 19, during the pandemic lockdown, using the Self-Rating Anxiety Scale and the Italian Emotion Awareness Questionnaire. An unexpected anxious phenomenology was found, affecting anxiety and the ideo-affective domain, while somatic symptomatology appeared to be less severe. The highest anxiety symptoms were breathing difficulties. These findings supported the hypothesis that the COVID-19 pandemic may be a risk condition for an increased state of anxiety in older adolescents and suggested the need to provide (1) an effective, empathic communication system with direct participation of older adolescents, (2) a psychological counseling service for the stress management of adolescents.
Behavioral Factors Related to the Incidence of Frailty in Older Adults
Authors: Shimada Hiroyuki , Doi Takehiko , Tsutsumimoto Kota , Lee Sangyoon , Bae Seongryu , Arai Hidenori
Published: September 2020

Frailty is a widely prevalent geriatric condition whereby individuals experience age-related functional declines. This study aimed to identify behavioral factors related to the incidence of frailty in older adults. Participants were 2631 older adults (average age: 71) without physical frailty at a baseline assessment in 2011–2012 who took part in a second-wave assessment in 2015–2016. Physical frailty was defined as having limitations in at least three of the following domains: weight loss, low physical activity, exhaustion, slow walking speed, and muscle weakness. Participants completed a 16-item questionnaire examining cognitive, social, and productive activity as well as instrumental activities of daily living (IADL) as varying dimensions of lifestyle activity. During the follow-up period, 172 participants (6.5%) converted from nonfrail to frail. Logistic regression showed that the odds ratios (ORs) for conversion were significantly lower in the participants who had high IADL scores (OR: 0.78; 95% confidence interval (CI): 0.64–0.96), cognitive activity (OR: 0.74; 95% CI: 0.62–0.89), social activity (OR: 0.52; 95% CI: 0.43–0.63), and total activity (OR: 0.81; 95% CI: 0.75–0.87). There was no significant association between frailty and productive activity. Health care providers should recommend an active lifestyle to prevent frailty in older adults.
Quantification of Lumbar Spinal Canal Stenosis by Quantitative Fat-Suppressed Contrast-Enhanced Magnetic Resonance Imaging
Authors: Jin Yong Jun
Published: September 2020

Fat-suppressed T1-weighted magnetic resonance images (MRIs) enhanced with gadolinium can evaluate the internal vertebral venous plexus and cauda equina. This study compared such findings with clinical situations and discusses whether these are helpful for symptomatic grading and selection at the surgical level in patients with lumbar central stenosis. A total of 263 patients (337 levels < 75 mm2 of dural cross sectional area (DCSA)) were included. The enhancement patterns of dorsal epidural vein (DVCE), periradicular vein (PVCE) and intraradicular vein (IRCE) were assessed qualitatively. The quantification of IRCE was acquired by the ratio (%) (enhancement parameters: MS/P1, MS/P2, WR/P1, WR/P2) of signal intensities between the cauda equina (MS-IRCE: maximal spot rootlet, WR-IRCE: whole rootlets) and psoas muscle (P1, P2). Receiver-operator characteristic curves were plotted to obtain imaginary cutoff values for the prediction of symptomatic appearance or operation decision. All levels were classified into seven groups on the basis of pain distribution and the presence of IRCE. PVCE was significantly related to high incidences of symptoms, unilaterality and operation. DVCE and IRCE were connected with high incidences of symptoms, bilaterality and operation. IRCE was also related to high visual analogue scale (VAS), small DCSA and high enhancement parameters. The order of the group was concordant with the degree of enhancement parameters (p = 0.000). Cutoff values of enhancement parameters for prediction were as follows: symptoms (147/123/140/121), bilaterality (165/139/157/137) and operation (164/139/159/138). Enhancement patterns and parameters could help in stratification, grading and decision-making at the surgical level.
Use of Virtual Reality for the Management of Anxiety and Pain in Dental Treatments: Systematic Review and Meta-Analysis
Authors: López-Valverde Nansi , Muriel-Fernández Jorge , López-Valverde Antonio , Valero-Juan Luis Francisco , Ramírez Juan Manuel , Flores-Fraile Javier , Herrero-Payo Julio , Blanco-Antona Leticia Alejandra , Macedo-de-Sousa Bruno , Bravo Manuel
Published: September 2020

(1) Background: Dental treatments often cause pain and anxiety in patients. Virtual reality (VR) is a novel procedure that can provide distraction during dental procedures or prepare patients to receive such type of treatments. This meta-analysis is the first to gather evidence on the effectiveness of VR on the reduction of pain (P) and dental anxiety (DA) in patients undergoing dental treatment, regardless of age. (2) Methods: MEDLINE, CENTRAL, PubMed, EMBASE, Wiley Library and Web of Science were searched for scientific articles in November 2019. The keywords used were: “virtual reality”, “distraction systems”, “dental anxiety” and “pain”. Studies where VR was used for children and adults as a measure against anxiety and pain during dental treatments were included. VR was defined as a three-dimensional environment that provides patients with a sense of immersion, transporting them to appealing and interactive settings. Anxiety and pain results were assessed during dental treatments where VR was used and in standard care situations. (3) Results: 32 studies were identified, of which 8 met the inclusion criteria. The effect of VR in children was significant, both for anxiety (standardized mean difference (SMD) = −1.75) and pain (SMD = −1.46). (4) Conclusions: The findings of the meta-analysis show that VR is an effective distraction method to reduce pain and anxiety in patients undergoing a variety of dental treatments; however, further research on VR as a tool to prepare patients for dental treatment is required because of the scarcity of studies in this area.
Management of a Submacular Hemorrhage Secondary to Age-Related Macular Degeneration: A Comparison of Three Treatment Modalities
Authors: Jeong Seongyong , Park Dong-Geun , Sagong Min
Published: September 2020

This paper aims to compare the effects of three treatment modalities for a submacular hemorrhage (SMH) secondary to exudative age-related macular degeneration (AMD). Seventy-seven patients with an SMH were divided into three groups: small-sized (optic disc diameter (ODD) ≥ 1 to < 4), medium-sized (ODD ≥ 4 within the temporal arcade) and large-sized (ODD ≥ 4, exceeding the temporal arcade). Patients received anti-vascular endothelial growth factor (anti-VEGF) monotherapy, pneumatic displacement (PD) with anti-VEGF or a vitrectomy with a subretinal tissue plasminogen activator (tPA) and gas tamponade based on the surgeon’s discretion. The functional and anatomical outcomes were evaluated. Among the 77 eyes, 45 eyes had a small-sized, 21 eyes had a medium-sized and 11 eyes had a large-sized SMH. In the small-sized group, all treatment modalities showed a gradual best-corrected visual acuity (BCVA) improvement with high hemorrhagic regression or displacement rates (over 75%). In the medium-sized group, PD and surgery were associated with better BCVA with more displacement than anti-VEGF monotherapy (67% and 83%, respectively, vs. 33%). In the large-sized group, surgery showed a better visual improvement with a higher displacement rate than PD (86% vs. 25%). Our findings demonstrated that visual improvement can be expected through appropriate treatment strategy regardless of the SMH size. In cases with a larger SMH, invasive techniques including PD or surgery were more advantageous than anti-VEGF monotherapy.
CaRE @ Home: Pilot Study of an Online Multidimensional Cancer Rehabilitation and Exercise Program for Cancer Survivors
Authors: MacDonald Anne Marie , Chafranskaia Aleksandra , Lopez Christian J. , Maganti Manjula , Bernstein Lori J. , Chang Eugene , Langelier David Michael , Obadia Maya , Edwards Beth , Oh Paul , Bender Jacqueline L. , Alibhai Shabbir MH , Jones Jennifer M.
Published: September 2020

Background: Although facility-based cancer rehabilitation and exercise programs exist, patients are often unable to attend due to distance, cost, and other competing obligations. There is a need for scalable remote interventions that can reach and serve a larger population. Methods: We conducted a mixed methods pilot study to assess the feasibility, acceptability and impact of CaRE@Home: an 8-week online multidimensional cancer rehabilitation and exercise program. Feasibility and acceptability data were captured by attendance and adherence metrics and through qualitative interviews. Preliminary estimates of the effects of CaRE@Home on patient-reported and physically measured outcomes were calculated. Results: A total of n = 35 participated in the study. Recruitment (64%), retention (83%), and adherence (80%) rates, along with qualitative findings, support the feasibility of the CaRE@Home intervention. Acceptability was also high, and participants provided useful feedback for program improvements. Disability (WHODAS 2.0) scores significantly decreased from baseline (T1) to immediately post-intervention (T2) and three months post-intervention (T3) (p = 0.03 and p = 0.008). Physical activity (GSLTPAQ) levels significantly increased for both Total LSI (p = 0.007 and p = 0.0002) and moderate to strenuous LSI (p = 0.003 and p = 0.002) from baseline to T2 and T3. Work productivity (iPCQ) increased from T1 to T3 (p = 0.026). There was a significant increase in six minute walk distance from baseline to T2 and T3 (p < 0.001 and p = 0.010) and in grip strength from baseline to T2 and T3 (p = 0.003 and p < 0.001). Conclusions: Results indicate that the CaRE@Home program is a feasible and acceptable cancer rehabilitation program that may help cancer survivors regain functional ability and decrease disability. In order to confirm these findings, a controlled trial is required.
Inter- and Intra-Rater Reliability of Individual Cerebral Blood Flow Measured by Quantitative Vessel-Flow Phase-Contrast MRI
Authors: Chang Kwang-Hwa , Lee Yuan-Hao , Chen Chia-Yuen , Lin Ming-Fang , Lin Ying Chin , Chen Jyh-Horng , Chan Wing P.
Published: September 2020

Vessel flow quantification by two-dimensional (2D) phase-contrast magnetic resonance imaging (PC-MRI) using a three-dimensional (3D) magnetic resonance angiography (MRA) model to measure cerebral blood flow has unclear analytical reliability. The present study aimed to determine the inter- and intra-rater reliability of quantitative vessel-flow PC-MRI and potential factors influencing its consistency. We prospectively recruited 30 Asian participants (aged 20–90 years; 16 women; 22 healthy and 8 stroke patients) for performing 1.5-T MR equipped with a head coil. Each participant was first scanned for time-of-flight magnetic resonance angiography (TOF-MRA) images for localization of intracranial arteries. The 2D PC-MRI for each cerebral artery (total 13 arteries in fixed order) was performed twice by two well-trained operators in optimal position. Using the same 3D MRA as a map and facilitated with the non-invasive optimal vessel analysis (NOVA) system, each scan was taken on a plane perpendicular to the target artery. Two consecutive full 13-artery scans were performed at least 15 min apart after participants were removed from the scanner table and then repositioned. A total of four PC flow images obtained from each target artery were transmitted to a workstation facilitated with the NOVA system. Flow data were calculated semi-automatically by the NOVA system after a few simple steps. Two-way mixed-effect models and standard errors of measurements were used. In 13 cerebral arteries, repeatability, using the intra-rater estimate expressed as the average-measures intraclass correlation coefficient, ranged from 0.641 to 0.954, and reproducibility, using the inter-rater estimate, ranged from 0.672 to 0.977. Except in the middle cerebral artery and the distal segment of the anterior cerebral artery, repeatability and reproducibility were excellent (intraclass correlation coefficient exceeded 0.8). The use of quantitative vessel-flow PC-MRI is a precise means to measure blood flow in most target cerebral arteries. This was evidenced by inter-rater and intra-rater correlations that were good/excellent, indicating good reproducibility and repeatability.
Unveiling the Hidden Diversity of Rock-Inhabiting Fungi: Chaetothyriales from China
Authors: Sun Wei , Su Lei , Yang Shun , Sun Jingzu , Liu Bingjie , Fu Rong , Wu Bing , Liu Xingzhong , Cai Lei , Guo Liyun , Xiang Meichun
Published: September 2020

Rock-inhabiting fungi (RIF) are nonlichenized fungi that naturally colonize rock surfaces and subsurfaces. The extremely slow growth rate and lack of distinguishing morphological characteristics of RIF resulted in a poor understanding on their biodiversity. In this study, we surveyed RIF colonizing historical stone monuments and natural rock formations from throughout China. Among over 1000 isolates, after preliminary delimitation using the internal transcribed spacer region (ITS) sequences, representative isolates belonging to Trichomeriaceae and Herpotrichiellaceae were selected for a combined analysis of ITS and the nuclear ribosomal large subunit (nucLSU) to determine the generic placements. Eight clades representing seven known genera and one new genus herein named as Anthracina were placed in Trichomeriaceae. While, for Herpotrichiellaceae, two clades corresponded to two genera: Cladophialophora and Exophiala. Fine-scale phylogenetic analyses using combined sequences of the partial actin gene (ACT), ITS, mitochondrial small subunit ribosomal DNA (mtSSU), nucLSU, the largest subunit of RNA polymerase II (RPB1), small subunit of nuclear ribosomal RNA gene (SSU), translation elongation factor (TEF), and β-tubulin gene (TUB) revealed that these strains represented 11 and 6 new species, respectively, in Trichomeriaceae and Herpotrichiellaceae. The 17 new species were described, illustrated for their morphologies and compared with similar taxa. Our study demonstrated that the diversity of RIF is surprisingly high and still poorly understood. In addition, a rapid strategy for classifying RIF was proposed to determine the generic and familial placements through preliminary ITS and nucLSU analyses, followed by combined analyses of five loci selected from ACT, ITS, mtSSU, nucLSU, RPB1, and/or the second subunit of RNA polymerase II gene (RPB2), SSU, TEF, and TUB regions to classify RIF to the species level.
A Statecharts-Based Approach for WSN Application Development
Authors: Hakala Ismo , Tan Xinyu
Published: September 2020

Wireless Sensor Network (WSN) software development challenges developers in two main ways: through system programming, which requires expertise in hardware and network management; and application programming, which requires domain-specific knowledge. However, domain programmers often lack WSN programming expertise. Likewise, system-specific programmers may find it difficult to understand domain-specific requirements. As a result, domain programmers often refrain from using WSN technology in domain-specific applications. Therefore, we propose a Finite State Machine (FSM)-based approach with an affiliated framework to decouple application functionality from WSN details. Instead of the traditional flat FSM, we use statecharts formalism because of its relaxed definition of system states. In this paper, we compare the statecharts paradigm against two basic WSN sensor node programming frameworks. The result exhibits that statecharts are an advanced paradigm in WSN application development. It motivated us to develop a statecharts framework. In our framework, we choose not to use the typical solution which converts statecharts to programming code. Instead of that, we implement a statecharts middleware associated with action libraries to interpret and actuate raw statecharts on an operating system. This approach allows domain programmers to concentrate on WSN application behavior, and system-specific programmers to focus on developing WSN services. We also introduce our statecharts middleware and present a living example with performance evaluation.
Mobile Elements in Ray-Finned Fish Genomes
Authors: Carducci Federica , Barucca Marco , Canapa Adriana , Carotti Elisa , Biscotti Maria Assunta
Published: September 2020

Ray-finned fishes (Actinopterygii) are a very diverse group of vertebrates, encompassing species adapted to live in freshwater and marine environments, from the deep sea to high mountain streams. Genome sequencing offers a genetic resource for investigating the molecular bases of this phenotypic diversity and these adaptations to various habitats. The wide range of genome sizes observed in fishes is due to the role of transposable elements (TEs), which are powerful drivers of species diversity. Analyses performed to date provide evidence that class II DNA transposons are the most abundant component in most fish genomes and that compared to other vertebrate genomes, many TE superfamilies are present in actinopterygians. Moreover, specific TEs have been reported in ray-finned fishes as a possible result of an intricate relationship between TE evolution and the environment. The data summarized here underline the biological interest in Actinopterygii as a model group to investigate the mechanisms responsible for the high biodiversity observed in this taxon.
A Small Subgroup Attack on Bitcoin Address Generation
Authors: Sala Massimiliano , Sogiorno Domenica , Taufer Daniele
Published: September 2020

We show how a small subgroup confinement-like attack may be mounted on the Bitcoin addresses generation protocol, by inspecting a special subgroup of the group associated to point multiplication. This approach does not undermine the system security but highlights the importance of using fair random sources during the private key selection.